146939-27-7 Usage
Atypical antipsychotic
Ziprasidone is an atypical antipsychotic and belongs to piperazine benzothiazole compound. For in vitro condition, the product has a very high affinity to the dopamine D2, D3, 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1D and α1 adrenergic receptor while having a moderate affinity to the histamine H1 receptor. However, it has antagonistic effect on dopamine D1, D2, 5-HT2A, 5-HT1D receptor while having agonistic effect on the 5-HT1A receptor. The product is capable of inhibiting the reuptake of 5-HT and norepinephrine via presynaptic membrane with the underlying mechanism of action remaining unclear. It may exert its anti-schizophrenia efficacy through the combined antagonist effect on dopamine D2 and 5-HT2 with the blocking strength being comparable to risperidone and haloperidol but stronger than olanzapine, quetiapine and clozapine. It is mainly used for the treatment of acute or chronic, onset or recurrent schizophrenia and is effective in treating both the negative as well as the positive symptoms of schizophrenia with especially a better efficacy in treating negative symptoms. It can reduce hallucinations, delusions, thought and action abnormal positive symptoms as well as alleviate the symptoms of mood monotonous and reduced volition activity and other negative symptoms.
Atypical antipsychotics, also known as the new generation of antipsychotics, refers to a class of antipsychotics drug with its blockage effect on dopamine D2 receptor be weaker than its blockage effect on the 5-HT2A receptor. Clinical drugs at present such as clozapine, risperidone, olanzapine, quetiapine and ziprasidone all belongs to this category. For atypical antipsychotics, except clozapine which has a relative long history of clinical application (1970s), all these other drugs are new antipsychotics which did not emerge until the late 1990s.
Atypical antipsychotics can not only block dopamine D2 receptors, but also more strongly block the effect of 5-HT2A receptor. When blocking the dopamine D2 receptor of midbrain-margin, it can also alleviate the positive symptoms; when blocking the 5-HT2A receptor on the presynaptic membrane of brain-cortical pathway, it can cause de-repressive release of dopamine and stimulate the dorsolateral dopamine D1 receptor of prefrontal cortex, alleviating the negative and cognitive symptoms, leading to excitement of the AVDM dopamine D1 receptors in the prefrontal cortex and the orbital part, further improving the symptoms of depression; when blocking the 5-HT2A receptor of the presynaptic membrane of the nigra-striatum pathway, it can cause the 5-HT2A receptor membranes, causing the de-repressive release of dopamine and can partially neutralizing the blocking effect of the drugs on the dopamine D2 receptor, therefore the extrapyramidal reactions are mild (long-term administration are also not easy to cause tardive dyskinesia); when causing blockage of the 5-HT2A receptor in the presynaptic membrane of the hypothalamic-funnel portion, it can cause de-repressive release of the dopamine, partially neutralizing the blocking effect of the drugs on the dopamine D2 receptor, therefore there is no obvious symptoms of hyperprolactinemia. It includes clozapine, olanzapine, quetiapine and ziprasidone.
Dosage and usage
The initial dose is 2 times per day with 20mg each time through oral administration. The bioavailability is usually bioavailability 30% with administration together with food being able to double the absorption of this product, reaching the bioavailability of 60%; administration with high-fat meal together can make the bioavailability be up to 97%. Adjustment of the dose can start at two days later, usually twice daily with the dose range being within 20~80mg and the maximum dose being 100mg. Patients of mild to moderate liver and kidney damage don’t need to adjust the dose. Ziprasidone is mainly metabolized in the liver with the metabolites being mainly excreted from the urine and partially discharged through fecal. The terminal T1/2 is about 7h.
The above information is edited by the lookchem of Dai Xiongfeng.
Uses
Different sources of media describe the Uses of 146939-27-7 differently. You can refer to the following data:
1. It is a kind of antipsychotic and can be used as the antagonist of the dopamine D2-serotonin 5-HT2.
2. Labelled Ziprasidone, which is used as an antipsychotic. Combined serotonin (5HT2) and dopamine (D2) receptor antagonist.
3. Labeled Ziprasidone, intended for use as an internal standard for the quantification of Ziprasidone by GC- or LC-mass spectrometry.
Production method
6-Chloro-1,3-dihydro-2H-indol-2-ketone (I) and bromoacetic acid can have acylation reaction under the action of polyphosphoric acid to give the compound (II). And then be stirred together with silicon hydride and triethyl trifluoroacetic acid at room temperature to give the compound (III). Finally, it can have reaction with N-(3-benzisothiazole-yl) piperazine in MIBK containing sodium carbonate to give the product.
Chemical Properties
Tan Solid
Definition
ChEBI: A piperazine compound having 1,2-benzothiazol-3-yl- and 2-(6-chloro-1,3-dihydro-2-oxindol-5-yl)ethyl substituents attached to the nitrogen atoms.
Biological Functions
"Ziprasidone is chemically similar to risperidone but with a substitution of piperzinyl and benzisothiazole for
piperidinyl and benzisoxazole and with minor aromatic modification. Like risperidone, ziprasidone is a high-affinity
antagonist at 5-HT2A/C and D2 receptors as well as at adrenergic α1/α2 and histamine H1 receptors. Moreover,
ziprasidone can activate 5-HT1A receptors that regulate dopaminergic neurotransmission in brain regions
involved in critical cognitive functions. Thus, in addition to D2 partial agonism, 5-HT1A agonism is now
thought to be an important pharmacological property for atypical antipsychotic drug efficacy.
General Description
Different sources of media describe the General Description of 146939-27-7 differently. You can refer to the following data:
1. Ziprasidone (Geodon, a benzisothiazolpiprazinylindolonederivative) also has the structuralfeatures of a hybrid molecule between a butyrophenone antipsychoticand a trazodone-like antidepressant. It is highlymetabolized to four major metabolites, only one of which, Smethyldihydroziprasidone,likely contributes to its clinical activity. In humans, less than 5% of the dose isexcreted unchanged. Reduction by aldehyde oxidase accountsfor about 66% of ziprasidone metabolism; two oxidative pathwaysinvolving hepatic CYP3A4 account for the remainder.
2. Ziprasidone, 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, is available as the hydrochloride monohydrate for oral administration (Geodon) and as the mesylate trihydrate saltfor intramuscular (IM) injection. The compound is well absorbedwith peak plasma levels occurring at 6 to 8 hours afteroral administration. The oral absorption is enhanced approximatelytwofold in the presence of food. Ziprasidone isbound about 99% to plasma proteins, primarily to albuminand α1-acid glycoprotein. Ziprasidone is not displaced in thepresence of two highly protein bound drugs, warfarin andpropranolol. Ziprasidone is extensively metabolized withonly about 5 % of the drug excreted unchanged.23 In humans,two major pathways are responsible for the metabolism ofziprasidone: (a) oxidation by CYP3A4 (one third) and (b) reductionby aldehyde oxidase (two thirds).The combinedaction of these metabolic pathways leads to four majorcirculating metabolites: benzisothiazole piperazine sulfoxide(BITP-sulfoxide), benzisothiazole piperazine sulfone (BITPsulfone),ziprasidone sulfoxide, and S-methyldihydroziprasidone.
Mechanism of action
Ziprasidone
(half-life, 6 hours) has an oral bioavailability of approximately 60%, which can be enhanced in the presence of fatty
foods. It is extensively metabolized (<5% excreted unchanged) by aldehyde oxidase, which results in reductive
cleavage of the S–N bond, and then by S-methylation. Ziprasidone also can undergo CYP3A4-catalyzed
N-dealkylation and S-oxidation.
Check Digit Verification of cas no
The CAS Registry Mumber 146939-27-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,6,9,3 and 9 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 146939-27:
(8*1)+(7*4)+(6*6)+(5*9)+(4*3)+(3*9)+(2*2)+(1*7)=167
167 % 10 = 7
So 146939-27-7 is a valid CAS Registry Number.
InChI:InChI=1/C21H21ClN4OS/c22-17-13-18-15(12-20(27)23-18)11-14(17)5-6-25-7-9-26(10-8-25)21-16-3-1-2-4-19(16)28-24-21/h1-4,11,13H,5-10,12H2,(H,23,27)/i7D2,8D2,9D2,10D2
146939-27-7Relevant articles and documents
Synthesis of 3H- and 14C-labelled CP-88,059: A potent atypical antipsychotic agent
Howard,Shenk,Smolarek,Marx,Windels,Roth
, p. 117 - 125 (1994)
The syntheses of 3H- and 14C-labelled CP-88,059 [i.e., 5-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one] are described. CP-88,059 (5b) is a combined D2/5-HT2 antagonist currently undergoing clinical evaluation as an antipsychotic agent with reduced potential for induction of EPS in schizophrenic patients. Displacement of bromine from the 7-position of the benzisothiazole moiety, by reductive dehydrogenation with tritium gas and Pd/BaSO4 catalysis, provided 3H-CP-88,059 (5c). Incorporation of 14C into the ethylene portion of the molecule was achieved via the Friedel-Crafts acylation of 6-chlorooxindole with [2-14C]-chloroacetyl chloride, followed by triethylsilane reduction of the aryl carbonyl and coupling with N-(1,2-benzisothiazol-3-yl)piperazine in refluxing aqueous Na2CO3.
Purification method and preparation method for ziprasidone mesilate
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Paragraph 0033-0051, (2018/07/30)
The invention discloses a purification method for ziprasidone mesilate. The purification method comprises the following steps: (1) taking a ziprasidone mesilate crude product, heating for dissolving the ziprasidone mesilate crude product into a mixed solvent formed by tetrahydrofuran and water, and adding carbon for decoloration, and separating out solids, wherein the volume ratio of tetrahydrofuran to water is 15 to (1-5); and (2) washing and drying the solids so as to obtain a ziprasidone mesilate pure product. The purification method is simple and safe to operate and relatively high in yield and purity, does not have special requirements on equipment and can meet the requirements on large-scale industrial production, the industrial production efficiency is improved, the materials are greatly saved, and the industrial production cost is lowered. The invention further discloses a preparation method of high-purity ziprasidone mesilate by virtue of the purification method.
PROCESS FOR PURIFICATION OF ZIPRASIDONE
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Page/Page column 3-4, (2011/07/30)
The present invention relates to a process for the preparation of pure ziprasidone. Thus, for example, ziprasidone tosylate was added to water and aqueous ammonia at room temperature, the contents were heated to 65 °C and maintained for 30 minutes, filtered, washed with water to obtain a wet solid, tetrahydrofuran was added to wet solid and maintained at reflux for 30 minutes. The separated solid was filtered and dried at 65 °C to obtain pure ziprasidone.
