Tinidazole

Tinidazole Basic information
Pharmacology and mechanism of action Pharmacology and mechanism of action Indications Side effects Contraindications Interactions Preparations References
Product Name:Tinidazole
Synonyms:TIMTEC-BB SBB006917;TINIDAZOLE;1-(2-(ethylsulfonyl)ethyl)-2-methyl-5-nitro-1h-imidazol;1-(2-(ethylsulfonyl)ethyl)-2-methyl-5-nitro-imidazol;1-(2-(ethylsulfonyl)-ethyl)-2-methyl-5-nitroimidazole;bioshik;1-[2-(Ethylsulfonyl)ethyl]-2-Methyl-5-nitro-;Tinidazole API
CAS:19387-91-8
MF:C8H13N3O4S
MW:247.27
EINECS:243-014-4
Product Categories:ZARONTIN;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;19387-91-8
Mol File:19387-91-8.mol
Tinidazole Structure
Tinidazole Chemical Properties
Melting point 118-120?C
Boiling point 528.4±30.0 °C(Predicted)
density 1.4338 (rough estimate)
refractive index 1.6320 (estimate)
storage temp. Sealed in dry,Room Temperature
solubility Practically insoluble in water, soluble in acetone and in methylene chloride, sparingly soluble in methanol.
form neat
pka2.30±0.34(Predicted)
color Off-White to Pale Yellow
λmax317nm(H2O)(lit.)
Merck 14,9447
BRN 618182
Stability:Stable. Incompatible with strong oxidizing agents.
InChIKeyHJLSLZFTEKNLFI-UHFFFAOYSA-N
CAS DataBase Reference19387-91-8(CAS DataBase Reference)
Safety Information
Hazard Codes Xn
Risk Statements 20/21/22-40
Safety Statements 26-36
WGK Germany 3
RTECS NI6255000
HS Code 2933290000
Hazardous Substances Data19387-91-8(Hazardous Substances Data)
ToxicityLD50 in mice (mg/kg): >3600 orally; >2000 i.p. (Miller)
MSDS Information
Tinidazole Usage And Synthesis
Pharmacology and mechanism of action Similar to metronidazole.
Pharmacology and mechanism of actionSimilar to metronidazole.
 
IndicationsInfections caused by Entamoeba histolytica and Giardia lamblia. Tinidazole is more effective than metronidazole in the treatment of giardiasis.
 
Side effects Side effects are similar to but milder than those caused by metronidazole. Gastrointestinal disturbances like nausea, vomiting, anorexia and metallic taste are common. Headache, tiredness, furred tongue and itching may occur. Thrombophlebitis may occur at the site of intravenous infusion [1].
 
ContraindicationsTinidazole should not be taken together with alcohol.
 
InteractionsA disulfiram-like reaction might occur if tinidazole is taken together with alcohol.
 
Preparations• Fasigyn® (Pfizer). Tablets 150 mg, 200 mg, 300 mg, 500 mg, 1 g. Oral suspension 200 mg per ml. Solution for injection 2 mg per ml.
• Tricolam® (Pfizer). Tablets 500 mg.
• Simplotan® (Pfizer). Tablets 1 g.
 


References1. Sawyer PR, Brogden RN, Pinder RM, Speight TM, Avery GS (1976). Tinidazole: a review of its antiprotozoal activity and therapeutic efficacy. Drugs, 11, 424–440.
Chemical Propertiessolid
OriginatorSimplotan,Pfizer,W. Germany,1971
UsesAntiprotozoal (Trichomonas, Giardia); antiamebic; antibacterial.
Usesanticonvulsant
Usesanti-ulcerative
UsesFor the treatment of trichomoniasis caused by T. vaginalis in both female and male patients. Also for the treatment of giardiasis caused by G. duodenalis in both adults and pediatric patients older than three years of age and for the treatment of intestin
DefinitionChEBI: Tinidazole is 1H-imidazole substituted at C-1 by a (2-ethylsulfonyl)ethyl group, at C-2 by a methyl group and at C-5 by a nitro group. It is used as an antiprotozoal, antibacterial agent. It has a role as an antiprotozoal drug, an antibacterial drug, an antiparasitic agent and an antiamoebic agent.
Manufacturing ProcessThe preparation of ethylsulfonylethyl-p-toluenesulfonate is carried out in the following manner: 69.0 grams (0.5 mol) ethylsulfonylethanol dissolved in 150 ml pyridine is cooled to 0°C with stirring and while maintaining the temperature between 0° to 10°C, 95 grams (0.5 mol) p-toluenesulfonyl chloride is added in portions over a 10 minute period. After this time, 250 ml water is added slowly and the mixture extracted with chloroform, the organic phase washed first with 2 N HCl, then with water, separated and dried. The product which crystallizes on cooling is filtered and dried to give 77.5% yield of this intermediate.
A mixture of 12.7 grams (0.1 mol) of 2-methyl-5-nitroimidazole and 58.4 grams (0.2 mol) ethylsulfonylethyl-p-toluenesulfonate is heated with stirring, under nitrogen, at 145° to 150°C for about 4 hours. After this time, the reaction mixture is extracted with 500 ml hot water, the aqueous portion adjusted with 10% Na2CO3 to a pH of 9 and extracted with chloroform (3 times with 150 ml portions). The separated organic phase is washed with water, dried with Na2SO4 and evaporated to dryness. The crude tinidazole product is then crystallized from benzene to give 4.36 grams of product having a MP of 127° to 128°C.
Therapeutic Function1-[2-(Ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole
Antimicrobial activityIts antibacterial and antiprotozoal activity is similar to that of metronidazole.The MIC against G. vaginalis is 0.2–2 mg/L; the hydroxy metabolite is significantly more active than that of metronidazole. H. pylori is inhibited by 0.5 mg/L. T. vaginalis and T. fetus at 2.5 mg/L and E. histolytica is inhibited by about 0.3–2.5 mg/L.
Pharmaceutical ApplicationsA 5-nitroimidazole available for oral administration and, in some countries, for intravenous infusion.
Mechanism of actionTinidazole has a mechanism of action that parallels that of metronidazole as well as a similar metabolic pathway leading to hydroxylation at the 2-methyl group catalyzed by CYP3A4. Basically, tinidazole appears to mimic the actions of metronidazole, although there are reports that it is effective against some protozoa which are resistant to metronidazole.
PharmacokineticsOral absorption :>95%
Cmax 2 g oral:40 mg/L after 2 h
800 mg (30-min infusion): 12 mg/L 6 min after end infusion
Plasma half-life: 12–14 h
Volume of distribution 0.64 L/kg :Plasma protein binding 12%
absorption and distribution
After a 2 g oral dose, concentrations remain at c. 10 mg/L at 24 h and 2.5 mg/L at 48 h. Daily doses of 1 g maintain plasma levels in excess of 8 mg/L, irrespective of whether the dose is oral or intravenous. It is well distributed, with concentrations in bile, CSF, breast milk and saliva similar to those reached in plasma.
The drug readily crosses the placenta. In women undergoing first trimester abortion, concentrations of 4.9 mg/kg (placenta) and 7.6 mg/kg (fetus) were found when the plasma concentration was 13.2 mg/L.
Metabolism and excretion
Metabolites include the 2-hydroxymethyl derivative, its glucuronide and two unidentified minor derivatives. In urine about half the drug remains unmetabolized.
The parent drug and its metabolites are excreted primarily in the urine and to a minor extent in the feces. The clearance rate is about 0.73 mL/min per kg and the urinary excretion is about 21% of the dose. Total clearance of the drug is 51 mL/min, renal clearance 10 mL/min. In healthy volunteers given an : intravenousinfusion of 800 mg [14C]tinidazole over 30 min, a mean of 44% of the dose was excreted in the urine during the first 24 h, increasing to 63% over 5 days: only 12% of the dose appeared in the feces. Unchanged tinidazole comprised 32% of urinary 14C in 0–:12 h urine. The 2-hydroxymethyl metabolite accounted for about 9% of the urinary 14C and was also present in plasma.
In renal failure the pharmacokinetics are not significantly different from those in healthy individuals. It is rapidly removed by hemodialysis and a normal dose should be given after each dialysis: if treatment precedes dialysis a half dose should be infused after the end of the procedure.
Clinical UseAnaerobic bacterial infections(prophylaxis and treatment)
Trichomoniasis
Giardiasis (single dose) Amebiasis (including amebic liver abscess)
Bacterial vaginosis
Gastric colonization with H. pylori (in combination with other agents)
Side effectsTinidazole is generally well tolerated. Infrequent and transient effects include nausea, vomiting, diarrhea and a metallic taste. Disulfiram-like reactions may occur and rare neurological disturbances and transient leukopenia have been described. Rash, which may be severe, urticaria and angioneurotic edema can occur.
SynthesisTinidazole, 1-2-(ethylsulfonyl)ethyl-2-methyl-5-nitroimidazole (37.2.12), is also made from 2-methyl-5-nitroimidazole (37.2.9), which upon being reacted with 2-ethoxysulfonyl-p-toluenesulfonate (37.2.11) transformed into the desired tinidazole.
The 2-ethoxysulfonyl-p-toluenesulfonate (37.2.11) necessary for this reaction is in turn made by tosylation of 2-ethylsulfonyl ethanol using p-toluenesulfonyl chloride.

Synthesis_19387-91-8

Veterinary Drugs and TreatmentsLittle information is presently available on the use of tinidazole in dogs, cats, or horses. It potentially could be useful for treating anaerobic infections, particularly associated with dental infections in small animals. Because of its antiprotozoal effects, it has been used as an alternative for treating giardiasis in small animals, and it could have efficacy against amebiasis, trichomoniasis or balantidiasis in veterinary species, but documentation of efficacy is not available. Tinidazole has a longer duration of action in dogs and cats than does metronidazole. In humans, oral tinidazole is FDA-approved for treating extraintestinal and intestinal amebiasis, (Entamoeba histolytica), giardiasis (Giardia duodenalis/lamblia), and trichomoniasis (T. vaginalis).
Drug interactionsPotentially hazardous interactions with other drugs
Alcohol: disulfiram-like reaction.
MetabolismTinidazole is excreted by the liver (up to 5
%) and kidneys as unchanged drug and metabolites. An active hydroxy metabolite has been identified.
Tinidazole Preparation Products And Raw materials
Raw materialsTosyl chloride-->2-(ETHYLSULFONYL)ETHANOL-->2-Methyl-5-nitroimidazole
Methylparaben 2-Methyl-4-nitroimidazole 2,4,6-Trinitrotoluene Methyl Tinidazole Bensulfuron methyl 1,2-Dimethyl-5-nitroimidazole Levamisole Parathion-methyl 2-METHYL-1H-IMIDAZOL-4-AMINE Kresoxim-methyl Imidazole Ethyl maltol Thiophanate-methyl Nitrobenzene Methyl acrylate Methyl acetate Methyl bromide

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