• hepatoprotector
• in the treatment of liver diseases

• 1,2-dithiolane and 1,2-dithiols
  • Esters
    • Anilides and other derivatives of malonic acid

• It is known that there are a large number of patients who suffer from liver damages caused by various factors such as alcohol, malnutrition, viruses, chemicals, toxicants, etc. The liver diseases may generally be classified by their types into acute hepatitis, chronic hepatitis, liver cirrhosis, and fulminant hepatitis. It is said to be very difficult to treat these liver diseases. Namely, currently available methods for the treatment such as treatments with pharmaceuticals e.g. liver protective agents such as various vitamins, saccharides, amino acids, glutathione, glycyrrhizin, liver hydrolyzates or adrenocortical hormones; cholagogues; immunomodulaters; or antiviral substances against viral hepatitis, are all nothing more than symptomatic treatments, and they are not adequately effective for the treatment of the existing liver damages.
• [0003]
  It has recently been reported that 1,3-dithiol derivatives represented by Malotilate as identified below, are effective for the treatment of liver damages (see Japanese Examined Patent Publications No. 18,576/1981, No. 18,577/1981 and No. 18,578/1981).
• Other 1,3-dithiol derivatives similar to Malotilate with respect to structure and pharmaceutical properties are described in US-A-4,118,506, EP-A-99 329 and US-A-4,022,907.
• As a result of extensive researches, the present inventors have found that certain novel 1,3-dithiol derivatives represented by the after-mentioned formula I, exhibit excellent activities for the treatment of a wide spectrum of liver damages, which are comparable or superior to the above-mentioned conventional 1,3-dithiol derivatives. The present invention has been accomplished on the basis of this discovery.
• Namely, the present invention provides a 1,3-dithiol-2-ylidene derivative of the formula:

• 200 mg tablets

• DOS 2,545,569 (Nihon Nohyaku; appl. 10.10.1975; J-prior. 18.10.1974, 22.10.1974).
• US 4,035,387 (Nihon Nohyaku; 12.7.1977; J-prior. 18.10.1974, 22.10.1974).

1H NMR PREDICTIONS

WATCH OUT

13C NMR PREDICTIONS

References

• Bührer M, Le Cotonnec JY, Wermeille M, Bircher J (1986). “Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis”. Eur. J. Clin. Pharmacol. 30 (4): 407–16. doi:10.1007/BF00607952.PMID 3743616.
• Siegers CP, Pauli V, Korb G, Younes M (August 1986). “Hepatoprotection by malotilate against carbon tetrachloride-alcohol-induced liver fibrosis”. Agents Actions 18 (5–6): 600–3. doi:10.1007/BF01964970. PMID 3766314.
• Younes M, Siegers CP (May 1985). “Effect of malotilate on paracetamol-induced hepatotoxicity”. Toxicol. Lett. 25 (2): 143–6.doi:10.1016/0378-4274(85)90074-8. PMID 4002245.

Biological Activity of  Malotilate

Malotilate is a Liver Protein Metabolism Improved Compound, Which Selectively INHIBIT the 5-lipoxygenase. IC50 Value : Target : 5-lipoxygenase in vitro : In an in vitro assay using RAT Invasion lung endothelial (RLE) cells, Invasion of tumor cells Which HAD BEEN treated with MT (10 ng / ml, 24 h) was not affected; however, when RLE cells had been treated with MT, invasion was significantly inhibited in three cell lines (SAS, Ca9-22 and HSC-4) and a tendency to inhibition WAS Also Observed in other Cell lines [1]. in Vivo : The Improvement Rates for choline esterase Were Significantly Greater Activity in the malotilate group than in the Control group Levels Significantly Increased Serum albumin in the malotilate group BUT not in the Control group. [2]. In the rats treated with MT for 19 days after iv inoculation of c-SST-2 cells, lung metastasis was also significantly suppressed [3]. Malotilate prevented increases in serum markers of type III and IV collagen synthesis as well as accumulation of the collagens, laminin and fibronectin in the Liver [4]. Toxicity : Malotilate cytotoxicity to PBMCs, Assessed by trypan blue dye Exclusion and lactate dehydrogenase (LDH) Release into the Culture Media, WAS found to be markedly Increased by the Addition of the NADPH generating system, indicating that metabolites play a significant role in toxicity [5].

References on  Malotilate

[1] Shibata T, et al Inhibitory Effects of malotilate on in vitro Cell Invasion of lung endothelial monolayer by human oral squamous carcinoma cells Tumour Cell Biol 2000 Sep-Oct; 21 (5):….. 299-308 [2 ...] Takase S, et al Effects of treatment on malotilate Alcoholic Liver disease Alcohol 1989 May-Jun; 6 (3):. 219-22. [3] Nagayasu H, et al Inhibitory Effects of malotilate on Invasion and.. Metastasis of RAT mammary carcinoma cells by modifying the Functions of Vascular endothelial cells Br J Cancer 1998 May; 77 (9):.. 1371-7. [4] Ryhanen L, et al The Effect of malotilate on type III and type.. . IV collagen, laminin and fibronectin Liver Metabolism in dimethylnitrosamine-induced fibrosis in the RAT J Hepatol 1996 Feb; 24 (2):. 238-45. [5] Nomura F, et al Detection of malotilate Toxicity in vitro with Peripheral.. . blood mononuclear cells as targets A preliminary report J Hepatol 1990 Jul; 11 (1):.. 65-9.