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Advanced Intermediate Flow Studies: Nevirapine
After looking through a number of flow articles that describe and illustrate processes toward the production of drug final products and advanced intermediates, I thought an article from Florida State — Tyler McQuade (open source Beilstein JOC 2013) was informative and storytelling. He was able to show some of the challenges that go into designing a flow methodology around process that have already been worked out in batch mode, and had been looked at in a number of labs already.
Before talking about the chemistry, Professor McQuade talks about a number of concerns in transferring technology from batch to flow: DOE, solvent exchange (precipitation and moving from one reaction to another), Cost of Goods Analysis – reaction concentrations, solvent costs, process time, by-product formation and purification. There certainly is a lot that goes into the strategy. To give you the framework: this group was looking to make a continuous process…
View original post 247 more words
System Suitability for USP Chromatographic Methods
System Suitability for USP Chromatographic Methods
How should system suitability tests (SSTs) be structured for USP monographs? More about USP experts group’s recommendations on the parameters and acceptance criteria for SSTs and the essential aspects of this new approach can be found in this News.
read
An interesting article from the USP experts group “Small Molecules” has been published in the Pharmacopoeial Forum 39(5). It deals with USP’s future requirements regarding system suitability tests (SST).
SSTs are performed each time an analytical method is used. Together with instruments qualification and methods validation, the SST ensures the quality of analytical test results. The SST shows that a procedure and an instrumental system are performing as they did when the procedure was validated and that the method is thus “fit for purpose” for the intended use.
General requirements can be found in the USP Chapter <621> Chromatography which also contains provisions and acceptance…
View original post 116 more words
The U.S. Food and Drug Administration approved Ofev (nintedanib) for the treatment of idiopathic pulmonary fibrosis (IPF).
Nintedanib
FDA approves Ofev to treat idiopathic pulmonary fibrosis
10/15/2014
The U.S. Food and Drug Administration today approved Ofev (nintedanib) for the treatment of idiopathic pulmonary fibrosis (IPF).
read at
see synthesis
https://newdrugapprovals.org/2014/05/21/in-battle-of-ipf-drugs-bis-nintedanib-impresses/
FDA approves Esbriet (pirfenidone ピルフェニドン 吡非尼酮) to treat idiopathic pulmonary fibrosis
The U.S. Food and Drug Administration today approved Esbriet (pirfenidone)
ピルフェニドン 吡非尼酮
for the treatment of idiopathic pulmonary fibrosis (IPF).
read at
SYNTHESIS
Click for synthesis
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US priority review for Eisai cancer drug lenvatinib
US priority review for Eisai cancer drug lenvatinib
Eisai has been boosted by news that regulators in the USA have agreed to a quicker review of its anticancer agent lenvatinib.
The US Food and Drug Administration has granted a priority review to Eisai’s New Drug Application for lenvatinib as a treatment for progressive radioiodine-refractory differentiated thyroid cancer. This means that the agency has assigned a Prescription Drug User Fee Act action date of April 14 next year, eight months after the NDA was submitted.
Read more at: http://www.pharmatimes.com/Article/14-10-15/US_priority_review_for_Eisai_cancer_drug_lenvatinib.aspx#ixzz3GH3iXiDU
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Final Concept Paper ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Final Concept Paper ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Currently, there are no harmonised approaches to technical and regulatory considerations for the lifecycle management of pharmaceutical products. Therefore, ICH has just published a Final Concept Paper for a new ICH Q12 Guideline: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle. The proposed ICH Guideline is intended to fill this gap. read
ICH has just published a Final Concept Paper for a new ICH Q12 guideline: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle.
Currently, there is a lack of a harmonised approach to technical and regulatory considerations for the lifecycle management of pharmaceutical products. Although there are concepts in ICH Q8, Q9, Q10 and Q11 for a more science and risk-based approach for assessing changes across the lifecycle, several gaps exist which hinder a full realization of the benefits intended. The original aim of ‘operational flexibility’…
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MALOTILATE, Malotilat
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
| Systematic (IUPAC) name | |
|---|---|
| diisopropyl 1,3-dithiol-2-ylidenemalonate | |
| Clinical data | |
| AHFS/Drugs.com | International Drug Names |
| Legal status |
|
| Routes | Oral |
| Identifiers | |
| CAS number | 59937-28-9 |
| ATC code | None |
| PubChem | CID 4006 |
| UNII | RV59PND975  |
| 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).
-
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.
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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:
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
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].
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.
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