DE2847064A1 - Use of 2-cyano-aziridine(s) to treat damage due to radiation - reduces the leukopenia resulting from damaged bone marrow - Google Patents

Abstract

The use of 2-cyanoaziridines (I) to avoid or reduce damage due to radiation is novel. An esp. pref (I) is 2- 2-cyanaziridin-1-yl- -2- 2carbamoylaziridin-1-yl -propane(Ia). Suitable doses are 5-500 mg/kg body wt. applied either as a single dose or several unit doses. As the effect drops slowly after approx 2 weeks, it can be necessary to repeat treatment with (I). (I) can be applied at the same time as or after radiation treatment to compensate for the damage to the bone marrow the radiation would normally cause. This damage to the bone marrow can be observed in the leucopaenia in peripheral blood ie in the reduction in the level of white blood corpuscles.

Description

The invention therefore relates to the novel use of the 2-Cyanaziridines, preferably in DE-OS 27 40 248, DE-OS 27 27 550, DE-OS 27 31 264, DE-OS 27 36 296,

DE-OS 28 33 986 described in the fight against radiation damage.

For the production of the pharmaceutical agents according to the invention the 2-cyanaziridine in a manner known per se with suitable pharmaceutical carrier substances mixed and shaped, for example, as tablets or dragees or with addition corresponding auxiliaries in water or oil, such as. E.g.

Olive oil, suspended or dissolved and filled in hard capsules.

Since the active ingredient is acid-labile, the preparation is optionally provided with a coating that is only soluble in the alkaline medium of the small intestine or a appropriate carrier, such as a higher fatty acid or carboxymethyl cellulose mixed in. Solid carriers are e.g. E.g. starch, lactose, mannitol, methyl cellulose, Talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid), Gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable Fats and solid high molecular weight polymers (such as polyethylene glycols), for oral application If desired, suitable preparations can contain flavorings and sweeteners.

From the experiments below it can be deduced that for the desired pharmacological effect of radiation neutralization a dose of approx. 5 to 500 mg / kg body weight is necessary, either all at once or in several individual doses can be applied. Since the effect wears off slowly after about 2 weeks, can re-treatment may be necessary.

The effectiveness of 2-cyanaziridines is demonstrated using the following animal experiments occupied, where 2- [2-cyanoaziridinyl- (1)] -2- [2-carbamoylaziridinyl- (1) J-propane, im the following BM 12.531 called, examined as an example of the substances of this group became.

1. Influence of BM 12,531 on the number of leukocytes in the peripheral Blood from rats pretreated with X-rays.

Experimental arrangement 10 female adult Sprague-Dawley rats each weighing 175-200 g were given an X-ray dose on the first day of the experiment irradiated from 175 r. 1 day before the irradiation and every 3 or 2 days After the irradiation, blood was drawn out with the aid of a heparinized piercing capillary taken from the retroorbital venous plexus and the number of leukocytes with the help of a Coulter Counters counted. BM 12.531 was administered at a dose of 50 mg / kg i.p., dissolved in physiological saline solution, 3 times a week, starting on the 1st day of the experiment, Applied approx. 3 hours after the irradiation.

The control group received only the same volume physiologically Saline solution. The body weight of the animals was also measured every 2 to 3 days certainly.

Result As the values in Table 1 show, it comes after the Application of X-rays to massive leukopenia that lasted up to 13 days the irradiation continues. Treatment with BM 12,531 could reduce this leukopenia can be intercepted to a highly significant degree on the 6th and 8th day after application (Student's t test).

If the radiation dose was increased to 350 r, a still was shown greater decrease in the number of leukocytes (Table 2).

In this case, too, treatment with 50 mg / kg BM 12,531 (dissolved in physiological saline solution, i.p., 3 times a week) a significant lower decrease in leukocytes on 7th, 9th, 14th, 16th and 18th days after irradiation cause.

These investigations show that the decrease in leukocytes is due to BM 12,531 can be intercepted after x-ray irradiation.

2. Influence of BM 12.531 on the survival time of X-rays Damaged Mice Female NMRI mice weighing 20-25 g were used. These animals received a radiation dose of 600 r on the 2nd day of the experiment. The survival time the animals were observed and recorded daily. BM 12,531 was given in dosages of 50 mg / kg or 5 mg / kg i.p. 2 times a week, starting approx. 3 hours after the Irradiation, applied. The control received the corresponding amount physiological Saline intraperitoneally.

Result As the values in Table 3 show, the application causes of 50 mg / kg BM 12,531 a significant delay in the lethality of the irradiated Animals. The lower dose of 5 mg / kg had a lesser effect.

These studies show that 2-cyanaziridines are not only used in the Are capable of X-rays induced leukocyte and thus immunosuppression but even the lethality of X-ray treated animals massively reduce.

Table 1 Influence of BM 12,531 (i.p.) on the number of leukocytes at Rats irradiated with 175 r number of leukocytes (x 10³ / µl) day 0. + 1. 4. 6. 8. 11. 13. 15.

Control 11.6 # 0.8 2.2 # 0.2 3.9 # 0.4 2.9 # 0.2 4.6 # 0.3 5.2 # 0.5 6.9 # 0.3 BM 12,531 50 mg / kg i.p.

3 times a week 11.8 # 0.6 2.3 # 0.2 5.9 # 0.4 5.5 # 0.4 5.1 # 0.3 5.6 # 0.4 6.9 # 0 , 3 Significance to control n.s. n.s. -3.77 / 17 -8.44 / 17 -1.17 / 18 n.s. n.s.

p <0.001 p <0.001 Table 2 Influence of BM 12.531 (i.p.) on the white blood cell count of rats irradiated with 350 r 0, 2, 4, 7, 9, 11. 14th, 16th, 18th, 23rd day Control 10.5 # 0.8 1.7 # 0.2 1.4 # 0.1 2.0 # 0.1 2.9 # 0.3 2.8 # 0 , 4 4.0 # 0.3 6.0 # 0.6 6.5 # 0.8 7.9 # 0.6 EM 12,531 50 mg / kg i.p.

3 times a week 10.3 # 0.4 1.9 # 0.2 1.7 # 0.1 3.2 # 0.2 3.2 # 0.4 5.9 # 0.4 5.9 # 0 , 5 7.5 # 0.5 10.7 # 1.3 7.8 # 0.6 Significance to control n.s. n.s. -1.6 / 17 -3.81 / 18 -2.31 / 18 -0.7 / 18 -3.08 / 17 -2.2 / 18 -2.79 / 18 n.s.

0.25 <0 <0.1 p <0.002 p <0.05 n.s. p <0.01 p <0.05 p <0.02 n.s.

Table 3 Influence of BM 12.531 (i.p.) on the mortality rate of irradiated Mice irradiated 20 mice each with 600 r treatment with dead survivors BM 12 531 (twice a week) on the 20th day Controls 16 4 5 mg / kg 13 7 10 mg / kg 8 12

Claims (3)

Use of 2-cyanaziridines as therapeutic agents for radiation damage Claims 1. Use of 2-cyanaziridines in combating radiation damage. 2. Use of 2-cyanaziridines of the general formula in the X the rest represents, where A is an oxygen or sulfur atom and Y is the group -CO-R1, -S02-R28 -SO-R3, -S-R3 or represent, where R1 is hydrogen, a nitrile group, a lower alkoxy, alkoxycarbonyl or N, N-dialkylaminocarbonyl group, a lower N-alkyl-N-phenyl or N, N-dialkylamino group, a saturated or unsaturated alkyl group, which is optionally a or several times by halogen, nitrile or a lower N-acylamino, N, N-dialkylamino, alkoxy, alkoxycarbonyl, acyloxy, N1 N-dialkylaminocarbonyloxy, alkylsulfonyl or alkyl mercapto group or optionally by halogen, nitro, phenyl, phenyl or naphthyl, phenylmercapto or phenyloxy group substituted by lower alkyl, alkoxy or alkyl mercapto groups, a lower dialkoxyphosphoryloxy or dialkoxyphosphono group, a cycloalkyl, N-succinimido or N-phthalimido group or one optionally mono- or multiply by halogen, nitro , Phenyl, nitrile, trifluoromethyl or a lower alkyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, alkylinercapto or acyloxy group-substituted aromatic rocyclic radical o which can be substituted for the remainder, a phenyl, phenoxy or optionally hydrogenated naphthalene radical, which can optionally be substituted one or more times by halogen, trifluoromethyl, sulfamoyl, nitro, nitrile, phenyl or a lower alkyl, N-acylamino, alkylmercapto, alkylsulfonyl, alkoxy , Alkoxycarbonyl, alkoxycarbonylalkyl, N, N-dialkylamino,, N-dialkylaminocarbonyl, N, N-dialkylaminocarbonylalkyl, acyl, acyloxy or acyloxyalkyl group, a methylenedioxy group or the remainder may be substituted, or a cycloalkyl or a saturated or aromatic heterocyclic radical, which can optionally be substituted one or more times by halogen, nitro, nitrile, trifluoromethyl, phenyl or a lower alkyl, alkoxy, alkoxycarbonyl, alkylmercapto, acyloxy or Alkylsulfonyl group can be substituted, R2 a lower, saturated or unsaturated alkyl group, which is optionally substituted one or more times by halogen atoms, a lower alkoxycarbonyl or acyloxy group, a cycloalkyl, an amino, a lower dialkylamino group, a phenyl group, which is optionally a - Or several times by a lower alkyl or alkoxy group, halogen or a nitro group or the remainder or the rest a saturated or aromatic heterocyclic radical which can optionally be substituted one or more times by halogen, nitro, nitrile, trifluoromethyl, phenyl or a lower alkyl, alkoxy, alkylsulfonyl, acyloxy, alkylmercapto or alkoxycarbonyl group, R3 is a lower alkyl - Or trifluoromethyl group or a phenyl group which is optionally substituted one or more times by a lower alkyl, acyloxy, alkylmercapto, alkylsulfonyl, alkoxycarbonyl or alkoxy group, halogen, a trifluoromethyl or nitro group, and R4 and R5, which are the same or are different, lower alkyl or alkoxy radicals or phenyl or phenoxy radicals optionally substituted by halogen, lower alkyl or alkoxy groups, or the radical mean, where R4 and R5 can also together form a lower alkylenedioxy group with 1-4 carbon atoms, or in which X is the remainder represents, where R is a straight-chain or branched, saturated or unsaturated alkyl radical which can optionally be substituted by halogen, alkoxy, amino, carbamoyloxy, cycloalkyl, hydroxy or imido groups or a heterocyclic radical, a cycloalkyl, aryl, Aralkyl, aryloxyalkyl or arylthioalkyl radical, the aryl group in each case optionally substituted by halogen, an alkyl, alkoxy, hydroxy, amino, nitro, cyano, acyl, carbalkoxy, thioalkyl, alkylsulfonyl or phenyl or the trifluoromethyl radical can be substituted, or in which X is the radical where R1 represents hydrogen, nitrile, carbamoyl, a lower alkoxycarbonyl or acyl radical, a saturated or unsaturated cycloalkyl group, which can optionally be substituted one or more times by halogen, nitrile, aryl, aryloxycarbonyl, lower alkoxy, acyloxy, a lower alkoxycarbonyl group optionally substituted by a lower N, N-dialkylamino group, a lower alkyl group optionally substituted by a ureido, lower acylamino or acyloxy group, an amino group substituted by carbamoyl, alkoxycarbonyl or acyl or by the remainder can be substituted, or which is optionally condensed with phenyl or can contain a hydrocarbon bridge with 1-3 C atoms or an oxygen bridge, a radical a straight-chain or branched saturated or unsaturated alkyl radical with 2-18 carbon atoms, a straight-chain or branched, saturated or unsaturated hydrocarbon chain, which can be substituted one or more times by nitrile, halogen, nitro, aryl, aryloxy, aryl mercapto, an optionally substituted hetaryl mercapto group, a saturated or unsaturated cycloalkyl group which can optionally be bridged with 1-3 carbon atoms, an optionally N-alkylated carbamoyl group, a lower alkoxycarbonyl group optionally substituted by an N, N-dialkylamino group, an optionally N-alkylated sulfamoyl group, an optionally N-alkylated -alkylated carbamic acid group; a lower acyl, acyloxy, alkylsulphonyl or alkylsulphinyl group, or a lower alkyl mercapto or alkoxy group, optionally substituted by phenyl or the radical may be substituted, or an optionally substituted aromatic or non-aromatic heterocyclic radical, or the group or a lower dialkoxyphosphoryloxy or dialkoxyphosphonyl radical, or the radical or a group in which the radicals -A-R5 can be identical or different, A is a valence stroke, a carbonyl, thiocarbonyl or -CO-CH2 group and R5 is hydrogen, nitrile, aryl, a lower straight-chain or branched, saturated or unsaturated alkyl group , which optionally one or more times by halogen, aryl, a or -Rest can be substituted, a lower alkoxy group optionally substituted by aryl, a lower alkylmercapto, alkylsulfinyl or alkylsulfonyl group, one optionally substituted one or more times by phenyl, hetaryl, a lower alkyl, alkylsulfonyl, acylamidocarbimidoyl or acyl group Amino group, an N-methyleneamino radical substituted by an optionally substituted aromatic heterocycle, aryl or lower alkyl group, an aryl mercapto, arylsulfinyl or arylsulfonyl group, an aryloxy or a cycloalkyl group, or an optionally substituted aromatic or non-aromatic heterocycle meaning where the aryl in all of the groups mentioned, optionally one or more times by halogen, nitrile, nitro, sulfamoyl, an optionally N-alkylated carbamoyl, trifluoromethyl, phenyl, phenoxy, a methylenedioxy group, a lower alkyl, alkoxy, acyl group , Acyloxy, alkoxycarbonyl, alkyl mercapto, alkylsulfinyl, A Alkylsulfonyl, phenylsulfonyl, an amino group which is mono- or polysubstituted by alkyl, phenyl or acyl, or the remainder may be substituted, or R1 is an optionally substituted aromatic or non-aromatic heterocyclic radical, or R1 is an aryl radical which can be substituted one or more times by halogen, nitrile, trifluoromethyl, sulfamoyl; one optionally by halogen, alkyl, alkoxy or the rest substituted phenyl, phenoxy or phenylsulfonyl group, a methylenedioxy group, a lower alkyl group optionally substituted by carbamoyl, a lower alkoxycarbonyl, alkocy, acyloxy, N-alkylaminocarbonyloxy, N-alkoxycarbonylamino or N-acylamino group, a lower Alkoxy, acyl, acyloxy, alkylmercapto, alkoxycarbonyl, alkylsulfinyl or alkylsulfonyl group, an amino group substituted by alkyl, aryl, acyl, alkoxycarbonyl or an optionally substituted by alkyl or aryl radical, or an amino group optionally N-alkylated carbamoyl groups or the remainder or the rest is substituted, or X is the radical -S (O) n-R2, where n is the numbers 0 or 1 and R2 is a straight-chain or branched, saturated or unsaturated alkyl group which can optionally be substituted one or more times by halogen Cycloalkyl or an aryl or an optionally substituted hetaryl radical optionally substituted by phenyl, halogen, nitro, a lower alkyl, alkoxy, alkylmercapto or alkylsulfonyl group, or X is the radical -S02-R2 ', where R2' is an optionally N-alkylated amino group, a straight-chain or branched, saturated or unsaturated alkyl group which can optionally be substituted one or more times by halogen or an N-acylamino group, a cycloalkyl, a phenyl group substituted by alkoxy, phenoxy or phenyl, a naphthyl or denote an optionally substituted hetaryl radical or X denotes the radical where Z is oxygen or sulfur, R3 and R4, which can be the same or different, hydroxy, piperidino, snilino, N-alkoxycarbonyl-amino, phenyl, phenyloxy, a lower alkyl or alkoxy group / or the remainder or R3 and R4 together also represent a lower alkylenedioxy group1 or X represents a 3-camphorcarboxylic acid, alkietinic acid or 6-acetamidopenicillin carboxylic acid radical, all of the aromatic and non-aromatic heterocyclic radicals mentioned, where appropriate, one or more times by halogen, nitro, Phenyl, a lower acyl, acyloxy, alkyl, alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl or amino group which is substituted one or more times by alkyl, aryl or acyl, and the N-containing heterocycles are oxidized can, or in which X is a straight-chain or branched, saturated or unsaturated or mono- or polyunsaturated alkyl radical, which can optionally be substituted one or more times by halogen, alkoxy, hydroxy, dialkylamino, cycloalkylainino, acylamino, acyl, Mitro- , Alkyl mercapto, alkylsulphinyl, alkylsulphonyl, nitrile, carbalkoxy, carbamoyl, optionally substituted by alkyl, alkoxy or carbalkoxy cycloalkyl -, Cycloalkenyl groups, which can optionally be bridged, an aliphatic or aromatic heterocyclic radical, the aryl, aryloxy, arylthio, acyloxy, alkoxycarbonylamino or ureido group can be substituted, optionally by alkyl, alkoxy or Oxo groups, optionally interrupted by heteroatoms, cycloalkyl or cycloalkenyl radical with 3-10 carbon atoms, which can optionally be bridged with 1-3 carbon atoms, is intended to mean an aryl or retaryl radical, the aryl or hetaryl group in each case optionally by ralogen, a Alkoxy, alkyl, hydroxy, carbalkoxy, carbamoyl, dialkylamino, cycloalkylamino, acylamino, nitro, cyano, acyl, alkylmercapto, alkylsulfinyl, alkylsulfonyl, sulfamoyl, the phenyl, the Drifluoromethyl, aryloxy, acyloxy or methylenedioxy radical can be substituted and their pharmacological salts in the fight against radiation damage. 3. Use of 2- [2-cyanoaziridinyl- (1)] - 2- [2-carbamoylaziridinyl- (1) J-propane in combating radiation damage. In addition to an anti-tumor activity, 2-Cyånaziridines also show one immunostimulating effect (DE-OS 27 40 248, DE-OS 27 27 550, DE-OS 27 31 264, DE-OS 27 36 296, DE-OS 28 33 986). This immune stimulating effect takes place among other things its expression in the increase in lymphocyte transformation, an increase in Macrophage activity and an enhancement of the delayed-type hypertensivity response. Another feature of this new class of substances are those that stimulate the bone marrow Effects that manifest themselves, for example, in leukocytosis after application of 2- [2-cyanaziridinyl- (1) Show I-2- [2-carbamoylaziridinyl- (1)] propane in healthy animals. Furthermore it has been proven that the 2-cyanaziridines are able to reduce the toxicity of the Reduce cytostatic agent cyclophosphamide. It is known that rays of all kinds (X-rays or neutrons) damage the bone marrow particularly badly. So far, no substances were known that are able to remove the stem cells of the bone marrow that have been damaged by the radiation stimulate proliferation in order to reduce the damaging effects of the rays or eliminate. The damage to the bone marrow from the rays becomes apparent among other things in the leukopenias observed in the peripheral blood, i.e. the decline of white blood cells. It has now been found that these leukopenias are avoided or ameliorated if at the same time or after an otherwise damaging radiation therapeutically sufficient amounts of 2-cyanaziridines are applied, whereby the damage to the bone marrow is compensated.