Process for the preparation of diorganotrisulfide

Details Process for the preparation of diorganotrisulfide Process for the preparation of diorganotrisulfide

2001-03-28

2003-04-29

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfur containing

C568S023000, C568S025000

Reexamination Certificate

active

06555712

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of diorganotrisulfides, a class of compounds having proven and potential bioactivity. The invention particularly relates to a catalytic process of preparing diorganotrisulfides in general, and diallyltrisulfides, in particular, from the reaction of elemental sulfur and organic halides in the presence of catalytic copper (II) halide and tin (II) chloride in a mixture of organic solvents.
BACKGROUND OF THE INVENTION
Garlic (
Allium Sativum
) has been used for more than 400 years in traditional medicine against cardiovascular diseases, cancer and various infections. A major sulfur component of fresh garlic is allin (S-2-propenyl-L-Cysteine-S-oxide) which is converted into allicin (diallyl thiosulfinate) upon softening of the bulb. Allicin, upon isolation, is spontaneously degraded to two major compounds, namely Ajoene (4,5,9-triihiadodeca-1,6,11-triene-9-oxide) and diallyltrisulfide (DATS). Extensive research has shown that both these compounds show very high bioactivity [S Fukushima, N Takada, T Hori & H Wanibuchi. J Cell Biochem. Suppl., 27. pp. 100-5 (1997)].
Diallyltrisulfide (DATS) is a highly bioactive agent and is domestically marketed in China since 1981, by the name DASUANSU, for treatment of bacterial, fungal and parasitic infections in man. Recent research has conclusively proved its bioefficacy. For example, the activity of DATS was investigated in several important protozoan parasites in vitro [Z.R. Lun, C. Burri, M. Menzinger & R. Kaminsky. Ann. Soc. Belg. Med. Trop., 74:1 pp. 51-9 (1994)]. The IC50 (concentration which inhibits metabolism or growth of parasites by 50%) for
Trypanosoma brucei brucei, T.b. rhodesiense, T.b. gambiense, T. evansi, T. congolense
and
T. equiperdum
was in the range of 0.8-5.5 micrograms/ml. IC50 values were 59 micrograms/ml for
Entamoeba histolytica
and 14 micrograms/ml for
Giardia Lamblia
. The cytotoxicity of the compound was evaluated on two fibroblast cell lines (MASEF,
Mastomys natalensis
embryo fibroblast and HEFL-12, human embryo fibroblast) in vitro. The maximum tolerated concentration for both cell lines was 25 micrograms/ml. The results indicate that DATS has potential to be used for treatment of several human and animal parasitic diseases. Inhibition of whole blood platelet-aggregation by DATS, present in the steam-distilled component of garlic extract was also found to be high [L. D. Lawson, D. K. Ransom & B. G. Hughes. Thromb. Res., 65:2. Pp. 141-56 (1992)]. Oil-soluble organosulfur compounds from Garlic, notably DATS, markedly inhibits the growth of canine mammary tumor cells (CMT-13). The inhibitory effect was also found to be modified by intracellular glutathione [S. G. Sundaram & J. A. Milber. Cancer Lett., 74:1-2, pp. 85-90 (1993)]. Results from the in-vitro study of antiproliferative effects of DATS on cultured human neoplastic (A549) and nonneoplastic (MRC-5) lung cells is quite encouraging [K Sakamoto, L. D. Lawson & J. A. Milber. Nutr. Cancer, 29:2, pp. 152-6 (1997)]. Addition of 10 micromolar Data reduced A549 growth by 47%. DATS treatment (10 microM) did not alter MRC-5 cell growth. DATS (10 microM) caused a marked and progressive increase in intracellular Ca
2+
in A549 cells during the first four hours after treatment. Intracellular Ca
2+
in A549 cells exposed to DATS returned to near control levels within one hour after refeeding the medium without DATS. Exposure to 1 microM DATS for 24 hours significantly induced apoptosis, as indicated by increased DNA fragmentation. The ability of DATS to suppress neoplastic growth is consistent with increasing evidence that several garlic components have anticarcinogenic and antitumorigenic properties. Studies on the effect of DATS on the activation of T cell and macrophage-mediated cytotoxicity suggest that DATS may be potentially useful in tumor therapy [Z. H. Feng, G. M. Zhang, T. L. Hao, B. Zhou, H. Zhang & Z. Y. Jiang, J. Tongji Med. Uni., 14;3 pp. 142-7 (1994)]. At high concentration (50 micrograms/ml), DATS had an inhibitory effect on T cell activation. But at appropriate concentrations (3.125-12.5 micrograms/ml), DATS augmented the activation of T lymphocytes by Con A. The augmentation of T cell activation by DATS was related to its inhibitory effect on the production of nitric oxide (NO) by macrophages. In a wide range of concentrations (1-100 micrograms/ml), DATS can inhibit the production of NO by macrophages. In addition, DATS can antagonize the inhibition of tumor derived immunosuppressive factors produced by S180 cells and Ehrlich ascitic cancer cells on the activation of T cells, and reduce the inhibitory rate significantly. DATS, despite its inhibition of the production of NO by macrophages, can also enhance the production of hydrogen peroxide (H
2
O
2
) by macrophages. DATS and related sulfides were also tested against
Sitophilus zeamais
(Motschulsky) and
Tribolium castaneum
(Herbst) for contact toxicity, fumigant toxicity, and antifeedant activity [Y. Huang, S. X. Chen & S. H. Ho., J. Econ. Entomol., 93:2 pp. 537-43 (2000)]. For adults of these two species of insects, the contact and fumigant toxicities of DATS was greater than that of methylallyl disulfide. These two compounds were also more toxic to
T. castaneum
adults than to
S. Zeamais
adults. Older
T. castaneum
larvae were more susceptible to the contact toxicity of the two compounds, whereas younger larvae were more susceptible to the fumigant toxicity of these compounds. Both compounds reduced egg hatching of
T. castaneum
and subsequent emergence of progeny. DATS totally suppressed egg hatching at 0.32 mg/ck2, and larval and adult emergence at 0.08 mg/cm2. Methylallyl disulfide significantly decreased the growth rate, food consumption, and food utilization of adults of both insect species, with feeding deterrence indices of 44% at 6.08 mg/g food for
S. zeamais
and 1.52 mg/g food for
T. castaneum
. However, it did not affect any nutritional indices of
T. castaneum
larvae. On the other hand DATS significantly reduced all of the nutritional indices in all of the insects tested. Feeding deterrence indices of 27 and 51% were obtained in
S. zeamais
adults and
T. castaneum
larvae, respectively, at the concentration of 2.98 mg/g food, whereas feeding deterrence of 85% was achieved in
T. castaneum
adults at a much lower concentration of 0.75 mg/g food. Hence, DATS is a more potent contact toxicant, fumigant and feeding deterrent than methylallyl disulfide. Finally, the spermicidal effect of some of the active principles of Garlic was found to be quite positive [Y. X. Qian, P. J. Shen, R. Y. Xu, G. M. Liu, H. Q. Yang, Y. S. Lu, P. Sun, R. W. Zhang, L. M. Qi & Q. H. Lu, Contraception. 34:3. Pp. 295-302 (1986). The inhibition of sperm motility was found to be concentration dependent and range from 20 seconds 200 minutes.
In spite of their importance, a straight forward, high yielding, catalytic and cost effective process for the preparation of diorganotrisulfide in general and diallyltrisulfide (DATS), in particular is yet to achieve. One of the most common preparative route for diorganotrisulfides involves the reaction of highly corrosive sulfur dichloride (s2Cl2) with organothiol at 0° C. [D. N. Harpp & R. A. Smith. J. Org. Chem., 44 pp. 4140 (1979); G. Derbesy & D. N. Harpp. Tetrahedron Lett., 35 pp. 5381 (1994)]. A major disadvantage of the process is the formation of by product such as disulfide, tetrasulfide. The shelf life of sulfurdichloride is very limited as a result of its tendency to decompose to element sulfur, chlorine gas and series of homologous sulfur dichlorides [D. N. Harpp., K. Steliou & T. H. Chan. J. Am. Chem. Soc., 100 pp. 1222 (1978); Q. E. Thompson. J. Org. Chem., 30. Pp. 2703 (1965)], which in turn leads to the formation of diorganopolysulfides and requiring multistage distillation for purification prior to every process. Notwithstanding the said difficulties, the m

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