Ciclesonide CAS 126544-47-6

Introduction：Basic information about Ciclesonide CAS 126544-47-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Ciclesonide Basic information

• Product Name: Ciclesonide
• Synonyms: (r)-11b,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with cyclohexanecarboxaldehyde 21-isobutyrate;Ciclesonide;(11β,16α)-16,17-[[(R)-CyclohexylMethylene]bis(oxy)]-11-hydroxy-21-(2-Methyl-1-oxopropoxy)-pregna-1,4-diene-3,20-dione;Ciclesonide(RPR251526);Ciclesonide containing impurity A CRS;Ciclesonide CRS;Zetonna;Pregna-1,4-diene-3,20-dione, 16,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-, (11β,16α)-
• CAS: 126544-47-6
• MF: C32H44O7
• MW: 540.69
• Product Categories: Other APIs;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids
• Mol File: 126544-47-6.mol

Ciclesonide Chemical Properties

• Melting point: 202-209?C
• Boiling point: 665.0±55.0 °C(Predicted)
• density: 1.23±0.1 g/cm3(Predicted)
• storage temp.: Sealed in dry,2-8°C
• solubility: Chlorofrom (Slightly), Methanol (Slightly)
• form: Solid
• pka: 14.25±0.70(Predicted)
• color: White to Off-White
• biological source: synthetic
• Water Solubility: water: <0.1g/L acetone: soluble ethanol: soluble
• InChIKey: LUKZNWIVRBCLON-GXOBDPJESA-N
• SMILES: [C@@]12(C(=O)COC(=O)C(C)C)O[C@H](C3CCCCC3)O[C@@H]1C[C@@]1([H])[C@]3([H])CCC4=CC(=O)C=C[C@]4(C)[C@@]3([H])[C@@H](O)C[C@]21C |&1:0,11,19,21,23,33,35,37,40,r|

Safety Information

• WGK Germany: WGK 3
• Storage Class: 11 - Combustible Solids

Ciclesonide Usage And Synthesis

Description

Ciclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactictreatment of persistent asthma. ICS treatment is a widely accepted standard of carefor maintenance therapy of chronic asthma, and the currently available agents includefluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, andbeclomethasone dipropionate. These agents exert their potent anti-inflammatoryeffects via modulation of the glucocorticoid receptor (GR). Although ICS drugs aregenerally safe and well tolerated compared with oral corticosteroids, many havemeasurable systemic exposures, and concerns over potential side effects resultingfrom it severely limit the dose at which they can be administered for long-termtherapy. Systemic adverse effects associated with corticosteroids include HPA axissuppression, osteoporosis, abnormal glucose metabolism, cataracts, and glaucoma,some of which could potentially occur with the long-term use of high dose ICS. Thekey differentiators for ciclesonide relative to other ICS drugs are its longer durationof action and lower systemic exposure. Ciclesonide is an isobutyryl ester prodrug. It iscleaved by the endogenous esterases in the lung to des-isobutyryl ciclesonide (des-CIC), which is a potent GR agonist. The binding affinity of des-CIC for human GR(K_i=0.31 nM) is similar to other ICS such as budesonide (K_i=0.44nM) and fluticasonepropionate (K_i=0.24nM), while ciclesonide itself has about 100-fold loweraffinity (K_i=37nM). In lung tissue, des-CIC undergoes reversible lipid conjugationto form oleate and palmitate ester conjugates, which act as a slow-release pool for thedrug and increase the pulmonary residence time. This, in turn, contributes to theenhanced local effects and the long duration of action.
Inhaled ciclesonide wasgenerally well tolerated in these clinical studies. Ciclesonide did not suppress biochemicalmarkers of adrenal function in 52-week studies; however, the long-term(＞52 weeks) systemic effects remain unknown. Ciclesonide is chemically producedvia a semi-synthesis starting from 16-α-hydroxyprednisolone by first converting to atriisobutyryl ester intermediate with isobutyric anhydride, and subsequent reaction ofthe triester with cyclohexane carboxaldehyde and hydrochloric acid in dioxane. Thelatter step produces the cyclic ketal as a mixture of diastereomers, which is subjectedto HPLC and fractional crystallization to produce ciclesonide.

Chemical Properties

White Solid

Originator

RecordatiEspana (Spain)

Uses

A glucocorticoid microemulsion nasal preparation allergy inhibitor rhinitis.

Definition

ChEBI: Ciclesonide is an organic molecular entity.

Brand name

Alvesco (Dynamit Nobel GmbH).

General Description

Ciclesonide (Omnaris) is a prodrug that requireshydrolysis of the isobutyrate ester at C21 to form theactive corticosteroid (des-ciclesonide). It has minimal oralbioavailability due to extensive metabolism, mainly byCYP3A4. The metabolites of ciclesonide have not beenfully characterized.

Synthesis

Two separate approaches to thesyntheses of the chiral ciclesonide have been described in thepatent literature. The first route involves a chiral resolutionstep and the second approach highlights a stereoselectivetrans acetalization approach. The first synthesis ofciclesonide started by reacting (11|?,16|á)-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione (1) withisobutyric anhydride to make the tri-isobutyl ester in 87% yield. Reaction of the tri-ester with cyclohexane carboxaldehydein the presence of HCl and 70% perchloric acid gavethe cyclohexane acetal 3, which was then separated into thedesired isomer ciclesonide (I) by HPLC or recrystallization.

storage

Store at +4°C

References

[1] Patent: CN103421075, 2017, B. Location in patent: Paragraph 0043-0045
[2] Patent: US2007/117974, 2007, A1. Location in patent: Page/Page column 4
[3] Patent: US2010/222572, 2010, A1. Location in patent: Page/Page column 9
[4] Patent: EP2392584, 2011, A1. Location in patent: Page/Page column 14

Ciclesonide Preparation Products And Raw materials

• Raw materials: 21-bromo-16α,17-[(R)-cyclohexylmethylenedioxy]-11β-hydroxypregna-1,4-dien-3,20-dione-->11β,16α,17α-trihydroxypregna-21-(2-methyl-1-oxopropoxy)-1,4-diene-3,20-dione-->Desisobutyryl Ciclesonide-->Isobutyric anhydride-->Cyclohexanecarboxaldehyde-->Isobutyryl chloride-->SODIUM ISOBUTYRATE-->Dichloromethane-->Tetrahydrofuran-->Boron trifluoride