DE4134224C2 - New 1-heterocyclylmethyl-3-nitro-1,2,4-triazoles - Google Patents

Description

The present invention relates to novel 1-heterocyclylmethyl-3-nitro-1,2,4-triazoles, process for the production of the same, including necessary interconnections, and their use in drugs that have an increased radiation-sensitizing effect exhibit.

It is known that the radiation resistance of some malignant tumors is highly likely reduced oxygen supply. Sometimes arise or permanently hypoxic cell areas that are effective radiation damage revoke. To destroy these hypoxic cell areas is acidic compared to good tissue-supplied tissue requires approximately three times the radiation dose, but this means that Tolerance limit of healthy tissue is exceeded. The "Sensitizer Oxygen" should thus be a means of choice to make radiotherapy more effective. In addition to various Ways to increase the oxygen partial pressure in the tumor tissue have been developed in the In recent years, electron-affine connections have been checked for their use as radio sensitizers. Except for 2-nitro-imidazole derivatives (see U.S. Patents 4,282,232 and 4,371,540), the most recent ones In the past, 3-nitro-1,2,4-triazole derivatives were increasingly investigated. This showed that these as radio sensitizers for hypoxic cells due to low neurotoxicity the previous ones Nitroimidazoles are superior (cf. Chem. Phar. Bull. (Japan) 37 (7) (1989) 1951). Next various 3-nitro-1,2,4-triazol-1-yl-acetic acid derivatives and 1 - ((3-alkoxy- or 3- amino-substituted or 3-carbonyloxy) -2-hydroxypropyl) -3-nitro-1,2,4-triazoles (cf. EP-PS 212 558 and 319 329, JP-PS 63 068 575, Int. J. Radiat. Oncol. Biol. Phys. 12 (7) (1986) 1063) or analogous fluorine-substituted derivatives (cf. EP-PS 294 847; Int. J. Radiat. Oncol. Biol. Phys. 16 (4) (1989) 1054), 1-glycosidyl-3-nitro-1,2,4- triazoles (cf. JP-PS 63 170 394, Eur. J. Med. Chem.-Chim. Ther. 19 (1) (1984) 89) and 1- (2-oxopropyl-substituted) -3-nitro-1,2,4-triazoles (see JP-PS 61 194019) and if necessary, tested for their radiation-sensitizing effect. The effect of this Compounds is, however, especially for those with a radiation-sensitizing effect necessary concentrations, due to neurotoxic and other side effects not always satisfactory.

There is therefore still a need for further compounds with radiation sensitization the effect, the low side effects and a better general tolerance than that have previously known compounds.  

Surprisingly, new 1-heterocyclylmethyl-3-nitro-1,2,4-triazoles were found which have an increased radiation-sensitizing effect and can be used in medicinal products are.

The structure of the compounds according to the invention is represented by the general formula (I):

in which Q for

• - 5-amino-1,3,4-oxadiazol-2-yl or
• - 5-oxo-1,3,4-oxadiazolin-2-yl or
• - 5-amino-1,2,4-triazol-3-yl or
• - 4-butyl-5- (2-methoxyethylcarbamoyl-methylsulfanyl) -1,2,4-triazol-3-yl or
• - 4- (3-nitro-1,2,4-triazol-1-ylmethyl) piperazin-1-yl

stands.

It has been found that the compounds of the general compound (I) according to the invention in which Q is

• - 5-amino-1,3,4-oxadiazol-2-yl or
• - 5-oxo-1,3,4-oxadiazolin-2-yl or
• - 5-amino-1,2,4-triazol-3-yl

is obtained by (3-nitro-1,2,4-triazol-1-yl) acetic acid hydrazide with C ₁

- building blocks, such as cyanogen or phosgene, or (3-nitro-1,2,4-triazol-1-yl) acetic acid ester accordingly, converting hydrazine derivatives into a disubstituted hydrazide and this a cyclocondensation under neutral, acidic or alkaline conditions without or with the help of diluents at temperatures from 0 ° C to 300 ° C submits.

The compound of the general formula (I) in which Q is 4-butyl-5- (2- methoxyethylcarbamoyl-methylsulfanyl) -1,2,4-triazol-3-yl, can be prepared by (3-nitro-1,2,4-triazol-1-yl) acetic acid hydrazide with butyl in a manner known per se isothiocyanate, the reaction product of a cyclocondensation to 1 - ((4-butyl-5- Subjects thioxo-1,2,4-triazolin-3-yl) methyl) -3-nitro-1,2,4-triazole and the latter with chlores alkyl acetic acid (N-methoxyethyl) amide.

According to a further process, the compound of the formula (I) in which Q is 4- (3- Nitro-1,2,4-triazol-1-yl-methyl) -piperazin-1-yl is obtained, in which 1-hydroxymethyl 3-nitro-1,2,4-triazole with piperazine or 3-nitro-1,2,4-triazole in a MANNICH reaction with Formaldehyde and piperazine.

Finally, it was found that the compounds of the formula (I) according to the invention in can be transferred to a formulation customary for medicinal products and good radiation Show sensitizing effects with minor neurotoxic and other side effects.

Here, the compounds of general formula (I) in a manner known per se formulated, preferably in the form of orally administrable agents or injection, infusion and Instillation solutions. For example, the most varied forms of tablets, Dragees and suppositories or i. v. or other applicable solutions or suspensions the organic or inorganic diluents or formulation auxiliaries such as Surfactants, emulsifiers, fillers or others for the corresponding galenic form necessary auxiliaries and possibly taste or color corrections called.

The drugs mentioned generally contain 0.1 to 99%, preferably 1 to 50% of at least one compound of the general formula (I).

The invention is explained in more detail using the following examples:  

example 1 1,4-bis ((3-nitro-1,2,4-triazol-1-yl) methyl) piperazine

0.1 mol (11.4 g) 3-nitro-1,2,4-triazole are suspended in 100 ml i-propanol and 10 ml H ₂ O, with 0.12 mol (12.4 g) 29% Formalin solution added and heated to boiling under reflux for 15 minutes. A solution of 0.1 mol (8.6 g) of piperazine in 10 ml of H ₂ O is then added dropwise with thorough stirring within 30 minutes.

There is an immediate failure of the reaction product. The mixture is heated for a further 1.5 hours Reflux, cools to room temperature and sucks 15.45 g of pure analytical product. If necessary, the product is recrystallized from 15% ethanol.

Example 2 1 - ((5-Amino-1,3,4-oxadiazol-2-yl) methyl) -3-nitro-1,2,4-triazole Level A (3-nitro-1,2,4-triazol-1-yl) acetic acid hydrazide

0.1 mol (18.6 g) (3-nitro-1,2,4-triazol-1-yl) methyl acetate are dissolved in 80-90 ml Methanol suspended, 0.115 mol (5.9 g) 97.53% hydrazine hydrate added, 4 hours heated under reflux, the solution filtered if necessary and cooled well in an ice bath. The precipitated needles, 16.37 g (88% of theory), are suctioned off. They melt at 122 123 ° C. Recrystallization is not necessary.

Level B 1 - ((5-Amino-1,3,4-oxadiazol-2-yl) methyl) -3-nitro-1,2,4-triazole

0.05 mol (9.3 g) (3-nitro-1,2,4-triazol-1-yl) acetic hydrazide are dissolved in 60 ml of water with gentle heating, cooled to approx. 25 ° C. and stirred with 0.055 mol (5.85 g) of cyanogen bromide were added in portions. Then 0.055 mol (5.5 g) of KHCO _{3 are} added in portions to this solution. The reaction product precipitates after about 10 minutes. The mixture is stirred for about 3-4 hours at room temperature, 8.9 g of reaction product is suctioned off and, if necessary, the product melting at 187.5-189 ° C. is recrystallized from the amount of water just required.

Example 3 1 - ((5-Oxo-1,3,4-oxadiazolin-2-yl) methyl) -3-nitro-1,2,4-triazole

0.05 mol (9.3 g) (3-nitro-1,2,4-triazol-1-yl) acetic acid hydrazide (Step A Example 2) are suspended in 90 ml of acetonitrile, with 0.0275 mol (4, 5 g) of diphosgene were added, the mixture was heated to 50 ° C. within 15 minutes, 0.1 mol (8.4 g) of NaHCO _{3 was} added and the mixture was stirred under NaHCO ₃ under reflux for 5 hours. The inorganic salts are then filtered off hot and the solution is evaporated to dryness in vacuo. The residue is mixed with 120 ml of methanol and heated to reflux for about 10 minutes, resulting in a clear solution. This is cooled to room temperature, causing the reaction product to fail. It is recrystallized from the amount of butanol just required. 5.5 g of reaction product with a melting point of 182-184 ° C. are obtained.

Example 4 1 - ((5-Amino-1,2,4-triazol-3-yl) methyl) -3-nitro-1,2,4-triazole

0.1 mol (2.3 g) sodium are dissolved in 200 ml methanol, with 0.105 mol (10.55 g) amino added guanidine hydrochloride, stirred under reflux for 15 minutes, filtered off from NaCl, with 0.1 mol (18.6 g) (3-nitro-1,2,4-triazol-1-yl) methyl acetate and added for 3 hours stirred under reflux. After 5-10 minutes, the resulting 1- (Carboxyaminoguanidino-methyl) -3-nitro-1,2,4-triazole. After cooling in the ice bath this is suctioned off, washed with water and optionally crystallized from 70% methanol lized. 19.8 g (87% of theory) of a compound are obtained which are at 164-166 ° C. easy decomposition melts.

0.02 mol (4.56 g) of this compound are about 70 minutes at 175-180 ° C bath temperature and kept under a vacuum of about 15 torr, triturated with ether after cooling and recrystallized from water or 50% ethanol. The resulting 3.2 g of the target compound Melting with decomposition at 216-220 ° C.  

Example 5 1 - ((4-Butyl-5- (2-methoxyethylcarbamoyl-methylsulfanyl) -1,2,4-triazol-3-yl) methyl) -3-nitro- 1,2,4-triazole Level A 1 - ((4-Butyl-5-thioxo-1,2,4-triazolin-3-yl) methyl) -3-nitro-1,2,4-triazole

0.1 mol (18.6 g) corresponding hydrazide (Step A Example 2) in 150 ml of acetonitrile dissolved while heating at reflux and stirring, dropwise with the equivalent amount (11.5 g) butyl isothiocyanate added, refluxed for 5-6 hours and in vacuo concentrated to residue. This is triturated with ether and recrystallized from ethanol. 23.2 g (77% of theory) corresponding thiosemicarbazide with a melt are obtained point of 99-103 ° C. 0.05 mol (15.1 g) of this thiosemicarbazide are in a solution of refluxing 0.065 mol (3.65 g) KOH in 130 ml water for 2 hours, cooled in an ice bath and acidified to a pH of 1-2.

The product which has crystallized through after 30 minutes is filtered off, washed with water and optionally recrystallized from methanol. 11 g of target product with a melt are obtained point of 143-145.5 ° C.

Level B 1 - ((4-butyl-5- (2-methoxyethylcarbamoyl-methylsulfanyl) -1,2,4-triazol-3-yl) - methyl) -3-nitro-1,2,4-triazole

0.05 mol (14.2 g) of the triazolinethione obtained in step A become a solution of Add 0.05 mol (1.15 g) sodium in 90 ml methanol, in vacuo to absolute dryness concentrated, dissolved in 150 ml of acetonitrile, optionally with a spatula tip KJ, with 0.05 mol (7.56 g) of chloroacetic acid (N-methoxyethyl) amide and added for 6 hours Heating stirred to reflux. The NaCl is suctioned off hot and the solution in an ice bath cooled down. A first part of the reaction product already fails. By narrowing the Mother liquor will receive another product. Both products are made from approx. 60 ml 50% Recrystallized ethanol. 12.9 g of the target product with a melting point of 127-129 ° C.

The chemical-physical data are listed in Table 1:  

Table 1

chemical-physical information on Examples 1-5

Pharmacological examinations

The in vivo toxicity and radiation sensitization of the 1-heterocyclymethyl 3-nitro-1,2,4-triazole derivatives.

To determine the effect of the sensitizer in vivo, the growth delay times of the tumor after irradiation with and without the sensitizer were determined on the breast cancer of the C3H mouse. The substances (1 mmol / kg) were in physiological saline for 30 min. injected ip before irradiation. The non-anesthetized animals were irradiated locally with a ⁶⁰ Co system (dose: 30 Gy; DL: 2.8 Gy / min.). Subsequently, the mean tumor diameter was measured 3 times a week, converted into tumor volumes and related to the volume on the day of treatment (V _t / V ₀ ). The relationship volume was plotted against time on a semi-logarithmic scale and the time until the one or two times the initial volume was reached was determined from the resulting straight line. On the basis of a calibration curve from the values of the tumors irradiated without substance, these times are converted into dose values and, after division by the actually applied dose, the sensitization factor is obtained. The corresponding results are listed in Table 2 and compared with the results of the comparative substance AK 2123. The improved sensitizing effect compared to the comparison substance is evident.

Table 2

Radiation sensitization and in vivo toxicity of 1-heterocyclylmethyl-3-nitro-1,2,4-triazoles

Reference substance

AK 2123 (3-nitro-1,2,4-triazol-1-yl- (N- (2-methoxy) ethyl acetic acid amide); compare Int. J. Radiat. Oncol. Biol. Phys. 12 (1986) 1063

Claims (6)

1. New 1-heterocyclylmethyl-3-nitro-1,2,4-triazoles of the general formula (I),
in which Q for

• - 5-Amino-1,3,4-oxadiazol-2-yl- or
• - 5-oxo-1,3,4-oxadiazolin-2-yl- or
• - 5-Amino-1,2,4-triazol-3-yl- or
• - 4-butyl-5- (2-methoxyethylcarbamoyl-methylsulfanyl) -1,2,4-triazolin-3-yl- or
• - 4- (3-nitro-1,2,4-triazol-1-ylmethyl) piperazin-1-yl

stands. 2. A process for the preparation of compounds of general formula (I) according to claim 1, in which Q is

• - 5-Amino-1,3,4-oxadiazol-2-yl- or
• - 5-oxo-1,3,4-oxadiazolin-2-yl- or
• - 5-amino-1,2,4-triazol-3-yl

is characterized in that (3-nitro-1,2,4-triazol-1-yl) acetic acid hydrazide with cyanogen halides or phosgene or (3-nitro-1,2,4-triazole) 1-yl) -acetic acid esters are reacted with appropriately substituted hydrazine derivatives to form a disubstituted hydrazide and this is subjected to cyclocondensation under neutral, acidic or alkaline conditions without or with the aid of diluents at temperatures from 0 ° C. to 300 ° C. 3. A process for the preparation of a compound of general formula (I) Claim 1, in which Q is 4-butyl-5- (2-methoxyethylcarbamoyl-methylsulfanyl) - 1,2,4-triazol-3-yl, characterized in that one is known per se Way (3-nitro-1,2,4-triazol-1-yl) acetic hydrazide with butyl isothiocyanate converts the reaction product of a cyclocondensation to 1 - ((4-butyl-5- Subjects thioxo-1,2,4-triazolin-3-yl) methyl) -3-nitro-1,2,4-triazole and the latter alkylated with chloroacetic acid (N-methoxyethyl) amide. 4. A process for the preparation of a compound of general formula (I) Claim 1, in which Q is 4- (3-nitro-1,2,4-triazol-1-yl-methyl) -piperazin-1-yl stands, characterized in that in a manner known per se 1- Hydroxymethyl-3-nitro-1,2,4-triazole with piperazine or 3-nitro-1,2,4-triazole in a MANNICH reaction with formaldehyde and piperazine. 5. Use of compounds of claim 1 as radiation-sensitizing Substances. 6. Use of compounds of claim 1 as a medicament in the Tumor therapy.