Ciclesonide

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
EINECS:
Product Categories:Other APIs;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids
Mol File:126544-47-6.mol
Ciclesonide Structure
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 neat
pka14.25±0.70(Predicted)
color White to Off-White
InChIKeyLUKZNWIVRBCLON-GXOBDPJESA-N
Safety Information
MSDS Information
Ciclesonide Usage And Synthesis
DescriptionCiclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactic treatment of persistent asthma. ICS treatment is a widely accepted standard of care for maintenance therapy of chronic asthma, and the currently available agents include fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, and beclomethasone dipropionate. These agents exert their potent anti-inflammatory effects via modulation of the glucocorticoid receptor (GR). Although ICS drugs are generally safe and well tolerated compared with oral corticosteroids, many have measurable systemic exposures, and concerns over potential side effects resulting from it severely limit the dose at which they can be administered for long-term therapy. Systemic adverse effects associated with corticosteroids include HPA axis suppression, osteoporosis, abnormal glucose metabolism, cataracts, and glaucoma, some of which could potentially occur with the long-term use of high dose ICS. The key differentiators for ciclesonide relative to other ICS drugs are its longer duration of action and lower systemic exposure. Ciclesonide is an isobutyryl ester prodrug. It is cleaved 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 (Ki=0.31 nM) is similar to other ICS such as budesonide (Ki=0.44nM) and fluticasone propionate (Ki=0.24nM), while ciclesonide itself has about 100-fold lower affinity (Ki=37nM). In lung tissue, des-CIC undergoes reversible lipid conjugation to form oleate and palmitate ester conjugates, which act as a slow-release pool for the drug and increase the pulmonary residence time. This, in turn, contributes to the enhanced local effects and the long duration of action.
Inhaled ciclesonide was generally well tolerated in these clinical studies. Ciclesonide did not suppress biochemical markers of adrenal function in 52-week studies; however, the long-term (>52 weeks) systemic effects remain unknown. Ciclesonide is chemically produced via a semi-synthesis starting from 16-α-hydroxyprednisolone by first converting to a triisobutyryl ester intermediate with isobutyric anhydride, and subsequent reaction of the triester with cyclohexane carboxaldehyde and hydrochloric acid in dioxane. The latter step produces the cyclic ketal as a mixture of diastereomers, which is subjected to HPLC and fractional crystallization to produce ciclesonide.
Chemical PropertiesWhite Solid
OriginatorRecordati Espana (Spain)
UsesA glucocorticoid microemulsion nasal preparation allergy inhibitor rhinitis.
DefinitionChEBI: Ciclesonide is an organic molecular entity.
Brand nameAlvesco (Dynamit Nobel GmbH).
General DescriptionCiclesonide (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.
SynthesisTwo separate approaches to the syntheses of the chiral ciclesonide have been described in the patent literature. The first route involves a chiral resolution step and the second approach highlights a stereoselective trans acetalization approach. The first synthesis of ciclesonide started by reacting (11|?,16|á)-11, 16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione (1) with isobutyric anhydride to make the tri-isobutyl ester in 87% yield. Reaction of the tri-ester with cyclohexane carboxaldehyde in the presence of HCl and 70% perchloric acid gave the cyclohexane acetal 3, which was then separated into the desired isomer ciclesonide (I) by HPLC or recrystallization.

Synthesis_126544-47-6


storageStore at +4°C
Ciclesonide Preparation Products And Raw materials
Desisobutyryl Ciclesonide Budesonide 16alpha-Hydroxyprednisonlone acetate Desonide Cyclohexanecarboxaldehyde Ciclesonide Prednisolone (r)-budesonide 11a,16b,17,21-Tetrahydroxy-pregna-1,4-diene-3,20-dione Halcinonide Prednisolone-21-acetate Ciclesonide

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