51322-75-9 Usage
Description
Tizanidine, also known by the brand name SIRDALUD, is a centrally-acting muscle relaxant with a chemical structure defined as a 2,1,3-Benzothiadiazole substituted at C-4 by a Delta1-imidazolin-2-ylamino group and at C-4 by a chloro group. It functions as an agonist at alpha2-adrenergic receptor sites, making it a valuable pharmaceutical compound for various applications.
Uses
Used in Pharmaceutical Industry:
Tizanidine is used as an internal standard for the quantification of Tizanidine by GCor LC-mass spectrometry, ensuring accurate measurement and analysis of the compound in various pharmaceutical applications.
Used in Medical Treatment:
Tizanidine is used as a muscle relaxant for the treatment of muscle spasms and a variety of spastic conditions. Its central action helps alleviate the symptoms and improve the quality of life for patients suffering from these conditions.
Used in Antiviral Applications:
Tizanidine could have therapeutic use as a SARS-CoV-2 main protease inhibitor, potentially playing a role in the development of treatments for COVID-19 and other viral infections.
Outline
Tizanidine is an imidazoline two nitrogen heterocyclic pentene derivative. The structure is similar to that of clonidine. In 1987, it was first listed in Finland as a central adrenalin α2 receptor agonist. Currently, it is used as a central muscle relaxant in clinic. It can be used to treat painful muscle spasm, such as neck waist syndrome and torticollis. It can also be used to treat postoperative pain, such as disc herniation and hip arthritis. It comes from the ankylosis of neurological disorders, such as multiple sclerosis, chronic myelopathy, cerebrovascular accident and etc.
Pharmacology
It selectively reduces the release of excitatory amino acids from interneurons and inhibits the multi synaptic mechanism related to muscle overstrain. This product does not affect the transmission of neuromuscular. It is well tolerated. It is effective for acute painful muscle spasms and chronic ankylosis originates from the spinal cord and brain. It can reduce the resistance of passive movement, reduce spasticity and clonus, and increase the intensity of voluntary movement.
Function
It is used to reduce skeletal muscle tension, muscle spasm and myotonia caused by brain and spinal cord injury, cerebral hemorrhage, encephalitis and multiple sclerosis.
Drug Interaction
In vitro studies of human liver microsomal cytochrome P450 isozymes showed that Tizanidine and its metabolites do not affect the metabolism of other enzymes.
Tizanidine makes the peak time of acetaminophen delayed by 16 minutes, but paracetamol does not affect the pharmacokinetic parameters of Tizanidine.
Ethanol increases the area under the curve of Tizanidine by 20%, resulting in an increase of 15% in the maximum peak concentration and an increased side effect in Tizanidine.The central nervous system inhibition of ethanol and Tizanidine has additive effect.
4mg Tizanidine’s single or repeated retrospective study showed that the use of oral contraceptives compared with patients who did not take oral contraceptives at the same time reduced the scavenging rate of Tizanidine Hydrochloride by 50%.
When combined with antihypertensive drugs and diuretics, hypotension and bradycardia can be induced.
It is prohibited to use combined with fluoxamine or ciprofloxacin(Cytochrome oxidase CYP1A2 inhibitor). Clinical studies showed that the pharmacokinetic parameters of Tizanidine (area under the curve, elimination half-life, maximum blood concentration, and oral bioavailability) will be increased when combined with fluoxamine and ciprofloxacin simultaneously, while the plasma clearance rate will be decreased. This pharmacokinetic interaction may lead to serious adverse events.
Precaution
The following patients should be cautious when taking the drug:
①Patients with liver dysfunction: This product is mainly metabolized by the liver. There have been reports of the deterioration of liver function.
②Patients with renal insufficiency: It is reported that the drug is slowly excreted by kidney and easy to maintain high blood concentration.
At the initial stage, its use may cause a sharp drop in blood pressure
This medicine can cause reflex movement ability and sleepiness, so it is not suitable for driving or manipulating machinery during medication.
There are differences in pharmacokinetics of different formulations of the drug. Food also plays a complex role in the pharmacokinetics of the drug.
Adverse reaction
For a small dose of painful muscle spasm, only mild transient lethargy, fatigue, dizziness, dry mouth, nausea and a slight decrease in blood pressure can be observed.
When used for spastic paralysis, the above adverse reactions are more common and obvious because of larger doses, but there is no need to stop taking drugs.
Contraindication
It is forbidden for those who are allergic to this medicine.
Originator
Sandoz (Switzerland)
Manufacturing Process
14 ml of benzoyl chloride are added to a solution of 11.5 g of ammonium
thiocyanate in 150 ml of acetone in an ice bath and the mixture is then stirred
for 10 min. This solution is heated to the boil at reflux together with 19 g of
4-amino-5-chloro-2,1,3-benzothiadiazole. The solution is cooled to room
temperature and diluted with a 4-fold quantity of water. The precipitate is
filtered off and rapidly brought to a boil together with 150 ml of a 2 N
aqueous sodium hydroxide solution and kept at the boil for 5 min. The
solution is cooled to room temperature, is acidified weakly with glacial acetic
acid, the precipitate is filtered off, washed with ether and recrystallized from
methanol. The N-(5-chloro-2,1,3-benzothiadiazol-4-yl)thiourea, obtained and
this is boiled for 1 h together with 9 g of methyl iodide in 150 ml of methanol.
After concentrating by evaporation, crude S-methyl-N-(5-chloro-2,1,3-
benzothiadiazol-4-yl)isothiuronium iodide is obtained. 9.8 g of S-methyl-N-(5-
chloro-2,1,3-benzothiadiazol-4-yl)isothiuronium iodide are heated to the boil
at reflux for 1 h together with 50 ml of methanol and 1.8 ml of ethylene
diamine. The solvent is then removed by evaporation and the moist residue is
boiled at reflux for 1 h together with 20 ml of n-amyl alcohol. The mixture is
subsequently shaken with 50 ml of chloroform and 150 ml of water until all
the material is dissolved. 40 ml of a 2 N aqueous sodium hydroxide solution
are added to the aqueous phase and extraction is effected with 200 ml of
chloroform. The organic phase is dried and concentrated by evaporation. After
recrystallizing the residue from methanol with the addition of some active
charcoal, 4-(2-imidazolin-2-yl-amino)-5-chloro-2,1,3-benzothiadiazole, having a melting point of 221-223°C, is obtained.
The 4-(2-imidazolin-2-yl-amino)-5-chloro-2,1,3-benzothiadiazole hydrochloride
may be obtained by the teaction of 4-(2-imidazolin-2-yl-amino)-5-chloro-
2,1,3-benzothiadiazole with hydrochloric acid.
Therapeutic Function
Muscle relaxant, Spasmolytic
Mechanism of action
Tizanidine is a centrally active muscle relaxant analogue of clonidine that is approved for use in reducing spasticity associated with cerebral or spinal cord
injury. Its mechanism of action for reducing spasticity suggests presynaptic inhibition of motor neurons at the α2-adrenergic receptor sites, reducing the release of
excitatory amino acids and inhibiting facilitatory ceruleospinal pathways, thus resulting in a reduction in spasticity. Tizanidine only has a small fraction of the
antihypertensive action of clonidine, presumably because of action at a selective subgroup of α2C-adrenoceptors, which appear to be responsible for the analgesic and
antispasmodic activity of imidazoline α2-agonists(20).
Clinical Use
Tizanidine is a centrally acting adrenergic α2 receptor agonist used to treat chronic muscle
spasticity conditions, such as multiple sclerosis.
Side effects
Postulated mechanisms include α2 receptor-mediated decreased release of norepinephrine and
serotonin from spinal interneurons. Tizanidine is structurally related to the α2 agonist
clonidine that is used to treat hypertension; however, the blood pressure–lowering potency of
tizanidine is approximately 10 to 20% that of clonidine. Nevertheless, patients may experience
hypotension with tizanidine, together with muscle weakness, that may result in dizziness and falls
in mobile patients. Tizanidine is rapidly and almost completely absorbed from the gastrointestinal
tract; however, the estimated bioavailability is only 10 to 15% because of extensive first-pass
metabolism, mainly by CYP1A2, which results in oxidative degradation of the imidazoline ring
and hydroxylation of the aromatic system. Elevated liver enzyme values are not frequent
with tizanidine use. Hepatic injury and death because of liver failure have been reported,
however, and this complication should be considered in view of its marginal antispasmodic
efficacy. Other frequently reported side effects of tizanidine are drowsiness and dry
mouth. Clonidine also has been used to treat spasticity; however, even less high-quality clinical
study data are available for this agent.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: enhanced muscle relaxant effect
with procainamide.
Antibacterials: concentration increased by
ciprofloxacin - avoid; concentration possibly
increased by norfloxacin; concentration possibly
reduced by rifampicin.
Antidepressants: concentration increased by
fluvoxamine - avoid.
Antihypertensives: enhanced hypotensive effect.
Oral contraceptives: clearance of tizanidine reduced
by 50%.
Metabolism
Tizanidine undergoes rapid and extensive first pass metabolism in the liver mainly via the cytochrome P450 isoenzyme CYP1A2. The metabolites (mainly inactive) constitute 70% of the administered dose and are excreted via the renal route.
Check Digit Verification of cas no
The CAS Registry Mumber 51322-75-9 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 5,1,3,2 and 2 respectively; the second part has 2 digits, 7 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 51322-75:
(7*5)+(6*1)+(5*3)+(4*2)+(3*2)+(2*7)+(1*5)=89
89 % 10 = 9
So 51322-75-9 is a valid CAS Registry Number.
InChI:InChI=1/C9H8ClN5S/c10-5-1-2-6-8(15-16-14-6)7(5)13-9-11-3-4-12-9/h1-2H,3-4H2,(H2,11,12,13)
51322-75-9Relevant articles and documents
Preparation method of tizanidine hydrochloride
-
, (2021/07/21)
The invention discloses a preparation method of tizanidine hydrochloride, and belongs to the field of medicine preparation. According to the preparation method, 5-chloro-4-amino-2,1,3-benzothiadiazole and 1-acetyl-2-imidazolinone are taken as raw materials, and condensation, alcoholysis and salification are performed, further refining can be performed; then the tizanidine hydrochloride can be prepared. The operation is simpler, more convenient and safer, and the preparation method is more suitable for industrial production. The tizanidine hydrochloride prepared by the method is higher in yield, the obtained tizanidine hydrochloride is also higher in purity; the method has important industrial value, and can protect the supply of the bulk drug tizanidine hydrochloride and benefit the public.
Preparation method for benzothiadiazole derivative
-
Paragraph 0012; 0042-0043; 0045-0046; 0048-0049; 0051-0052, (2019/04/10)
The invention discloses a preparation method for a benzothiadiazole derivative, and specifically relates to a preparation method for tizanidine hydrochloride. The preparation method includes the following steps: (a) taking a compound II and a compound III or a salt thereof, performing reaction in an organic solvent in the presence of an acid-binding agent, and obtaining an intermediate IV throughalkalization, filtration and refining; and (b) preparing tizanidine hydrochloride shown as a formula I by taking the intermediate IV obtained by step (a) as a raw material. The method is high in yieldand purity, simple in operation, high in production efficiency, environmentally friendly, safe and suitable for industrial mass production, and has wide market application prospects. The preparationsteps are shown in the description.
A process for making a benzothiadiazole derivative
-
, (2008/06/13)
A process for producing 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole is disclosed, which comprises the reaction between 5-chloro-4-amino-2,1,3-benzothiadiazole and 1-acyl-2-imidazolidinone. This process allows the product to be prepared in a high yield from easily obtainable starting materials.
