Patent Application
20060257322
The invention relates to the subjects that are characterized in the claims: pharmaceutical agents that contain at least one fluoroalkyl-containing metal complex that has a critical micelle-formation concentration of <10−3 mo/l and a hydrodynamic diameter (2Rh) of >1 nm, and at least one natural or synthetic epothilone or epothilone derivative, and their use for diagnosis, therapy and monitoring of the course of therapy of tumors, in particular by intravenous administration.
Tumor therapy faces a number of problems that mostly arise from the fact that the selected therapy modality is not directed solely at the tumor and its metastases but generally also affects the surrounding normal tissue. The unavoidable damage of the normal tissue, which surrounds the tumor, or of the entire organism, in many cases makes it impossible to administer substance or radiation in doses that are sufficient for tumor treatment. By physical measures, the radiation therapy can be focused on the tumor, but the surrounding tissue cannot be completely kept out of the radiation field. Similar arguments hold true for the local administration of cytostatic agents such as epothilones and epothilone derivatives. Comparable complications also follow in chemotherapy by inadequate tumor specificity of the compounds.
In the past, a number of transport mechanisms (e.g., vehicles) were examined that are to introduce chemotherapeutic agents purposefully into the tumor. In Patent Application WO 97/30969, for example, pharmaceutical agents are described that contain a fluoroalkyl-containing compound. By the thixotropic nature of these compounds, the formation of a locally limited, temporary vascular occlusion (embolization) results after local, intravascular administration. In the application, it is further disclosed that the compositions can contain additives for interventional radiology or for tumor therapy, e.g., chemotherapy agents (in particular cytostatic agents, e.g., 5-fluorouracil, cisplatin, doxorubicin, or mitomycin C). By the combination (embolizing agent and chemotherapy agent), it is achieved that the therapeutic agent is slowly released from the embolus over an extended period (chemoembolization).
This method has the drawback, however, that the tumor can only be addressed locally, since the compositions immediately produce an occlusion of the vessel (embolus) at the site of the administration. The cytostatic agent that is contained in the composition then also diffuses only locally at the site of the occlusion into the adjacent tissue. The target-specific, local administration requires the insertion of a catheter selectively into the tumor-supplying blood vessel. Because of the high viscosity of the compositions, the latter must be administered under high pressure. This is therefore a greatly invasive treatment method that is very uncomfortable for the patients and is associated with the increased risk of side effects.
The method has the drawback, moreover, that the therapeutic effect can occur only locally—close to the embolus—and thus, on the one hand, tumor metastases are not detected and, on the other hand, the danger exists that the embolus is not formed specifically on the tumor and the therapy therefore only inadequately reaches the tumor.
In addition, the method requires the presence of a sufficiently large vessel that supplies the tumor with blood to make a catheterization possible at all. This greatly limits the selection of the types of tumors that can be treated with this method; this process is basically therefore only used for treating liver tumors.
The object of the invention is thus to make available pharmaceutical agents that on the one hand exhibit high effectiveness and specificity relative to tumors, address all regions of the body and therefore also treat satellite metastases, and at the same time are as gentle as possible to the patients, especially with respect to the administration of the pharmaceutical agents. This object is achieved by the invention.
It has been found, surprisingly enough, that pharmaceutical agents that contain at least one fluoroalkyl-containing metal complex, which has a critical micelle-formation 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, are very well suited for diagnosis, therapy and monitoring of the course of therapy of tumors. It has been found that the therapeutic agents according to the invention show a surprisingly high effectiveness for combating tumors (see Tumor Therapy Tests 1 to 16) and at the same time show decisive advantages in the administration and dispersion: the agents are solutions of comparatively low viscosity (Example 1) that can be dispersed in the entire body because of the systemic (intravenous) administration (Example 2) and thus also can address satellite metastases. This intravenous administration (non-invasive) has clear advantages for patients with respect to discomfort in comparison to administration via catheter (as is necessary for the agents that are disclosed in WO 97/30969).
It was found, moreover, that fluoroalkyl compounds, which are described in, for example, Patent Applications WO 02/14309 and WO 97/30969, have the capacity to mediate the solution of hydrophobic substances, e.g., epothilones, in aqueous systems and accordingly to transport their pharmacokinetic and pharmacodynamic properties, i.e., without in this case essentially altering their distribution behavior. The structures that develop have a smaller hydrodynamic diameter than, for example, liposomes and are trapped only in a small portion of MPS in the liver and spleen. The therapeutic agent (e.g., natural or synthetic epothilone or epothilone derivatives) is transported with the aid of the fluoroalkyl-containing compound to the target site (tumor) and has a prolonged dwell time there. The micellar encapsulation results in an elevated stability of epothilones in an aqueous medium. The local therapy effect (tumor monitoring, partial or complete tumor emission) can be tracked without renewed administration of a diagnostic agent with the corresponding radiological process, since its long dwell time extends over a chemotherapy cycle. The fluoroalkyl-containing metal complex thus fulfills several functions: contrast media in imaging for the visualization of tumors, carrier for the epothilones to the site of action (tumor) and contrast media for therapy monitoring.
In imaging diagnosis, only a few substances that show a direct tumor concentration are available. In animal-experimental studies, it was possible to show that the above-mentioned fluoroalkyl-containing metal complexes preferably accumulate in tumors and dwell for a long time there. As paramagnetic compounds, the pharmaceutical agents according to the invention are therefore also very well suited for imaging diagnosis of tumors (Example 2, FIG. 1).
It has now turned out, surprisingly enough, that specifically these substances with prolonged dwell times in the tumor can also be readily charged with therapeutic agents, especially natural or synthetic epothilones or epothilone derivatives and, on the one hand, are suitable as vehicles for tumor concentration, and, on the other hand, are extremely well suited for intravenous administration and addressing of metastases. They can thus focus the therapeutic action on the tumors and the metastases present in the body, can be administered intravenously in a simple and uncomplicated manner, and by the dispersion in the body, there is no danger of the tumor not being reached.
The therapeutic effectiveness of the agents according to the invention can be enhanced by x rays or other rays that cause an accumulation or release of the active substance in the tumor, or their action can be increased. (Solberg, T. D.; Iwamoto, K. S.; Norman, A. Calculation of Radiation Dose Enhancement Factors for Dose Enhancement Therapy of Brain Tumors. Phys Med Biol. (1992), 37: 439-443).
The pharmaceutical agents according to the invention that consist of 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. In particular, those fluoroalkyl-containing metal complexes according to the invention whose 2 Rh ≧2 nm, preferably ≧3 nm, are suitable. The hydrodynamic diameter is determined by dynamic photocorrelation spectroscopy. In the substances according to the invention, the critical micelle-formation concentration (CMC) is usually <10−3 mol/l, in especially suitable cases <10−4 mol/l, and in quite especially suitable cases <10−5 mol/l. The determination of the CMC is described in H.-D. Dörfler “Grenzflächen und Kolloidchemie [Interface and Colloid Chemistry]”; Weinheim, N.Y., Basel, Cambridge, Tokyo; VSH 1994.
As epothilone or epothilone derivates, the compounds that are mentioned in, for example, 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, U.S. Pat. No. 6,204,388, U.S. Pat. No. 6,387,927, U.S. Pat. No. 6,380,394, U.S. Ser. No. 02/52,028, U.S. Ser. No. 02/58,286, U.S. Ser. No. 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, and WO 02/8440 can be used.
Epothilones or epothilone derivatives that can preferably be used are described in Claim 50. Epothilones and epothilone derivatives that can especially preferably be used are described in Table 2.
In DE 100 41470A1, DE 199 21 086A1 and DE 199 23 001A1, epothilone and epothilone derivatives are proposed for combination therapy with additional substance classes that can be used in tumor therapy, such as, for example, platinum complexes, e.g., cisplatin. Here, a combination therapy means, however, the administration, separated in time, of two therapeutically active principles; i.e., two monotherapies are performed together: in this case, the treatment, on the one hand, with a cytostatic agent (epothilone or epothilone derivative), and, on the other hand, with the cytotoxic substance cisplatin, which binds to DNA and thus primarily kills quick-growing cells.
It was not proposed in the documents, however, to combine the fluoroalkyl-containing metal complexes of this invention with epothilones in a single preparation as a formulation for epothilones. The fluoroalkyl-containing metal complexes are now distinguished by especially good compatibility and themselves have no anti-tumor action.
In an embodiment of this invention, the compounds of general formula I according to claims 7 to 10 are used as preferred compounds. In this case, these are known compounds that are described in WO 97/26017. Also, their production can be found in this WO publication. Surprisingly enough, it has been shown that these compounds also together with epothilones or epothilone derivatives are very well suited for diagnosis, therapy and monitoring of the course of therapy of tumors. Metal complexes 1-4, 6 and 11-13 (cf. also Table 1) are used as quite especially preferred compounds.
In another embodiment of this invention, those compounds of general formula Ia according to claims 11 to 20 are used as preferred compounds. These compounds are known and are described in WO 99/01161. Their use according to this invention has not yet been described. Of these compounds, metal complex 14 (cf. Table 1) is quite especially preferably used.
In other preferred embodiments of the invention, the compounds of general formula Ib according to claims 21 to 28, of general formula Ic according to claims 29 to 35, and of general formula Id according to claims 36 to 43 can be used. These compounds and their production are described in DE 100 40 380 (WO 02/13874).
In another preferred embodiment of the invention, galenical formulations that contain paramagnetic and diamagnetic fluoroalkyl-containing substances can be used. The paramagnetic and diamagnetic substances are preferably present in a dissolved state in an aqueous solvent.
As paramagnetic, fluoroalkyl-containing compounds, all above-mentioned metal complexes of general formulas I, Ia, Ib, Ic and/or Id can be used in the formulations according to the invention.
The diamagnetic, perfluoroalkyl-containing substances are those according to claims 45 to 49; they are also described—exactly like the above-mentioned galenical formulations—in Patent Application DE 100 40 380 (WO 02/13874).
In summary, it is noted that gadolinium complexes 1-16 that are cited in Table 1 meet the criteria according to the invention as quite especially preferred compounds.
Both the paramagnetic compounds of general formulas I, Ia, Ib, Ic and Id according to the invention and the formulations that consist of paramagnetic and diamagnetic fluoroalkyl-containing substances according to the invention are extremely well suited together with epothilones or epothilone derivatives for diagnosis, therapy and the monitoring of the course of therapy of tumors.
The term “metal ion equivalent” as used in the claims is a common term that is known to one skilled in the art in the field of complex chemistry. A metal ion equivalent is an equivalent of metal ions that can bind to, e.g., a carboxylate group instead of hydrogen. For example, a Gd3+ can bind to 3 carboxylate groups, i.e., ⅓ Gd3+ corresponds to metal ion equivalent R1 in formula (III) (see Claim 7) if the metal is gadolinium.
Preferred fluorine complex: epothilone molecule ratios are 100:1 to 1:1, especially preferred are the ratios of 20:1 to 5:1.
In an especially preferred embodiment, the pharmaceutical agents according to the invention are administered intravenously.
The invention therefore relates to pharmaceutical agents according to the invention for intravenous administration. In a preferred embodiment, the latter are used in the therapy of tumors. In another preferred embodiment, the latter are used in the graphic visualization of tumors, especially in the monitoring of the course of therapy in the treatment of tumors.
In addition, the invention relates to the use of pharmaceutical agents according to the invention for the production of a medication or diagnostic agent for intravenous administration. In a preferred embodiment, the latter are used in the therapy of tumors. In another preferred embodiment, the latter are used in the graphic visualization of tumors, especially in the monitoring of the course of therapy in the treatment of tumors.
In addition, the agents according to the invention can be used in combination with an additional radiation therapy for the therapy of tumors.
In addition, the invention relates to a process for treating tumors, characterized in that the agents according to the invention are administered intravenously to the patient in a pharmaceutically effective amount.
In addition, the invention relates to a process for imaging visualization of tumors, characterized in that the agents according to the invention are administered intravenously to the patient and the metal complex that is contained in the agent is detected in the body by means of a suitable system, whereby a local increase of the signal shows the presence of the tumor. The detection can take place by, e.g., MRI or CT based on the metal ion that is contained in the metal complex. In a preferred embodiment, the imaging visualization of tumors can be used for the monitoring of the course of therapy of tumors. In this case, the process for imaging visualization of tumors is used at least two times at the beginning of the tumor treatment and/or during the tumor treatment and/or after the end of the tumor treatment, and the result of the later detection is compared to the earlier detection(s). The course of the therapy thus can be monitored.
FIG. 1: FIG. 1 shows an MR cross-sectional image (axial) for 24 hours (a), 192 hours (b), as well as 336 hours (c) after i.v. administration of 200 μmol of .Gd/kg of body weight of the formulation of Example 1, F1-E (T:Tumor; N:Tumor necrosis).
The examples that are indicated below are used to explain the subject of the invention.
The table presented below provides a list of the metal complexes that are preferably used for a production of a formulation.
The table that is indicated below provides a list of epothilones A-N that are used in these examples:
x mmol of epothilone (Table 2) is dissolved in 50 μl of ethanol (40° C.) and converted into y ml of a gadolinium complex solution (complex no.) from z mmol of Gd/I of the compound of Table 1.
On the site of instillation, a white fog forms spontaneously, and said fog disappears after a brief shaking. A clear solution is present.
Tumor Inoculation: In nu/nu hairless mice, a human non-small-cell lung tumor was induced subcutaneously in the area of the right femur muscle by inoculation of A549 cells (4×106 cells/30 μl of full medium). About 4 weeks after the tumor induction, the slow-growing tumor reached rice grain size. At this time, imaging was begun.
MR Imaging: (Siemens 1.5 T. SE sequence, TR/TE 400/15 ms, α 90°, axial, 7 layers). Images of tumors before (baseline) and 5, 10, 20 minutes, and 24, 96, 192 and 336 hours after intravenous (i.v.) administration of 200 μmol of Gd/kg of body weight of the formulation of Example 1, F1-E. Typical cross-sectional images are shown in FIG. 1. The cross-sectional images of FIG. 1 show the strong concentration (homogeneous enhancement) of the formulation in the tumor at time 24 hours p.i., as well as its slow abatement subsequently with simultaneous increase of signal intensity in tumor necrosis.
x mmol of epothilone (Tab. 2) is dissolved in 50 μl of ethanol (40° C.) and converted into y ml of a gadolinium complex solution that consists of z mmol of Gd/l of the compound of Table 1 (Complex No.). After being shaken for a short length of time, a clear homogeneous solution is produced.
A549 lung tumors were induced in hairless mice (4×106 cells/30 μl of full medium). Animal weights and tumor surface areas/volumes were determined, and in this case, the tumor surface area or the tumor volume (based on an ellipsoid of revolution) was calculated. Length and width of the tumor were measured with vernier calipers. After reaching the size of a pea, the treatment was begun.
(Explanations regarding the information in Table 4):
Test Solutions:
The animal weights and tumor sizes were measured over a period of 20 days after intravenous administration.
Table 4 that is indicated below sets forth the dosages of tumor-therapy tests 1-16 that are used:
Results of Tumor-Therapy Tests:
Tumor-Therapy Test No. 1
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 2
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 3
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 4
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 5
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 6
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 7
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 8
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 9
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 10
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 11
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 12
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 13
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 14
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 15
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Tumor-Therapy Test No. 16
In group (c), the tumor growth was inhibited over about 20 days compared to control groups (a) and (b) (Tab. 1). The relative animal weights, with the exception of group (a), indicated a small weight loss in the first days after substance administration (Tab. 2).
Summary of the Results of the Tumor-Therapy Tests
It is shown that these new inventive formulations have definite advantages compared to the prior art (EPO alone), i.e., produce a significant delay of tumor growth. This advantage is statistically significant (p<0.001, t-test).
Also, the higher doses are very well tolerated, which corresponds to good compatibility of these formulations.
In particular, the substances according to the invention are extremely well suited for intravenous administration. The intravenous administration of low-osmolar solutions causes only slight discomfort to the patient's body.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 102005008309.9, filed Feb. 17, 2005, and U.S. Provisional Application Ser. No. 60/657,694, filed Mar. 3, 2005, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102005008309.9 | Feb 2005 | DE | national |
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/657,694 filed Mar. 3, 2005, which is incorporated by reference herein
| Number | Date | Country | |
|---|---|---|---|
| 60657694 | Mar 2005 | US |
