Radioprotective Activity and Synthesis of Siladithioacetals and Germadithioacetals Derived from N-substituted Naphthylethylimidazoline

A number of organosilicon and organogermanium derivatives and some related compounds including the N-substituted. 2-[1-naphthylmethyl]-2-imidazoline and 2-[1-(1-naphthyl)ethyl]-2-imidazoline have been prepared and the toxicity of some compounds have been determined in mice. In this paper we report the synthesis and the evaluation of the pharmacological activity of new organosilicon and organogermanium, compounds such as sila- and germadithioacetals derived from N-substituted naphthylimidazolne.

To a stirred mixture of freshly distilled triethylamine (0.96 g, 9.5 retool) and l-(l-thioethyl)-2- [1-(1-naphthyl)ethyl]-2-imidazoline (2.70 g, 9.5 retool) in 30 ml of THF was added dropwise with stirring a solution of diisoamyldichlorosilane (1.28 g, 4.75 mmol) in 30 ml of THF. The reaction mixture was refluxed under an argon atmosphere for 5 hours. After filtration, the residue was concentrated under vacuum to give 8 (3.2 g, 88 %). Germadithioacetai 4 (method B) A solution of bis(diethylamino)diisoamylgermane (1.71 g, 4.75 mmol) in 30 ml of THF was added slowly with stirring to a solution of 1-(1-thioethyl)-2-[ l-(1-naphthyl)ethyl]-2-imidazoline (2.70 g, 9.5 mmol) in 30 ml of THF. The reaction mixture was refluxed under argon atmosphere for 5 hours. After cooling to room temperature, the volatile material was removed under vacuum to afford 4 (3.38 g, 91%). The physiochemical data and the analyses are reported in  Synthesis of selenodiazadiisoamyigermetane 14 Using the same experimental procedure as for the synthesis of 13, the reaction of dichlorodiisoamylgermane (3.13 g, 10.96 retool) in the presence of triethylamine (2.22 g, 21.92 retool)or bis(diethylamino)diisoamylgermane (3.93 g, 10.96 retool) with 1,3-bis(trimethylsilyl)selenourea (2.93 g, 10.96 retool) does not lead to 14 but afford only the selenagermaadamantane 15 (2.50 g, 87 %) as a yellow solid, and 1,3-bis(trimethylsilyl)carbodiimide. Synthesis of hexaselenatetrakis(isoamylgerma)adamantane 15 A solution of LiEt3BH (57.20 mmol in 57.2 ml of THF) was added dropwise to elemental selenium (2.26 g, 28.60 retool) via syringe. The mixture was stirred for hour at room temperature. A solution of trichloroisoamylgermane (4.77 g, 19.07 retool) in 25 ml of anhydrous THF was added at 0 C for hour. After the addition the reaction mixture was warmed to room temperature and stirred until the red colour of the selenium salt had disappeared (5 days). The solvent was removed in vacuo and the residue was extracted with toluene. After filtration and concentration the residue solid was crystallized from pentane to afford 15 (4.5 g, 90 %). To a stirred solution ofN-Boc 2-[1-(1-naphthyl)ethyl]-2-imidazoline (23.86 g, 74.00 mmol) in 150 ml of acetic acid was added dropwise a solution of chlorhydric acid (10 ml, 36%). The mixture was stirred at 40 C for 5 hours. The mixture was diluted with 400 ml of water and the aqueous layer was extracted with dichloromethane (4x150 ml). The organic layer was washed with a solution of NaOH (25 %). The organic layer was then dried over NazSO4. Evaporation of solvent in vacuo gave 16  Using the same experimental procedure as for the synthesis of 17, the reaction of 16 (3.66 g, 16.32 mmgl with propylene sulfide (1.29 ml, 16.40 mmol) leads to a yellow pasty product 18  To a stirred solution of selenourea (10 g, 81.29 mmol) and triethylamine (36 ml, 186.96 mmol) in 200 ml of THF was added dropwise a solution of chlorotrimethylsilane (20.6 ml, 81.29 mmol) in 50 ml of THF. The reaction mixture was refluxed under an argon atmosphere for 8 hours. After filtration, the residue was concentrated in vacuo to afford 19 (18.47 g, 85 %). mp: 146-148 C (dec.).

Pharmacology: evaluation of radioprotection
Threemonth-old male mice (Swiss, France), 25 g body weight, were used. The radioprotective effect of compounds was evaluated by determining the dose reduction factor (DRF), defined as the ratio of 50% lethal-dose irradiation 30 days (LDs0/30 days) of injected mice to that of control mice. Initially the survival rate was determined 30 days after irradiation in different groups of 10 mice receiving an intraperitoneal (i.p.) injection of the test compound with a dose equal to half or one-eighth of its LDso 15 or 90 rain before whole-body irradiation delivered with a dose equal to the LDoo/30 days of control mice (7.5, 7.75 or 8 Gy according to the irradiation date), or with a dose equal to this dose + 2 Gy. When necessary, other irradiation doses were tested in order to evaluate the irradiation LD_o of protected mice by the Kraber method (calculated or graphic). [19] The radiosensitivity of the strain was regularly monitored by the determination of lethality curves of males and females. The LD0/30 days was between 6.5 + 0.3 and 6.75 + 0.3 Gy according to the date (P < 0.05). Under these conditions significant protection was observed with a DRF value superior to 1.15.
The toxicity was evaluated by a Probit analysis of the LD0, [20][21] the dose range being determined in a preliminary study. Five groups of ten mice were then injected with different doses within this range.

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Radioprotective Activity ad Synthesis of Siladithioacetals and Germadithio Acetals Deri ed from N-Substituted Napthylethylemidazoline Using the same procedures described above, the reaction between bis(diethylamino)diisoamylgermane or dichlorodiisoamylgermane and 1,3-bis(trimethylsilyl)selenourea does not lead to stable heterocycle but gives only the selenagermaadamantane 15   Reaction mechanism The formation of the selenagermaadamantane may be explained by two ways as follows (Scheme 6). Synthesis of 1,3-bis(trimethylsilyi)selenourea 19 The reaction between equimolar amounts of selenourea and chlorotrimethylsilane in the presence of triethylamine in anhydrous refluxing tetrahydrofuran gives 19 (Scheme 10) in yield of 85 %.   The 2-[1-(l-naphthyl)ethyl]-2-imidazoline (NEI) compounds seems to be less toxic than their 2-(lnaphthyimethyl)-2-imidazoline (NMI) homologous. For example, NEI (16) show a two times lower molar toxicity than NMI. The lower toxicity of organometallic compounds compared with basic materials is confirmed by comparison between the toxicity of 13 and 19. Indeed compound 13 is eight times less toxic (LD.o > 600 mg/Kg) than the starting derivative 19 (LDs0 > 75 mg/Kg). This means that the organogermanium compound 13 have a toxicity four times lower than 19 one (expressed in mol fractions).
The results of the radioprotective activity will be reported at a later date.
Radioprotective Activity ad Synthesis of Siladithioacetals and Germadithio A cetals Derived from N-Substituted Napthylethylemidazoline