14769-73-4 Usage
Uses
Used in Medical Applications:
Levamisole is used as a treatment for initial and secondary immunodeficient conditions, autoimmune diseases, chronic and reoccurring infections, large intestine adenocarcinoma, helmintosis, and rheumatoid arthritis. It is also a drug of choice for ascardiasis, showing high effectiveness in treating patients infected with A. duodenale. However, it is less effective against ancylostomiasis and strongyloidiasis and not effective against N. americanus.
Used in Veterinary Medicine:
Levamisole is used as an anthelmintic drug for treating parasitic worm infections in pigs, sheep, and cattle. It helps in controlling and eliminating various types of parasitic worms, contributing to the overall health and well-being of the animals.
Used as a Biological Response Modifier:
Levamisole is used as a biological response modifier, which means it can stimulate or enhance the body's immune response. It is believed to have a gangliostimulating effect on parasite tissues in both the parasympathetic and sympathetic regions, as well as an immunomodulatory effect on the host organism.
Synonyms and Brand Names:
Levamisole is also known by various synonyms such as decaris, tetramizole, solacil, ergamisol, tramisol, and immunol. The brand name for Levamisole is Ergamisol, which is manufactured by Janssen.
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.
Indications
Levamisole (Ergamisol) is an antiparasitic drug that has
been found to enhance T-cell function and cellular immunity.
The drug improves survival of patients with resected
colorectal cancers when combined with 5-fluorouracil;
the mechanism of this interaction is not
known. Levamisole does not have antitumor activity
against established or metastatic cancer and has not
been found useful in the adjuvant therapy of cancers
other than colorectal cancer.
The major adverse effects of levamisole are nausea
and anorexia. Skin rashes, itching, flulike symptoms, and
fevers also have been observed.
Indications
Levamisole (Ergamisol) was originally developed as an
antihelminthic drug. It potentiates the
stimulatory effects of antigens, mitogens, lymphokines,
and chemotactic factors on lymphocytes, granulocytes,
and macrophages. It has been shown to increase T
cell–mediated immunity.
Levamisole has been used successfully in treating
chronic infections. It also has been approved for use in
combination with fluorouracil in the treatment of colorectal
cancer.
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].
Side effects
Nausea, gastrointestinal upsets and very mild neurological
problems have been reported.
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.
Preparations
Available as levamisole hydrochloride: 118 mg is equivalent to 100 mg base.
? Ketrax? (Zeneca). Oral solution 40 mg base per 5 ml. Tablets 40 mg base.
? Solaskil? (Rh?ne-Poulenc Rorer). Tablets 30 mg base, 150 mg base.
? Ergamisol? (Lederle). Tablets 50 mg base.
? Levamisol? (Janssen). Tablets 50 mg base.
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
Manufacturing Process
To a stirred and refluxed suspension of 17 parts of 1,2-dibromoethane, 7.8
parts of sodium hydrogen carbonate and 50 parts of 2-propanol is added a
mixture of 3.4 parts of dl-2-thio-1-phenyl-imidazolidine, 9 parts of a 20%
potassium hydroxide solution in 40 parts of 2-propanol over a period of about
1 hour. After the addition is complete, the whole is stirred and refluxed for an
additional 3 hours. The reaction mixture is evaporated. To the residue are
added 18 parts of a 15% potassium hydroxide solution. The whole is extracted
with toluene. The extract is dried and evaporated. The oily residue is dissolved
in acetone and gaseous hydrogen chloride is introduced into the solution. The
precipitated solid salt is filtered off and recrystallized from 2-propanol, yielding
dl-2,3,5,6-tetrahydro-6-phenyl-imidazo[2,1-b]thiazole hydrochloride; melting
point 264°C to 266°C.dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrochloride, 188 g
(0.785 mol), is suspended in a mixture of 500 ml of water and 500 ml of
methylene chloride. The suspension is stirred mechanically while 20% sodium
hydroxide solution is added until the solution is basic. Ice is added from time
to time to keep the temperature below the boiling point of the methylene
chloride. The methylene chloride layer is separated, washed with water, dried
over potassium carbonate and evaporated. The oily residue crystallizes with
the evolution of the heat when poured into a beaker containing 100 ml of
ether. The free base is washed with ether. The yield of dl-6-phenyl-2,3,5,6-
tetrahydroimidazo[2,-b]thiazole is 151.4 g (0.746 mol), 94%. The product has
a melting point of 90°C.A solution of 204.3 g (1 mol) of dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-
b]thiazole and 232.3 g (1 mol) of d-10-camphorsulfonic acid in 1,750 ml of
chloroform is allowed to crystallize overnight at -28°C. The solvate is
recovered by filtration and washed with ice cold chloroform (400 ml). The
solvate is dried (decomposed) under nitrogen 7 hours and then in air
overnight. The yield of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole
d-10-camphorsulfonate is 202.5 g (0.464 mol) 92.8%, melting point 139°C to
140°C [α]D25+ 82.6 (C = 16, H2O).A solution of 150 g (0.344 mol) of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, d-10-camphorsulfonate in water is treated with 15.5 g (0.378
mol) of 98% sodium hydroxide and the liberated base extracted with
chloroform. The chloroform solution is washed with water followed by sodium
chloride solution and dried over magnesium sulfate. Evaporation of the solvent
left 72.1 g of residue which crystallized shortly. The free base hereby obtained
has a melting point of 60°C to 61.5°C and an optical rotation [α]D25+ 85.1 (C
= 10, CHCl3).The free base d(+)6-phenyl-2,3,5.6-tetrahydroimidazo[2.1-b]thiazole is
dissolved in 112 ml of acetone and 178 ml of isopropanolic hydrogen chloride
is added all at once. The hydrochloride crystallizes at once. After cooling to
below 0°C, the salt is recovered by filtration and washed with acetone. The
product weighs 75.2 g (0.312 mol), 91%, from the camphorsulfonate, melting
point 227°C to 227.5°C [α]D25+ 123.1 (C = 15, H2O).
Therapeutic Function
Antiinflammatory
Antimicrobial activity
Its principal activity is against Asc. lumbricoides and hookworms. Worms are paralyzed and passed
out 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 soluble
in 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 with
activation and proliferative growth of T-lymphocytes, increased numbers of monocytes and
activation of macrophages, and also with increased activity and hemotaxis of neutrophylic
granulocytes. Levamisole also exhibits anthelmint action. It also increases the body’s overall resistivity and restores altered T-lymphocyte and phagocyte function. It can also fulfill
an 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%
Cmax 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 extensively
metabolized in the liver. It is excreted chiefly in the urine.
Clinical Use
Ascariasis
Hookworm infection
Levamisole has been used in rheumatoid arthritis and some
other conditions that are said to respond to its immunomodulatory
activity.
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 the
treatment of many nematodes in cattle, sheep and goats, swine,
poultry. In sheep and cattle, levamisole has relatively good activity
against abomasal nematodes, small intestinal nematodes (not
particularly good against Strongyloides spp.), large intestinal nematodes
(not Trichuris spp.), and lungworms. Adult forms of species
that are usually covered by levamisole, include: Haemonchus spp.,
Trichostrongylus spp., Osteragia spp., Cooperia spp., Nematodirus
spp., Bunostomum spp., Oesophagostomum spp., Chabertia spp., and
Dictyocaulus vivapurus. Levamisole is less effective against the immature
forms of these parasites, and is generally ineffective in cattle
(but not sheep) against arrested larval forms. Resistance of parasites
to levamisole is a growing concern.
In swine, levamisole is indicated for the treatment of Ascaris
suum, Oesophagostomum spp., Strongyloides, Stephanurus, and
Metastrongylus.
Levamisole has been used in dogs as a microfilaricide to treat
Dirofilaria immitis infection in the past, but is rarely used today.
It has also garnered some interest as an immunostimulant in the
adjunctive therapy of various neoplasms.
Because of its narrow margin for safety and limited efficacy
against many equine parasites, levamisole
is not generally used in
horses as an antiparasitic agent. It has been tried as an immune
stimulant, however.
Check Digit Verification of cas no
The CAS Registry Mumber 14769-73-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,4,7,6 and 9 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 14769-73:
(7*1)+(6*4)+(5*7)+(4*6)+(3*9)+(2*7)+(1*3)=134
134 % 10 = 4
So 14769-73-4 is a valid CAS Registry Number.
InChI:InChI=1/C11H12N2S.ClH/c1-2-4-9(5-3-1)10-8-13-6-7-14-11(13)12-10;/h1-5,10H,6-8H2;1H/t10-;/m1./s1
14769-73-4Relevant articles and documents
Supercritical fluid extraction: A novel method for the resolution of tetramisole
Keszei, Sandor,Simandi, Bela,Szekely, Edit,Fogassy, Elemer,Sawinsky, Janos,Kemeny, Sandor
, p. 1275 - 1281 (1999)
A new resolution method, based on the selective distribution of enantiomers between a chiral solid and an achiral supercritical fluid phase, is reported. The chiral solid phase is formed from the optically active dicarboxylic acid derivative, (2R,3R)-O,O'-dibenzoyltartaric acid, and the racemic base (tetramisole). A new method is also described for the enrichment of enantiomeric mixtures which have an enantiomeric ratio other than 1:1. This is based on the partial salt formation of the enantiomeric mixture with an achiral substance, which is then followed by supercritical fluid extraction of the free enantiomer. The extract has an enantiomeric composition which is different from the starting mixture. The method is applied to an enantiomeric mixture of tetramisole with hydrochloric acid.
Effect of ultrasound-assisted crystallization in the diastereomeric salt resolution of tetramisole enantiomers in ternary system with O,O′-dibenzoyl-(2R,3R)-tartaric acid
Szeleczky, Zsolt,Kis-Mihály, Erzsébet,Semsey, Sándor,Pataki, Hajnalka,Bagi, Péter,Pálovics, Emese,Marosi, Gy?rgy,Pokol, Gy?rgy,Fogassy, Elemér,Madarász, János
, p. 8 - 17 (2016)
The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30 min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3 W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166 °C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1 M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150 °C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.
Effect of achiral support on the resolution of tetramisole by supercritical fluid extraction
Szekely, Edit,Simandi, Bela,Laszlo, Krisztina,Fogassy, Elemer,Pokol, Gyoergy,Kmecz, Ildiko
, p. 1429 - 1434 (2002)
The enantiomers of tetramisole were produced by partial diastereomeric salt formation with O,O′-dibenzoyl-(2R,3R)-tartaric acid monohydrate and subsequent supercritical fluid extraction (SFE) of the unreacted enantiomers in the presence of an achiral support. The effect of the activated carbon and Perfil 100 on the efficiency of chiral separation were studied. The kinetics of the process was found to be an important factor affecting enantioselectivity. When the parameters were properly set, much better resolution efficiency (F) and higher enantiomeric purity were achieved than in the equilibrium. The presence of Perfil 100 and activated carbon caused an increase as high as 53 and 84% in F, respectively, compared to that achieved without using any supporting material. Thus during the development of a resolution procedure, beside the proper resolution agent, optimised molar ratio and other parameters, the selection of achiral addict(s) may be also an important point.
Total Synthesis of (-)-Xylogranatopyridine B via a Palladium-Catalyzed Oxidative Stannylation of Enones
Schuppe, Alexander W.,Huang, David,Chen, Yifeng,Newhouse, Timothy R.
supporting information, p. 2062 - 2066 (2018/02/19)
We report a total synthesis of the pyridine-containing limonoid alkaloid (-)-xylogranatopyridine B in 11 steps from commercially available dihydrocarvone. The central pyridine ring was assembled by a late-stage fragment coupling approach employing a modified Liebeskind pyridine synthesis. One fragment was prepared by an allyl-palladium catalyzed oxidative enone β-stannylation, in which the key bimetallic β-stannyl palladium enolate intermediate undergoes a β-hydride elimination. This methodology also allowed introduction of alkyl and silyl groups to the β-position of enones.
Enantioselective aza-Henry reaction for the synthesis of (S)-levamisole using efficient recyclable chiral Cu(II)-amino alcohol derived complexes
Choudhary, Manoj K.,Tak, Rajkumar,Kureshy, Rukhsana I.,Ansari, Amamudin,Khan, Noor-Ul H.,Abdi, Sayed H.R.,Bajaj, Hari C.
, p. 85 - 93 (2015/09/07)
Chiral Cu(II) complexes were generated in situ by the interaction of aminoalcohol based ligands L1-L6 derived from (1R,2S)-(-)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol, (R or S)-valinol and (S)-2-amino-1,1-diphenylpropan-1-ol with 4-tert-butyl-2,6-diformylphenol and screened for aza-Henry reaction of a variety of aromatic, aliphatic N-tosylaldimine and aromatic N-benzenesulfonamide aldimine in toluene at RT. Excellent enantioselectivity, diastereoselectivity (99%) of β-nitro-N-tosylaldamine with good yield (80%) was achieved in case of complex L2-Cu(II) with low catalyst loading. The enantio-pure aza-Henry product obtained was straightforwardly transformed into the enantioenriched chiral vicinal diamine (ee; 96%) with good yield in successive two steps and was further used for the synthesis of (S)-levamisole (an anthelminthic agent). The catalytic system worked well up to five cycles with retention of enantioselectivity.
Preparation and immunological evaluation of organic acid salts of levamisole
Feng, Xiaoling,Yang, Yi,Wang, Jianhua
, p. 634 - 640 (2014/06/09)
Four kinds of organic acid salts of levamisole were prepared from levamisole hydrochloride and organic acids (L-ascorbic acid, tartaric acid, citric acid and ferulic acid) by solvent crystallization method, respectively. The salts were characterized by elemental analysis, UVVIS, FTIR, ESI-MS, DSC-TGA, solubility in water, melting point, optical rotation and pH in water. The immunosuppressed mice models were established by intraperitoneal injection of cyclophosphamide to verify and compare the effects of levamisole hydrochloride and organic acid salts of levamisole on immune functions of immunosuppressed mice. The results showed while significantly increasing the contents of serum IgM and IgG and the immune organ indexes in cyclophosphamide-induced immunosuppressed mice, levamisole ferulate and levamisole tartrate presented higher increases in IgG contents and immune organ indexes than other salts did. Thus, it could be concluded that levamisole ferulate and levamisole tartrate were more effective on immune enhancement than other salts.
Oxazoline-based organocatalyst for enantioselective strecker reactions: A protocol for the synthesis of levamisole
Sadhukhan, Arghya,Sahu, Debashis,Ganguly, Bishwajit,Khan, Noor-Ul H.,Kureshy, Rukhsana I.,Abdi, Sayed H.R.,Suresh,Bajaj, Hari C.
supporting information, p. 14224 - 14232 (2013/11/06)
A chiral oxazoline-based or-ganocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N-benzhydrylimines with trime-thylsilyl cyanide (TMSCN) as a cyanide source at -20°C to give α-aminoni-triles in high yield (96%) with excellent chiral induction (up to 98% ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organo-catalyst in these reactions. The organo-catalyst has been characterized by single-crystal X-ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.
Silylation-based kinetic resolution of monofunctional secondary alcohols
Sheppard, Cody I.,Taylor, Jessica L.,Wiskur, Sheryl L.
supporting information; experimental part, p. 3794 - 3797 (2011/10/02)
The nucleophilic small molecule catalyst (-)-tetramisole was found to catalyze the kinetic resolution of monofunctional secondary alcohols via enantioselective silylation. Optimization of this new methodology allows for selectivity factors up to 25 utilizing commercially available reagents and mild reaction conditions.
Enantioselective metal-free diamination of styrenes
Roeben, Caren,Souto, Jose A.,Gonzalez, Yolanda,Lishchynskyi, Anton,Muniz, Kilian
, p. 9478 - 9482 (2011/11/06)
Metal-free and asymmetric: The first enantioselective diamination of styrenes simply requires a chiral hypervalent iodine(III) reagent as an oxidant and bismesylimide as a nitrogen source (see scheme, Ms=methanesulfonyl). The reaction proceeds under mild conditions and with high enantiomeric excess.
A new facile chemoenzymatic synthesis of levamisole
Kamal, Ahmed,Khanna, G.B. Ramesh,Krishnaji,Ramu
, p. 613 - 615 (2007/10/03)
An efficient and facile chemoenzymatic synthesis of levamisole by employing lipase-mediated resolution of 3-hydroxy-3-phenylpropanenitrile followed by its conversion to β-amino alcohol as the key intermediate is described.
