| Identification | More | [Name]
Ziprasidone | [CAS]
146939-27-7 | [Synonyms]
ZIPRASIDONE-D8
5-[2-[4-(1,2-Benzisothiazol-3yl)-1-piperazinyl-d8]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one
2H-Indol-2-one, 5-2-4-(1,2-benzisothiazol-3-yl)-1-piperazinylethyl-6-chloro-1,3-dihydro-
ZIPRASIDONE: ZIPRASIDONE HYDROCHLORIDE MONOHYDRATE
1,2-Benzisothiazole, 3-(1-piperazinyl)-, monohydrochlorideH-indol-2-one, 6-chloro-5-(2-chloroethyl)-1,3-dihydro
5-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one
CP-88059：CP-88059-1 | [EINECS(EC#)]
203-794-9 | [Molecular Formula]
C21H21ClN4OS | [MDL Number]
MFCD00866661 | [Molecular Weight]
412.94 | [MOL File]
146939-27-7.mol |
| Chemical Properties | Back Directory | [Appearance]
Tan Solid | [Melting point ]
213-215°C | [Boiling point ]
554.8±50.0 °C(Predicted) | [density ]
1.369±0.06 g/cm3(Predicted) | [storage temp. ]
Sealed in dry,Room Temperature | [solubility ]
DMSO (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
13.34±0.20(Predicted) | [color ]
Brown to Dark Brown | [Usage]
Labelled Ziprasidone, which is used as an antipsychotic | [Merck ]
14,10171 | [CAS DataBase Reference]
146939-27-7(CAS DataBase Reference) |
| Hazard Information | Back Directory | [Chemical Properties]
Tan Solid | [Originator]
Geodon,Pfizer,USA | [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. | [Manufacturing Process]
Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-
1,3-dihydro-2H-indol-2-one
A 20-gallon glass lined tank, under a nitrogen atmosphere, was charged with
33.5 liters of water and 9.4 kilograms (kg) of sodium carbonate (dense, 89.1
moles, 3.4 eq.). The resulting mixture was stirred to give a solution. To the
solution 6.4 kg of 2-chloroethyl-6-chloro-oxindole (27.8 moles, 1.06 eq.) was
charged, followed by 6.7 kg of 3-piperazinyl-1,2-benzisothiazole hydrochloride
(26.2 moles, 1.0 eq.). This was stirred and heated to reflux (100°C). After 11
hours the reaction was sampled for high pressure liquid chromatography
(HPLC) assay. The reflux was continued for another 2 hours then the reaction
was cooled to 25°C and the slurry stirred for 1 hour. The product was
observed and found to be essentially free from lumps and gummy matter. The
product was collected by filtration. A 14 liter water was added to the tank and
cooled to 12°C and then used to wash the product. The cake was pulled as
dry as possible, and the product was returned to the tank along with 40 liters
of isopropyl alcohol (IPO). This was cooled and then stirred for 2 hours and
the product was collected by filtration. The cake was washed with 13.4 liters
of fresh IPO, then dried under vacuum at 30° to 40°C. After drying, 17.3 kg
of the title compound was obtained. This was in excess of the theoretical
weight yield due to some residual carbonate in the crude product.
Recrystallization of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-
chloro-1,3-dihydro-2H-indol-2-one
To a clean and dry 100-gallon glass lined tank was charged 9.0 kg of the
material obtained above and 86 gallons of tetrahydrofuran (THF). The slurry
was heated to reflux and held for 1 hour. The hazy solution was then filtered
through a 14" sparkler precoated with filter aid and backed with a Fulflo filter
to a clean, dry, and "spec free" glass-lined tank on a lower level. The batch
was concentrated by vacuum distillation. Another 8.3 kg of the material
obtained in above was dissolved in 83 gallons of THF in the upper tank. This
was filtered to the lower tank. The tank lines and sparkler were rinsed with 10
gallons of THF. The batch was concentrated to about 22 gallons, then cooled
to 5°C and stirred for 1 hour. The product was collected by filtration. Then 20
gallons of fresh IPO were cooled in the tank and used to rinse the product
cake. The product was collected and dried under vacuum at 45°C; yielding
9.05 kg of product (83.8% yield for the coupling and recrystallization. The
product matched the spectra of a standard NMR and showed the correct
retention time by HPLC with 99.7% assay. Another way for preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2-H-
indol-2-one.
A clean and dry 20-gallon glass lined tank was charged with 19 L of water and
4.44 kg of sodium carbonate, after the carbonate had dissolved 4.29 kg (17.5
moles) of 5-(2-chloroethyl)-6-chloro-oxindole and 3.62 kg (16.5 moles) of 1-
(1,2-benzisothiazol-3-yl)piperazine were added. The aqueous slurry was
heated to reflux and the temperature maintained for 14 hours. When the
reaction was complete the solution was cooled to 20°C and filtered. The wet
product was reslurried in 23 L of isopropyl alcohol at room temperature for 2
hours. The product was collected by filtration on 2 large Buchner funnels, each
was washed with 3.4 L of fresh isopropyl alcohol. The product was vacuum
dried at 30° to 40°C. until no isopropyl alcohol remained, giving 5.89 kg
(86.4% yield) of the desired free base which matched a standard sample by
high performance liquid chromatography (HPLC).
A clean and dry 20-gallon reactor was charged with 17.4 gallons of deionized
water and 4.44 L of concentrated hydrochloric acid, to give a 0.77 M solution.
To the solution was added 4.44 kg of the anhydrous 5-(2-(4-(1,2-
benzisothiazol-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one
free base. The slurry was warmed to 65°C and held for 18 hours. The slurry
was cooled to room temperature. The product was filtered and washed with
2x5-gallon portions of deionized water, and then air dried at 50°C for 30
hours. The dried product contained 4.4% water and the x-ray diffraction
method confirmed that the desired product was obtained. | [Brand name]
Geodon (Pfizer). | [Therapeutic Function]
H-Indol-2-one, 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl)ethyl)-6-chloro-1,3-dihydro-, monohydrochloride monohydrate | [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]
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. | [General Description]
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. |
| Questions And Answer | Back Directory | [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 chemicalbook of Dai Xiongfeng.
| [Uses]
It is a kind of antipsychotic and can be used as the antagonist of the dopamine D2-serotonin 5-HT2.
| [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.
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