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.
