Classifications

• • 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
  • A61K31/30—Copper compounds
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• the present invention relates to the use of copper compounds of the general formula Cu (L) 2 or hydrates thereof, wherein the ligands L are independently melphalan and tegafur, as antitumor agents.
• chemotherapeutic agents which are highly effective in the treatment of malignant tumors and at the same time have a high selectivity and thus bring as few side effects as possible, represents an important goal of today's research.
• a large number of cytostatics are already known. which can be divided into several groups based on their different mechanisms of action.
• pyrimidine, purine and pteridine derivatives such as e.g. Fluoro or bromouracil antimetabolites, which can inhibit or mislead the course of biological processes because of their property of being structurally similar to essential natural metabolites and of being able to replace or compete with them in the organism.
• the group of mitotic inhibitors includes e.g. the plant components colzemid, podophylin derivatives and Vinka alkaloids, which impair the course of mitosis in cells, thereby preventing cell division and thus killing fast-growing tumor cells.
• cytostatic agents are alkylating compounds whose action is mainly based on the alkylation of nucleic acids, whereby the DNA is altered and, as a result, impaired cell division and ultimately cell death is initiated.
• alkylating cytostatic agents are N-Lost derivatives such as chlorambucil, cyclophosphamide and melphalan (4- [bis (2-chloroethyl) amino] -L-phenylalanine).
• melphalan has been proposed for the treatment of various Krebser ⁇ diseases.
• Alkeran® which contains melphalan as an active substance, is a medicine used in multiple myeloma, ovarian cancer and breast cancer.
• compounds of the formula D 2 -MT which consist of a metal atom such as copper or manganese, two ⁇ -diketone ligands and a ligand containing a substance having at least one N, O or S-containing group represents, such as melphalan exist.
• metal compounds have been shown to be effective in the treatment of, for example, adenocarcinoma, sarcoma, leukemia, melanoma and renal cell carcinoma in in vivo experiments, with a superior efficacy compared to melphalan.
• the object underlying the present invention was therefore to provide new approaches for effective anti-tumor treatment.
• An object of the present invention is therefore the use of one or more compounds of the formula (I) for antitumor treatment.
• the ligands L coordinated to the copper atom provide 4- [bis (2-chloroethyl) amino] -L-phenylalanine (melphalan) or / and 5-fluoro-1- (tetrahydro-2-furyl) -uracil (Tegafur)
• both ligands are L melphalan or tegafur, most preferably both are L melphalan ligands.
• the particularly preferred compound according to the present invention is Cu (melphalan) 2 or the corresponding water of crystallization Ver ⁇ binding.
• This copper compound is known in principle (MD Joesten et al., Inorganica Chimica Acta, 159 (1989) 143-148), where it was suggested that the melphalan molecules function as bidentate ligands, which together with two molecules Arrange water around the Cu atom tetragonal bipyramidal-like.
• the melphalan groups are present in the four equatorial positions around the copper, the water molecules are arranged axially to the copper atom.
• Joesten et al. show a Syn ⁇ these Anlagenkeit for compounds of the invention.
• a possible antitumoral activity of the compounds is not addressed or even investigated.
• the amazing anti-tumor efficacy of Cu (melphalan) 2 was first discovered in the context of the present invention.
• the compounds of the formula (I) have proven to be very effective antitumor agents.
• the compounds according to the invention are suitable for the treatment of colon cancer, brain tumor, eye tumor, pancreatic carcinoma, bladder carcinoma, lung cancer, breast cancer, ovarian tumor, uterine cancer, bone tumor, gall bladder and bile duct carcinoma, head and neck cancer, skin cancer, testicular cancer, kidney tumor, germ cell tumor, Liver cancer, leukemia, malignant lymphoma, neural tumor, neuroplastoma, prostate cancer, soft tissue tumor, esophageal cancer and carcinomas in unknown primary tumor.
• Studies have shown that the compounds of the formula (I) and in particular Cu (melphalan) 2, above all, allow effective treatment of kidney and lung cancer.
• the Cu compounds of the formula (I) used according to the invention have a much higher antitumor activity than the ligands themselves, ie melphalan or tegafur.
• This increase in efficacy achieved in the treatment with the copper compounds of the formula (I) can be attributed to a synergistic effect which is determined by the inclusion of the melphalan or tegafur ligands in a Cu compound according to the present invention is obtained.
• the compounds of the formula (I) have immunomodulatory and anti-proliferative properties and also antiangiogenic activity. Furthermore, the compounds of the invention have a greatly increased hydrolytic stability compared to conventional anti-tumor agents, whereby they can be used in a wide range of tumor control. In addition, it has been found that the compounds of formula (I) selectively damage tumor tissues and substantially do not affect healthy tissue. Thus, in contrast to most known chemotherapeutic agents, the compounds of the formula (I) enable anticancer treatment with no or only slight side effects.
• a further advantage of the copper compounds used according to the invention is that these compounds do not cause drug resistance and, under certain conditions, are capable of inducing apoptosis in cancer cells.
• the copper compound Cu (melphalan) 2 which is particularly preferred according to the present invention, is a blue solid which is chemically stable and has a long-lasting effect.
• this connection can overcome the blood-brain barrier, thus enabling the treatment of brain tumors.
• This compound proved to be far more effective as melphalan, as shown for example by studies on renal cell carcinoma and lung metastasis.
• Cu (tegafur) 2 which is furthermore preferred according to the invention, a comparable activity could be demonstrated.
• the copper tegafur compound according to the invention has been found as an antitumor agent, which does not have these disadvantages and also is much more effective .
• compounds of the formula (I) can be used singly or as mixtures of two or more of these compounds for anti-tumor treatment.
• the compounds of formula (I) may be formulated or administered together with conventional pharmaceutical excipients and adjuvants known to those skilled in the art.
• additives or auxiliaries are physiologically compatible carrier substances, diluents, colorants and / or flavorings.
• the copper compound of the formula (I) can be in a form suitable for topical, parenteral, intravenous, intramuscular, subcutaneous, intraperitoneal or transdermal administration.
• the copper compound of formula (I) is provided in the form of tablets or as an intravenous injection.
• the compounds of the formula (I) can be injected selectively into cavities or via a catheter into the blood vessels of the tumor regions or of the organ in which the tumor is located.
• the compounds of the formula (I) or mixtures of such compounds can be administered together with other active substances, these other active substances being, for example, likewise antitumor agents, antibiotics or substances having other effects.
• the compound of the formula (I) can be used in various stages of the tumor disease to be treated.
• a reduction in the symptoms associated with the tumor disease a reduction in the extent of the tumor disease (eg a reduction in tumor growth), a stabilization of the state of the tumor disease (eg an inhibition of tumor growth), a prevention a further spread of the tumor disease (eg metastasis), prevention of the onset or recurrence of a tumor disease, a delay or slowing down the course of the tumor disease and / or an improvement of the state of the tumor disease (eg a reduction of the tumor) can be achieved.
• the compound of formula (I) is administered in an amount which is sufficient to achieve the particular desired purpose.
• the effective amount in each case depends on various factors, such as the choice of complex, the mode of administration, the type and extent of the tumor disease and the age, weight and general condition of the patient.
• 1 ⁇ g / kg body weight of the patient is administered to 0.5 mg / kg body weight of the patient, and more preferably from 10 ⁇ g / kg body weight of the patient to 0.1 mg / kg body weight of the patient of the compounds of the invention.
• the preparation of the copper compounds of the formula (I) can easily be prepared on the basis of synthesis instructions described in the prior art (see, for example, MD Joesten, Inorganica Chimica Acta, 159 (1989) 143-148).
• Another important advantage of the present invention is that the copper compounds used in accordance with the invention are synthetically readily accessible in high purity, which represents an important prerequisite for the provision as medicaments.
• Another object of the present invention is the use of one or more compounds of formula (I) for the manufacture of a medicament for the treatment of tumors.
• Figures Figure 1 shows an IR spectrum (KBr) of Cu (melphalan) 2 .
• Figure 2 shows a mass spectrum of Cu (melphalan) 2 .
• Figure 3 is a representation of a structural proposal for Cu (MeI) 2 • 2H 2 O.
• the structural formula shows the molecular composition and the molecular weight.
• Figure 4 is a synthesis scheme of the synthesis of Cu (Tf) 2 according to Example 2.
• FIG. 5 is a graph showing a comparison of kidney weight and renal volume of the control mice treated according to Example 3 and mice treated with Cu (MeI) 2 according to the present invention.
• Figure 6 is a graph showing the lung weight and the number of lung metastases in the mice treated according to Example 3.
• FIG. 7 shows a comparison of the vessel densities of the control mice treated according to Example 3 and of mice treated with Cu (melphalan) 2 (CD 31 evaluation).
• Figure 8 shows the average tumor volume in the
• Figure 9 shows the relative tumor volumes (RTV) for groups treated with copper-melphalan or with melphalan alone.
• Figure 10 shows a statistical analysis of the two dose groups from Figure 9.
• the total solution was transferred to centrifuge tubes and centrifuged for 4 minutes at 4000 revolutions / minute. A blue substance remained as sediment, the supernatant solution showed a yellowish-green color. The supernatant solution was discarded. 5 ml of ethanol (pure) were added to the sediment, shaken and the solid was again centrifuged off at 4000 revolutions / minute for 4 minutes. The supernatant solution showed a yellowish-green color and was discarded. 5 ml of ethanol (pure) were again added to the sediment, shaken and the solid was removed by centrifuging at 4000 revolutions / minute for 4 minutes, the yellowish-green solution being discarded.
• the purification was repeated until the supernatant solution was colorless, usually about 25 ml of ethanol (pure) are required.
• the solid was dried in air and, after drying, gave a pale blue, visibly homogeneous product which could easily be pulverized very well and very finely.
• the solubility behavior of the copper tegafur compound obtained corresponded approximately to that of a copper (II) salt; in water a pale blue color of the solution and the formation of a foam on shaking were obtained.
• the properties of the substance indicate that the compound Cu (Tf) 2 may have a salt-like character.
• FIGS. 5 to 7 The results of the investigation are shown in FIGS. 5 to 7. This shows that the compound of the invention Cu (MeI) 2 compared to the control to a much lower kidney weight and kidney volume resulted (see Figure 5), which ver ⁇ the efficacy of the compounds of the invention for the treatment of malignant tumors veraulicht. Furthermore, it can be seen from Figure 6 that the lung weight of the mice treated with Cu (MeI) 2 is also reduced compared to the control and to mice given melphalan alone.
• the advantageous effect of the compounds according to the invention on the formation of metastases in the lungs is also particularly clear from the right-hand part of FIG. 6, where lung metastasis formation of the mice treated according to the invention, the control mice and the mice treated with melphalan alone is compared. The mice treated according to the invention showed a considerably lower lung metastasis formation than the control mice and than the mice treated with MeIphalan only.
• test mice were examined for vessel density, as shown in Figure 7. It is clear from this that the compounds according to the invention have antiangiogenic activity.
• RENCA murine renal cell carcinoma model
• Group 1 Negative Control Group 2 Positive Control Melphalan (Glaxo)
• Group 3 and 4 MOC-melphalan 2.5 mg / kg and 5 mg / kg, respectively.
• an antiangiogenic substance was administered as a positive control.
• the start of therapy was for Cu- (melphalan) 2 on the day 1 post Op. Fixed. It was treated daily until day 7 (see treatment scheme). After 19 days the experiment was terminated because the control tumors required termination due to tumor size for ethical reasons.
• the implantation day was counted as day 0. Duration of the trial 19 days.
• the selected dosage of the test substance was based on a previous preliminary test for dose determination and efficacy.
• Sections with a thickness of 5-10 ⁇ m were prepared from the pieces of tissue. The preparations were immunohistochemically stained with an anti-CD31 antibody (pecam-1) and the number of vessels in the control and treatment group was counted. Two sections with three areas each were used for counting the vessels of each tumor.
• Cu- (melphalan) 2 is significantly antitumorally effective at both the doses of 2.5 mg / kg and 5 mg / kg, with better efficacy than melphalan alone at approximately half-equimolar dosing. At about quarter-equimolar dosage, a comparable efficacy to Mel ⁇ phalan is obtained.
• the study protocol corresponds to that of example 4, only a different therapy interval was selected and other dose groups.
• Group 1 Negative Control Group 2 Positive Control Melphalan (Glaxo)
• Groups 3 and 4 Cu Melphalan 2 5 mg / kg and 7.5 mg / kg, respectively.
• the start of therapy was for all groups on the day 10 post.
• Op. Fixed It should be treated daily from day 10 to day 17 (see treatment scheme). Due to toxicities, the treatment period decreased to days 10-14. After 18 days, the experiment was terminated because the control tumors required termination due to tumor size for ethical reasons.
• the implantation day was counted as day 0. Duration of the experiment 18 days.
• Cu- (melphalan) 2 is significantly antitumorally effective against the primary tumor at both the doses of 8.8 ⁇ mol / kg and 13.2 ⁇ mol / kg. Compared with pulmonary metastases and lymph node metastases, a significant antimetastatic effect of a dosage of 13.2 ⁇ mol / kg was found. At a dosage of 8.8 ⁇ mol / kg, Cu (melphalan) 2 is also significantly antiangiogenic.
• mice 2 x 10 6 OVCAR-3 / P19 tumor cells were sc injected into female NOD / SCID mice. The mice were treated as follows.
• Treatment started at a mean tumor volume of 80 mm 3 . In the control group a stable and steady tumor growth was observed. The average tumor volume during treatment is shown in Figure 8.
• the relative tumor volumes RTV
• the relative tumor volume results from the ratio of the volume on day x and the tumor volume at the beginning of the treatment on the same test animal.
• the RTVs from the start of treatment for chemotherapeutic groups are shown in Figure 9. This clearly shows that copper melphalan has better efficacy than meiphalane.
• Figure 10 shows a statistical analysis of both dose groups.
• both treatment groups (groups 2 and 3) had a statistical significance (p ⁇ 0.01, student's t-test) both in tumor volume and in the relative tumor volume compared to the control group.
• p ⁇ 0.01, student's t-test a statistically significantly better effect by copper melanophalane over Meiphalan at the end of the treatment (day 37) could be confirmed.
• mice treated with Meiphalan only exceeded the tumor volume at the start of treatment at the end of the study.
• 6 out of 8 mice had a RTV> 1.
• group 2 test animals totaled between 20% tumor regression and 98% growth, respectively.
• one test animal had an RTV of 2.78, all others were in a range of 0.43 to 0.78.
• a tumor regression between 22% and 57% could be observed. Both the frequency of tumor regression and the severity of the regression were significantly higher in the copper-melphalan-treated group.

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• 2004
  • 2004-11-24 DE DE102004056727A patent/DE102004056727A1/de not_active Withdrawn
• 2005
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