Levamisole CAS 14769-73-4

Introduction：Basic information about Levamisole CAS 14769-73-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Levamisole Basic information

• Product Name: Levamisole
• Synonyms: L-6-PHENYL-2,3,5,6-TETRAHYDROIMIDAZOL(2,1-B) THIAZOLE;IMMUNOPURE(R) PHOSPHATASE SUPPRESSOR;LEVAMISOLE;LEVAMISOLE BASE;(s)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole;lepuron;levomysol;l-tetramisole
• CAS: 14769-73-4
• MF: C11H12N2S
• MW: 204.29
• EINECS: 238-836-5
• Product Categories: 14769-73-4
• Mol File: 14769-73-4.mol

Levamisole Chemical Properties

• Melting point: 60-61.5°
• alpha: D25 -85.1° (c = 10 in chloroform)
• Boiling point: 344.4±45.0 °C(Predicted)
• density: 1.32±0.1 g/cm3(Predicted)
• storage temp.: Sealed in dry,2-8°C
• solubility: Chloroform (Slightly), Methanol (Slightly)
• pka: 10.00±0.40(Predicted)
• form: Solid
• color: Off-White to Pale Yellow
• InChI: InChI=1S/C11H12N2S/c1-2-4-9(5-3-1)10-8-13-6-7-14-11(13)12-10/h1-5,10H,6-8H2/t10-/m1/s1
• InChIKey: HLFSDGLLUJUHTE-SNVBAGLBSA-N
• SMILES: S1CCN2C[C@H](C3=CC=CC=C3)N=C12
• CAS DataBase Reference: 14769-73-4(CAS DataBase Reference)
• EPA Substance Registry System: Levamisole (14769-73-4)

Levamisole Usage And Synthesis

Pharmacology and mechanism of action

Levamisole is the L-isomer of tetramisole and is more active than the racemic mixture. It was introduced in 1966 as a veterinary drug and a little later as a human anthelminthic drug against ascariasis. The drug has also shown to be effective against hookworms (Ancylostoma duodenale and Necator americanus), but results of reported studies are inconsistent ^[1]. The mechanism of action of levamisole in helminthiasis is through its stimulation of autonomic ganglia (nicotinic receptors) of the worms. On exposure to the drug, immature and adult worms show spastic contraction followed by tonic paralysis. This mechanism seems to be common to other anthelminthics such as pyrantel and bephenium hydroxynaphthoate ^[2]. In higher doses, levamisole acts as an immunostimulant. It restores depressed cell-mediated immune mechanisms in peripheral T-lymphocytes, but may have marginal effects in immunologically competent individuals ^[3]. The clinical implication of this effect in the treatment of helminthiasis is unknown.

Indications

Monoinfections with Ascaris lumbricoides. In polyinfections, mebendazole is the drug of choice.

Side effects

During the treatment of nematode infections the drug produces minor side effects including nausea, vomiting, abdominal pain and headache ^{[4, 5]}. During prolonged treatment as an immunomodulator in rheumatic arthritis and in cancer patients, serious side effects such as blood disorders (agranulocytosis, neutropenia and thrombocytopenia), kidney damage, influenza-like reactions, vasculitis, photosensitivity and allergy to the drug have been reported ^{[6, 7]}.

Contraindications and precautions

The drug should be avoided in patients allergic to the drug. Administration of levamisole may provoke a reaction similar to that seen after intake of alcohol together with disulfiram. During long-term treatment, patients with kidney damage or with blood disorders may experience exacerbation of their diseases.

Interactions

Levamisole has been reported to displace the protein binding of rifampicin in vitro ^[8]. The clinical significance of this is as yet unknown.

References

1. Miller MJ (1980). Use of levamisole in parasitic infections. Drugs, 19, 122–130.
2. van Wauwe J, Janssen PAJ (1991). On the biochemical mode of action of levamisole: an update. Int J Immunopharmacol, 13, 3–9.
3. Renoux G (1980). The general immunopharmacology of levamisole. Drugs, 19, 89–99.
4. Lionel ND, Mirando EH, Nanayakkara JC, Soysa PE (1969). Levamisole in the treatment of ascariasis in children. BMJ, 4, 340–341.
5. Farid Z, Bassily S, Miner WF, Hassan A, Laughli LW (1977). Comparative single-dose treatment of hookworm and roundworm infections with levamisole, pyrantel and bephenium. J Trop Med Hyg, 80, 107–108.
6. Chrisp P, McTavish D (1991). Levamisole/fluorouracil: A review of their pharmacology and adjuvant therapeutic use in colorectal cancer. Drugs & Aging, 14, 317–337.
7. Amery WK, Butterworth BS (1983) The dosage regimen of levamisole in cancer: is it related to efficacy and safety Int J Immunopharmacol, 5, 1–9.
8. Pérez-Gallardo L, Blanco ML, Soria H, Escanero JF (1992). Displacement of rifampicin bound to serum proteins by addition of levamisole. Biomed Pharmacother, 46, 173–174.

Originator

Solaskil,Specia,France,1971

Uses

Levamisole is used for initial and secondary immunodeficient conditions, autoimmunediseases, chronic and reoccurring infections, large intestine adenocarcinoma, helmintosis,and rheumatoid arthritis. Synonyms of this drug are decaris, tetramizole, and others.
Levimasole is also a drug of choice for ascardiasis. Numerous investigations show that asingle dose of levamisole heals from 90 to 100% of patients with ascardiasis, in particularthose infected with A. duodenale. It is less effective against ancylostomiasis and strongyloidiasis. However, it is not effective against N. americanus. It seems likely that it has agangliostimulating effect on parasite tissues in both the parasympathetic and sympatheticregions. Moreover, it is presumed that this drug has an immunomodulatory effect on thehost organism. Synonyms of this drug are decaris, solacil, ergamisol, tramisol, immunol,and others.

Uses

Biological response modifier.

Definition

ChEBI: Levamisole is a 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole that has S configuration. It is used (generally as the monohydrochloride salt) to treat parasitic worm infections in pigs, sheep and cattle and was formerly used in humans as an adjuvant to chemotherapy for the treatment of various cancers. It is also widely used as an adulterant to coccaine. It has a role as an antinematodal drug, an antirheumatic drug, an immunomodulator, an immunological adjuvant and an EC 3.1.3.1 (alkaline phosphatase) inhibitor. It is an enantiomer of a dexamisole.

Indications

Levamisole (Ergamisol) is an antiparasitic drug that hasbeen found to enhance T-cell function and cellular immunity.The drug improves survival of patients with resectedcolorectal cancers when combined with 5-fluorouracil;the mechanism of this interaction is notknown. Levamisole does not have antitumor activityagainst established or metastatic cancer and has notbeen found useful in the adjuvant therapy of cancersother than colorectal cancer.
The major adverse effects of levamisole are nauseaand anorexia. Skin rashes, itching, flulike symptoms, andfevers also have been observed.

Indications

Levamisole (Ergamisol) was originally developed as anantihelminthic drug. It potentiates thestimulatory effects of antigens, mitogens, lymphokines,and chemotactic factors on lymphocytes, granulocytes,and macrophages. It has been shown to increase Tcell–mediated immunity.
Levamisole has been used successfully in treatingchronic infections. It also has been approved for use incombination with fluorouracil in the treatment of colorectalcancer.

Brand name

Ergamisol (Janssen).

Therapeutic Function

Antiinflammatory

Antimicrobial activity

Its principal activity is against Asc. lumbricoides and hookworms. Worms are paralyzed and passedout in the feces within a few hours.

Pharmaceutical Applications

The l-isomer of tetramisole, available as the monohydrochloride.The d-isomer has no anthelmintic activity. It is very solublein water and is stable in the dry state.

Mechanism of action

Levamisole has immunomodulating activity. It is believed that it regulates cellular mechanisms of the immune system, and the mechanism of its action may be associated withactivation and proliferative growth of T-lymphocytes, increased numbers of monocytes andactivation of macrophages, and also with increased activity and hemotaxis of neutrophylicgranulocytes. Levamisole also exhibits anthelmint action. It also increases the body’s overall resistivity and restores altered T-lymphocyte and phagocyte function. It can also fulfillan immunomodulatory function by strengthening the weak reaction of cellular immunity,weakening strong reaction, and having no effect on normal reaction.

Pharmacokinetics

Oral absorption: c. 90%
C_max 150 mg oral: 0.5 mg/L after c. 2 h
Plasma half-life: c. 4 h
Volume of distribution: 100–120 L
Levamisole is rapidly absorbed from the gut and extensivelymetabolized in the liver. It is excreted chiefly in the urine.

Clinical Use

Ascariasis
Hookworm infection
Levamisole has been used in rheumatoid arthritis and someother conditions that are said to respond to its immunomodulatoryactivity.

Side effects

Nausea, gastrointestinal upsets and very mild neurologicalproblems have been reported.

Synthesis

Levamisole, 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole (31.1.4), is synthesized in various ways. One of them begins with α-bromoacetophenone, the reaction of which with 2-imino-1,3-thiazolidine gives 3-phenacyl-2-imino-1,3-thiazolidine (31.1.1). Reacting this product with acetic anhydride gives 3-phenacyl-2-acetylimino-1,3- thiazolidine (31.1.2). The ketone group in the resulting compound is reduced to an alcohol using sodium borohydride, and the resulting hydroxyl group in (31.1.3) is replaced with chlorine using thionyl chloride. Heating the product in acetic anhydride, the imidazole cycle closes, forming the product (31.1.4).

A somewhat different approach was realized when using styrene oxide as the initial starting material. Reacting it with 2-imino-1,3-thiazolidine gives 3-(2-phenyl-2-hydroxyethyl)- 2-imino-1,3-thiazolidine (31.1.5), which is subsequently treated with thionyl chloride and then acetic anhydride to give the desired levamisole (31.1.4).
Finally, the following scheme of making the product has been proposed using the same styrene oxide. Styrene oxide is reacted with aziridine, forming 2-aziridion-1- phenylethanol-1 (31.1.6). Treating this with potassium isothiocyanate or thiourea gives 3- (2-phenyl-2-hydroxyethyl)-2-amino-1,3-thiazolidine (31.1.5), and subsequent treatment with thionyl chloride (such as described above) and then with acetic anhydride gives the desired levamisole (31.1.4).

Veterinary Drugs and Treatments

Depending on the product licensed, levamisole is indicated for thetreatment of many nematodes in cattle, sheep and goats, swine,poultry. In sheep and cattle, levamisole has relatively good activityagainst abomasal nematodes, small intestinal nematodes (notparticularly good against Strongyloides spp.), large intestinal nematodes(not Trichuris spp.), and lungworms. Adult forms of speciesthat are usually covered by levamisole, include: Haemonchus spp.,Trichostrongylus spp., Osteragia spp., Cooperia spp., Nematodirusspp., Bunostomum spp., Oesophagostomum spp., Chabertia spp., andDictyocaulus vivapurus. Levamisole is less effective against the immatureforms of these parasites, and is generally ineffective in cattle(but not sheep) against arrested larval forms. Resistance of parasitesto levamisole is a growing concern.
In swine, levamisole is indicated for the treatment of Ascarissuum, Oesophagostomum spp., Strongyloides, Stephanurus, andMetastrongylus.
Levamisole has been used in dogs as a microfilaricide to treatDirofilaria immitis infection in the past, but is rarely used today.It has also garnered some interest as an immunostimulant in theadjunctive therapy of various neoplasms.
Because of its narrow margin for safety and limited efficacyagainst many equine parasites, levamisoleis not generally used inhorses as an antiparasitic agent. It has been tried as an immunestimulant, however.

References

[1] Tetrahedron Asymmetry, 2002, vol. 13, # 13, p. 1429 - 1434
[2] Ultrasonics Sonochemistry, 2016, vol. 32, p. 8 - 17

Levamisole Preparation Products And Raw materials

• Raw materials: Dimethyl sulfoxide-->Tosyl chloride-->L-Glutamic acid-->Hydrochloric acid-->Sodium hydroxide-->1,2-Dibromoethane-->Potassium hydroxide-->tetramisole-->Dichloromethane-->Water
• Preparation Products: Levamisole hydrochloride