Means, having a radio-sensitizing effect on hypoxic tumor cells in radiation therapy of malignant tumors

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology and Oncology. Goal - the creation of non-toxic radio-sensitizing agent in therapy of tumors. For this proposed use of the ester of succinic acid, which has a higher radio-sensitizing effect, low toxicity, high solubility, which enables you to use the drug for parenteral, including intravenous injection. 1 Il.

The invention relates to medicine and relates to a new use of known chemical compounds, namely mono--(2'-methyl-5'-nitroimidazol-1')-ethyl ester of succinic acid of the formula

< / BR>
(I)

It is known that compound I has anti-parasitic action.

It is known that malignant tumors contain resistant to irradiation hypoxic cells, which determine the radioresistance of the tumor and reduce the effectiveness of radiation therapy. A promising way to increase the radiosensitivity of hypoxic cells is the use of chemical radio sensibilizators increasing the damaging effect of exposure to hypoxia and do not affect radiocasting radiation damage hypoxic tumor cells without changing the radiosensitivity well-oxygenated normal tissues.

The most famous radio sensibilizators hypoxic cells are representatives of the class of imidazole, among which two drug-metronidazole (synonyms: flagyl, trichopol) formula

(II) misonidazole formula

(III)

Known in clinical practice as a means of enhancing the radiosensitivity of tumors by radiation therapy.

Misonidazole has a more pronounced radio-sensitizing effect compared with metronidazole, however, it is 3 times more toxic than metronidazole. Clinical radiation showed that misonidazole (III) has such adverse characteristics such as the ability to cause neuropathy and Central encephalopathy. For these reasons, misonidazole has not found wide application in clinical practice as radiosensibility hypoxic tumour cells.

The closest analogue on the chemical structure and the biological effects of the proposed compound I is metronidazole (II). Metronidazole is used in clinical practice as radiosensibility hypoxic tumor cells.

The main disadvantage of metronidazole is that radio-sensitizing effect igoe, it has low solubility in a neutral aqueous solutions (0.5 wt.). In this regard, metronidazole had to use orally, rectally or by combining these two methods.

Given the above, it is still a further search for new drugs that can increase the radiosensitivity of hypoxic cells in tumors.

The purpose of the invention the expansion of the means having a high radio-sensitizing effect, low toxicity, high solubility in a neutral aqueous solutions.

The objective is achieved by use of known chemical compounds mono--(2'-methyl-5'-nitroimidazol-1')-ethyl ester of succinic acid of the formula I in a new role, namely as a means of having a radio-sensitizing effect on hypoxic tumor cells and increase the effectiveness of radiation therapy of malignant tumors.

The proposed connection is a white crystalline substance, so pl. to 108.5-110aboutC, soluble in neutral aqueous solutions (15-20 wt.).

The study of radio-sensitizing properties of compound I were compared with metronidazole (II).

A suspension of E. coli B/r containing compound I or II in a concentration of 0.01 M, before irradiation was saturated with argon (irradiation under conditions of severe hypoxia or oxygen. Irradiation was carried out at the accelerator LINAC-25 fast electrons with an energy of 20 MeV at a dose of 60 Gy/min

The drawing shows the effect of compounds (I) and (II) on the survival of E. coli B/r, irradiated in the atmosphere of argon and oxygen (abscissa dose, Gy; the ordinate the percentage of surviving cells).

The results obtained indicate that the proposed connection I, also known as drug II, increase the radiosensitivity of hypoxic bacteria E. coli B/r 2 times, but do not affect the radiosensitivity of bacteria irradiated in the atmosphere of oxygen. The proposed connection I selectively sencibilisiruet hypoxic bacterial cells, shooting 49% protective effect hard hypoxia.

To prove the ability of the proposed compound I to increase the radiosensitivity of hypoxic cells in animal experiments on tumor cells of ascitic Ehrlich carcinoma and cool stem cells, when the oxygen concentration in ascitic fluid of less than 1 mm RT. Art. shows high radio-sensitizing effect of the connection.

So, after a radiation dose of 6 Gy, the number of mn per 1000 tumor cells is 46 7 (non-irradiated control 13 1), while after the introduction of the compound I and the subsequent exposure to the same dose (6 Gy) number of mn per 1000 tumor cells is 85 11.

As can be seen from the data presented, the introduction of compound I (20 mg / mouse or 0.5 LD50) for 30 min before irradiation increases the radiosensitivity of irradiated hypoxic cells in ascitic Ehrlich carcinoma 1.8 times.

It is known that metronidazole (II) increases the radiosensitivity of hypoxic tumor cells in 1.4.

In the study by well-known methods radio-sensitizing actions proposed connection I on hematopoietic stem cells (CFU) hypoxia created by dragging a rubber band abdominal cavity of mice 10 min before irradiation at a dose of 7 Gy. This led to a significant increase in the yield of splenic colonies formed SOME survivors through 8 days after exposure.

Quantitative assessment of radio-sensitizing effect was estimated leftline introduction radiosensibility - regulating drug.

The value of K is determined by the formula

K 100 100 where Nand Ngthe average number of colonies on the spleen after irradiation (7 Gy) mice with and without a tourniquet, respectively;

N is the average number of colonies on the spleen after pretreatment with the compounds and subsequent irradiation (7 Gy) mice with a tourniquet.

The value of K for the proposed compound I is 69% while for metronidazole (II) entered in the equivalent dose (0.5 LD50), it is only 32%

It is established that the proposed connection I introduced intravenously to mice and rats, accumulates in the blood after 1 h in the amount of 0.68 mg/ml, while metronidazole over 3 h after oral administration contains blood in the amount of 0.45 mg/ml

Thus, the concentration level of the proposed connection exceeds the maximum concentration level in the blood of metronidazole (0.45 mg/ml) in 1.5 times.

Studies have also shown that the connection I much better penetrates into the Central hypoxic zone tumors (80% of the content in the blood) compared with metronidazole for which this rate is 40-60%

Assessment toxicity to mice offer the drug is I I is 2.0 g/kg body weight intraperitoneal route of administration and 2.5 g/kg by intravenous method of administration.

For metronidazole LD50intraperitoneal method of administration of 2.5 g/kg body weight, intravenous LD50metronidazole is not determined due to low solubility in neutral water solutions.

Thus, the proposed compound I exhibits in comparison with the known drug of the same purposes metronidazole (II) increased radio-sensitizing activity against hypoxic tumor and hematopoietic stem cells of mice.

In addition, compound I has a higher than metronidazole, the ability to accumulate in the Central areas of the tumors containing radioresistant hypoxic cells, which creates conditions for the manifestation of the connection I high radio-sensitizing activity.

The connection I unlike metronidazole may be introduced into the body intravenously, which creates conditions for rapid advances in high blood concentrations of the drug required to increase the radiosensitivity of hypoxic tumor cells at the time of exposure.

Thus, the results of tests conducted on various biological objects, allow us to conclude that t is the tumor more effectively than a known drug metronidazole.

The use of mono -(2-methyl - 5-nitroimidazole -1) -ethyl ester of succinic acid of the formula

< / BR>
as a means of having a radio-sensitizing effect on hypoxic tumor cells in radiation therapy of malignant tumors.

 

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The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl

The invention relates to methods of producing substituted imidazole derivatives and their non-toxic pharmaceutically acceptable acid additive salts

The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I

where (a) R1=n-C4H9, R2=R3=H;

b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine

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The invention relates to new chemical compounds with valuable pharmacological properties, namely, condensed the five-membered heterocycles of General formula

(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;

R4a hydrogen atom, alkyl or CNS group containing 1-6 carbon atoms, aryl, heteroaryl or kalkilya group containing 1-6 carbon atoms in the alkyl part;

R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the fourth position may be substituted with oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl - or aryl is

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

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R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl

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The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to methods of producing substituted imidazole derivatives and their non-toxic pharmaceutically acceptable acid additive salts

The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I

where (a) R1=n-C4H9, R2=R3=H;

b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

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