Metal Glycididaagolc, and preparation and uses thereof

Details Metal Glycididaagolc, and preparation and uses thereof Metal Glycididaagolc, and preparation and uses thereof

2000-04-06

2001-08-07

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S313700

Reexamination Certificate

active

06271250

ABSTRACT:

The present invention relates to nitroimidazole compounds, particularly a Metal Glycididaagolc, which is useful as sensitivity enhancers for chemotheraphy and radiotheraphy.
A variety of factors contribute to the efficiency of radiotheraphy and chemotheraphy. A major one of them is a fraction (10-50%) of anaerobic cells present in tumors, whose tolerance toward radiation or chemothrapeutant is 2.5-4 times higher than that of aerobic cells in tumors or normal cells. Thus, those anaerobic cells can not be efficiently killed at regular radiotherapeutic or chemotherapeutic dosage, and might induce tumor metastasis or relapse. Sensitivity enhancer is a chemical that can enhance the effect of radiation and chemothrapeutant to the anaerobic cells in tumors, but has much weaker effect to the aerobic normal tissue.
Zangondroff reported the enhanced radiation damage to mice by iodoacetic acid in 1954, which is the first time to demonstrate the effect of sensitivity enhancer. In the next decade, a lot of effort has been made to investigate the effect of sensitivity enhancer on cells. As a result, several compounds were screened, but the sensitivity enhancement is not always positive. In the early 1960s, Adams et al. established the method for screening sensitivity enhancers, and demonstrated that the nitroimidazole compounds have the sensitivity enhancement effect. However, insufficient sensitivity enhancement effect and serious gastrointestinal side effects resulted at the dosage that is required to be administered limited the clinical application of these compounds.
Since 1974, 2-nitroimidazole (MISO) had been investigated on clinical trials for more than ten years. The result shows that though 2-nitroimidazole has significant sensitivity enhancement effect, it has serious neurotoxicity, and therefore is not clinically applicable. After 1980s, a lot of new compounds, e.g. SR-2508, RSU-1069, Al-2123, DMM, RO-03-8799, have been synthesized through structural modification of MISO. Chinese patent No. 89102182.5 disclosed a method for preparation of an anticancer drug, namely, methyl nitroimidazoleamino acid. All the above mentioned compounds show unexpected side effects, and only a few of them are under further investigation. Thus, the anticancer sensitive enhancers are still not clinically applicable so far.
It is an object of the present invention to provide compound which is capable of enhancing the sensitivity of tumor cells to radiotheraphy and chemotheraphy, and therefore, enhance the damage of radiation and chemothrapeutant to tumor cells.
It is another object of the present invention to provide a process for preparing. a compound that is capable of enhancing the sensitivity of tumor cells to radiotheraphy and chemotheraphy, and therefore, enhance the damage of radiation and chemothrapeutant to tumor cells.
The sensitivity enhancers for radiotheraphy and chemotheraphy of the present invention, i.e. Metal Glycididaagolc, are compounds of the general formula (I):
wherein Me is a monovalent metal ion, a bivalent metal ion, a multivalent metal ions or a chelate thereof, which is connected to the organic moiety by an ironic bond. Preferably, the metal ion is Na
+
, K
+
, Ca
2+
, Al
3+
, Mg
2+
, Zn
2+
, or Ba
2+
; more preferably, the metal ion is Na
+
, or K
+
.
The present invention further provides a method a method for preparation of the compounds of the present invention, comprising the steps of:
a) Carrying out anhydridization reaction under heating conditions by using nitrilotriacetic acid and acetic anhydride, thereby an intermediate of nitrilotriacetic anhydride is resulted;
b) Esterifying the intermediate obtained in step a) with 5-nitroimidazole under heating to produce a glycididaagolc acid;
c) Salifing the glycididaagolc acid obtained in step (b) under heating with a salt containing a proper metal ion.
In one embodiment of the present invention, the anhydridization and esterification are carried out in N,N-dimethylformamide as the solvent at 45° C.
In a further embodiment of the present invention, the esterification is carried out at 40-45° C., and the glycididaagolc acid is obtained by adjusting pH of the reaction mixture to 3.5-4.0 with HCl, and cooling.
In another embodiment of the present invention, the salification is carried out below 70° C., and ethanol and the salt are added to control the pH of the reaction mixture in the range of 7-8, and ethanol concentration at 70-75% by weight.
In another embodiment of the present invention, the reaction of acetic anhydride and nitrilotriacetic acid is carried out in the presence of N,N-dimethylformamide at 45° C., thereby an intermediate is obtained. The mixture of the intermediate and 5-nitroimidazole is adjusted to pH 3.5-4.0 with 6N HCl, and then cooled to a temperature below 10° C. Glycididaagolc acid is obtained after cooling. The glycididaagolc acid thus obtained reacts to the salt containing a proper metal ion below 70° C. to give a metal glycididaagolc. Ethanol and metal salt are added in batches to the reaction mixture in the reaction process. The pH of the reaction mixture is controlled to 7-8. The preferred ethanol concentration for product crystallization is 70-75%.
The present invention further provides the uses of the compounds in the production of sensitivity enhancers used in radiotheraphy and chemotheraphy.
The compounds of the present invention is capable of inhibit the repairing of the damaged tumor anaerobic cells, thus is useful as sensitivity enhancers for radiotheraphy and chemotheraphy. The compound is also capable of killing anaerobic bacteria or anaerobic monads.
The compound of formula (I) may be administered in liquid or solid form on the oral, parenteral, or topical routes in all the common non-toxic, pharmaceutically accepted carriers, adjuvants and additives. The compound may also be combined with appropriate carriers to achieve delayed release of the compound. The amount to be administered is generally 300 to 1200 mg/square meter of body surface area, preferably, the amount is 800 mg/square meter of body surface area.
The compounds of the present invention are soluble in water, which is suitable to be administered as sensitivity enhancers in tumor radiotheraphy and chemotheraphy. The result of experiment shows that the compound of the present invention can significantly enhance the sensitivity of the variety of solid tumors to the radiotheraphy and chemotheraphy, and significantly reduces the noxious side effects of radiotheraphy and chemotheraphy. Since their low oil-water distribution coefficient, the compounds have lower affinity to brain tissue than other sensitivity enhancers, and therefore, have lower neurotoxicity. Further, it was demonstrated that:
1. The radiotherapeutic sensitivity enhancement effect on in vitro V
79
cells: The LD
50
of the compounds for aerobic and anaerobic cells are 35.70 mmol/l and 23.50 mmol/l, respectively. This demonstrates that the toxicity of the compounds to anaerobic cell is significantly higher than that to aerobic cell.
2. The radiotherapeutic sensitivity enhancement effect on radiated anaerobic cells: Experimental results show that the compounds have no radiotherapeutic sensitivity enhancement effect on radiated aerobic cell, the C
1.6
value is 0.48 mmol/l. The sensitivity enhancement ratio (SER value) of the compounds at a nontoxic concentration of 0.1-1.38 mmol/l is 1.26-2.32, which demonstrates that the compound selectively enhance the radiotherapeutic sensitivity on anaerobic cells.
3. Under the same experimental conditions, the radiotherapeutic sensitivity enhancement effect of the compounds is higher than that of either MISO or methyl nitroimidazole. The SER values are 1.76, 1.52, and 1.07, respectively.
4. In the therapy of lung cancer, melanoma, breast cancer and S
180
, compared with the result of control experiment, the application of the compounds of the present invention significantly lowers the tumor growing rate, enhances the tumor inhibition efficiency, and prolongs the delayed time of tumor g

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