New Drug Approvals

Home » GENERIC DRUG » MALOTILATE, Malotilat

MALOTILATE, Malotilat

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Recent Posts

Blog Stats

  • 3,719,611 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,674 other followers

add to any

Share

Malotilate.png

 Malotilate, Malotilat

(Kantec; Hepation; NKK 105)

Diisopropyl 1,3-dithiol-2-ylidenemalonate

Nihon Nohyaku Co., Ltd.  innovator

Malotilate (INN) is a drug used in the treatment of liver disease. It has been shown to facilitate liver regeneration in rats.[1]

DA-3857
NKK-105

CAS  59937-28-9
Name: 1,3-Dithiol-2-ylidenepropanedioic acid bis(1-methylethyl) ester
Additional Names: diisopropyl 1,3-dithiol-2-ylidenemalonate
Manufacturers’ Codes: NKK-105
Trademarks: Hepation (Nippon Chemiphar); Kantec (Daiichi)
Molecular Formula: C12H16O4S2
Molecular Weight: 288.38
Percent Composition: C 49.98%, H 5.59%, O 22.19%, S 22.24%
Properties: Pale yellow crystals, mp 60.5°. Sol in benzene, cyclohexane, n-hexane, ether.
Melting point: mp 60.5°
Therap-Cat: Hepatoprotectant.
Systematic (IUPAC) name
diisopropyl 1,3-dithiol-2-ylidenemalonate
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
  • Prescription only
Routes Oral
Identifiers
CAS number 59937-28-9 
ATC code None
PubChem CID 4006
UNII RV59PND975 Yes
Chemical data
Formula C12H16O4S2 
Mol. mass 288.38 g/mol

Brief background information

Salt ATC Formula MM CAS
A02AD02 C 12 H 16 O 4 S 2 288.39 g / mol 59937-28-9

Application

  • hepatoprotector
  • in the treatment of liver diseases

Classes of substances

  • 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.
  • 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).

    Figure imgb0001
  • 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:

    Figure imgb0002

 

Synthesis pathway

Synthesis a)



………………

US 4327223

http://www.google.co.in/patents/US4327223

EXAMPLE 1

Diisopropoxycarbonylketene disodium mercaptide crystals (8 g, 0.02 mol) was dissolved in 50 ml of dimethylsulfoxide, and 1,1,1-trichloroethane (2.7 g, 0.02 mol) and subsequently a 30% sodium hydroxide aqueous solution (2.7 g, 0.02 mol NaOH) were added thereto. Thus, reaction was carried out at 60° C. for 1 hour. The resulting mixture was poured into ice-water, and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 2.6 g of the object matter diisopropyl 1,3-dithiol-2-ylidene malonate; m.p. 60.5° C., yield 45%.

EXAMPLE 2

Diisopropyl malonate (18.8 g, 0.1 mol) and carbon disulfide (7.6 g, 0.1 mol) were dissolved in 200 ml of dimethylsulfoxide. Dropping thereto a 45% potassium hydroxide aqueous solution (31 g, 0.25 mol KOH) at 13°-17° C., gave a yellowish red solution containing diisopropoxycarbonylketene dipotassium mercaptide. At 20° C., 1,1,1-trichloroethane (26.6 g, 0.2 mol) was added, and 5 minutes after a 45% potassium hydroxide aqueous solution (18.6 g, 0.15 mol KOH) was dropped thereinto. The temperature was raised to 70° C. to carry out reaction for 30 minutes. The resulting mixture was poured into ice-water and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 23.6 g of the object matter diisopropyl 1,3-dithiol-2-ylidene malonate; m.p. 60.5° C., yield 82.1%.

EXAMPLE 3

Diisopropyl malonate (18.8 g, 0.1 mol) and carbon disulfide (7.6 g, 0.1 mol) were dissolved in 200 ml of dimethylsulfoxide. A 45% potassium hydroxide aqueous solution (49.6 g, 0.4 mol KOH) was dropped thereto at 15° C., then 1,1,1-trichloroethane (13.3 g, 0.1 mol) was added at 20° C., and reaction was carried out at 70° C. for 30 minutes. The resulting mixture was poured into ice-water and then extracted with benzene. Drying of the extract over anhydrous magnesium sulfate, distillation to remove benzene, and recrystallization from n-hexane gave 18.1 g of the object matter diisopropyl 1,3-diethiol-2-ylidene malonate; m.p. 60.5° C., yield 62.8%.

 

………………………………….

US 4035387

http://www.google.co.in/patents/US4035387

Example 1Synthesis of diisopropyl 1,3-dithiol-2-ylidene malonate (the compound 3)

1.1 Grams (0.03 mole) of 69% purity sodium hydride was suspended in 30 ml. of dry tetrahydrofuran. Into the resulting suspension, 5.6g (0.03 mole) of diisopropyl malonate was gradually dropped with ice-cooling. After completion of the generation of hydrogen gas, 8.2g (0.03 mole) of 2-methylthio-1,3-dithiolium iodide was added. The resulting mixture was heated under reflux for 1 hour, and then the reaction product was poured into a large amount of ice water to deposit crystals. The crystals were recovered by filtration, dried and then recrystallized from n-hexane to obtain 6.7g of white crystals, m.p. 59°-60° C., yield 77.5% .

The 2-methylthio-1,3-dithiolium iodide used as starting material was synthesized in the following manner;

44.4 Grams (0.2 mole) of 1,3-dithiol-2-thion-4,5-dicarboxylic acid was dissolved in 240 ml of nitromethane, and the resulting solution was heated to 80° C. Into this solution, 100 ml of iodomethyl was gradually dropped, and the resulting mixture was refluxed for 6 hours. After completion of the reaction, the formed crystals were recovered by filtration, washed with 100 ml of ether and then air-dried to obtain 48.4g of the desired compound, m.p. 114°-116° C. (decomp.), yield 87.0%.

 

………………………………………..

Fujinami, T.; et al.   The preparation of cyclic dithia and thiaza compounds by the reaction of potassium carbonate with heterocumulenes and alkylene dibromides or carbonate catalyzed by organostannyl compounds
Bull Chem Soc Jpn 1982, 55(4): 1174

 https://www.jstage.jst.go.jp/article/bcsj1926/55/4/55_4_1174/_pdf

 

…………………………………….

Trade Names

Country Trade name Manufacturer
Japan Kantek Daiichi
Ukraine No No

Formulations

  • 200 mg tablets

Links

  • 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

 

Literature References: Prepn from diisopropyl malonate: K. Taninaka et al., DE 2545569; eidem, US 4035387 (1976, 1977 both to Nihon Nohyaku); from the corresponding ketene mercaptide: H. Matsui et al., US 4327223 (1982 to Nihon Nohyaku). Effect on CCl4-induced liver injury in rats: Y. Imaizumi et al., Jpn. J. Pharmacol. 31, 15 (1981). Enhancement of rat liver protein synthesis:eidem, ibid. 32, 369 (1982). Pharmacokinetics and pharmacodynamics: M. Buhrer et al., Eur. J. Clin. Pharmacol. 30, 407 (1986). Clinical evaluation in liver cirrhosis: S. Takase et al., Gastroenterol. Jpn. 23, 639 (1988).

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.
  • Mayer, R.; et al.Synthesis of 1,3-dithiol-2-thiones (‘ Isotrithione’)
    Angew Chem Int Ed 1964, 76(3): 143
  • O’Connor, B.R.; Jones, F.N.Reactions of ethylene di- and trithiocarbonates with acetylenes. Anomalous reaction with bromocyanoacetylene to give a thioacyl bromide
    J Org Chem 1970, 35(6): 2002
  • Fujinami, T.; et al.   The preparation of cyclic dithia and thiaza compounds by the reaction of potassium carbonate with heterocumulenes and alkylene dibromides or carbonate catalyzed by organostannyl compounds
    Bull Chem Soc Jpn 1982, 55(4): 1174

 

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].

[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.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,674 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: