162401-32-3 Usage
Description
Roflumilast, also known as Daxas, is a selective phosphodiesterase 4 (PDE4) inhibitor. It is a potent, cell-permeable inhibitor of PDE4, selectively inactivating the second messenger cAMP by hydrolyzing the phosphodiester bond, producing AMP. Roflumilast demonstrates good bioavailability and has applications in respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). It was developed by researchers at the University of Liverpool in partnership with Nycomed and was approved in Germany in July 2010.
Uses
1. Used in Pharmaceutical Industry:
Roflumilast is used as an anti-asthmatic agent for the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD). It helps in reducing inflammation and improving lung function in patients with these conditions.
2. Used in Respiratory Disease Treatment:
Roflumilast is used as an add-on to bronchodilator treatment for maintenance therapy of severe chronic obstructive pulmonary disorder (COPD) associated with chronic bronchitis in adult patients with a history of frequent exacerbations.
3. Used in Ophthalmic Solutions:
Roflumilast is also used in the development of ophthalmic solutions, although the specific application reason is not provided in the materials.
4. Used in Inflammatory Condition Treatment:
Roflumilast is a selective, long-acting PDE-4 inhibitor approved for the treatment of inflammatory conditions of the lungs, such as asthma and COPD. It has demonstrated anti-inflammatory effects in preclinical cellular and animal models.
5. Used in Drug Synthesis:
Roflumilast is synthesized in four steps from 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde, and its primary metabolite, roflumilast N-oxide, is also a potent and competitive inhibitor of PDE4. The drug's synthesis and metabolism involve various chemical reactions and are mediated by CYP3A4 and CYP1A2.
Despite its effectiveness, Roflumilast has some dose-limiting side effects, including mild nausea, diarrhea, and weight loss. However, these symptoms typically subside after a few weeks of treatment.
Indications and Usage
Roflumilast is a selective oral phosphodiesterase-4 (PDE-4) inhibitor and a benzamide compound. It was developed by the German company Altana in 1993 and is the only oral PDE-4 inhibitor used to treat respiratory tract diseases approved for sale. Roflumilast is the first drug of its kind to target severe chronic obstructive pulmonary disease (COPD), and it is also the first oral anti-inflammation drug specifically developed for COPD patients. Its unique properties can help regulate COPD: when used in combination with bronchodilators to treat extremely severe COPD patients, roflumilast can has the advantage of further reducing symptoms and deterioration rate, thus making it the first drug that targets patients with recurring deteriorating phenotype-specific COPD and severe air flow obstruction related to chronic coughing and excess phlegm. Besides being a treatment for severe COPD, roflumilast can also be used to prevent and treat livestock respiratory tract diseases, excess mucosa bronchitis cough, asthmatic bronchitis, and acute bronchitis and air sacculitis accompanied by abnormal respiratory tract secretion.
Mechanisms of Action
Roflumilast selectively inhibits PDE4 to prevent the signal transduction for inflammatory reactions, and it then inhibits the damage on lung tissue caused by respiratory tract diseases such as COPD and asthma.
Pharmacokinetics
Roflumilast is taken orally and is metabolized by cytochrome oxidase P45(CYP)3A4 and CYP1A2 enzyme into N-oxide. Roflumilast N-oxide’s activity is only 2-3 times weaker than that of roflumilast, and it also has relatively high PDE-4 selectivity. 90% of PDE-4 inhibition in the body is achieved by roflumilast N-oxide, while the other 10% is achieved by the original drug. A daily 500ng oral dose of roflumilast for a healthy person will produce a free blood concentration of roflumilast N-oxide in 24 hours of about 1-2 nmol?L-1, and its serum protein binding rate is about 97%. Smoking has little impact on roflumilast’s pharmacokinetics. Roflumilast mostly affects inflammation cells related to asthma, including eosinophils, neutrophils, and mast cells. This drug can specifically affect a certain enzyme that participates in smooth muscle contraction, it can prevent cAMP decomposition, thus preventing the signal transduction for inflammatory reactions, and it is anti-inflammatory, giving it relatively good curative effects in clinically treating asthma and COPD. Roflumilast can also significantly extend the deterioration of respiratory symptoms while also dramatically increasing patients’ quality of life.
Pharmacokinetics
Roflumilast is well absorbed on oral administration
and has a half-life of 10 hours. Roflumilast is metabolized in the liver to its N-oxide derivative,
which also is a PDE4 inhibitor, and it has a plasma half-life of 20 hours.
Originator
BYK Gulden Lomberg Chemische Fabrik GmbH (Germany)
Biochem/physiol Actions
Roflumilast is a highly potent, orally active, and selective phosphodiesterase 4 (PDE4) inhibitor with an IC50 of 0.8 nM. Roflumilast has anti-inflammatory properties and is used clinically to treat COPD.
Mechanism of action
Roflumilast is the more potent of the two drugs, and along with its active metabolite, roflumilast-N-oxide, it is nonselective in its
inhibitory action on PDE4B and PDE4D. The PDE4B appears to be the most closely linked to anti-inflammatory effects, whereas the
PDE4D receptor subtype is thought to be linked to nausea, possibly through a central effect. Roflumilast exhibits 80% oral
bioavailability and has an elimination half-life of 10 hours, whereas the N-oxide has an elimination half-life of 20 hours and has shown
no drug interactions. Clinical trials in patients with asthma or COPD are quite promising.
Clinical Use
Roflumilast is currently undergoing clinical trials in Europe for use in the treatment of both
asthma and COPD.
Synthesis
The straightforward preparation of roflumilast begins with commercially available
methyl 3,4-dihydroxybenzoate (130). Alkylation of the more reactive 3-
hydroxyl group with (bromomethyl)cyclopropane (131) preceded a second alkylation of the remaining
p-phenol with chlorodifluoromethane in aqueous sodium hydroxide. These phase-transfer conditions
saponified the ester within 130 and after acidic quench, carboxylic acid 132 was ultimately furnished in
excellent yield (97%) over the three step protocol. Activation of 132 as the corresponding acyl halide
through use of thionyl chloride (SOCl2) and subsequent exposure to commercial aminopyridine 133
provided roflumilast (XII) in 81% yield.
References
1) Hatzelmann?et al.?(2010),?The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease; Pulm, Pharmacol. Ther.,?23?235
2) Rabe?et al.?(2011),?Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease; Br. J. Pharmacol,?163?53
3) Heckman?et al.?(2018),?Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial; Psychopharmacology (Berl.),?235?301
4) Vanmierlo?et al.?(2016),?The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses;?Behav. Brain Res.,?303?26
5) Tikoo?et al.?(2014),?Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy; Biochem. Biophy. Res. Commun.,?450?1581
6) Mollmann?et al.?(2017),?The PDE4 inhibitor roflumilast reduced weight gain by increasing energy expenditure and leads to improved glucose metabolism; Diabetes Obes. Metab.,?19?496
Check Digit Verification of cas no
The CAS Registry Mumber 162401-32-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,6,2,4,0 and 1 respectively; the second part has 2 digits, 3 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 162401-32:
(8*1)+(7*6)+(6*2)+(5*4)+(4*0)+(3*1)+(2*3)+(1*2)=93
93 % 10 = 3
So 162401-32-3 is a valid CAS Registry Number.
InChI:InChI=1/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)
162401-32-3Relevant articles and documents
Production and preparation method of roflumilast crystalline powder bulk drug
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Paragraph 0013; 0016-0025, (2021/03/06)
The invention discloses a production and preparation method of a roflumilast crystalline powder bulk drug. The method comprises the following steps of: 1) acylation reaction: dropwise adding thionyl chloride into a toluene solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and heating the reaction mixture to reflux, carrying out reaction for 2h, then conducting reduced pressure concentration to remove the solvent, dissolving the residue left by concentration in tetrahydrofuran, controlling the temperature of the solution at 15-20DEG C under stirring and dropwise adding the solution into a tetrahydrofuran solution of 4-amino-3, 5-dichloropyridine and sodium hydride; and 2) refining. The method has the beneficial effects that: a commercially available starting material of 1 (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) and a starting material of 2 (4-amino-3, 5-dichloropyridine) are selected as the starting materials, acylation and refining are carried out to obtain roflumilast, the process is stable, the yield is high, and industrial production is easy.
A method for preparing raw material for roflumilast and detection method
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, (2018/05/16)
The invention discloses a preparation method and a detection method of a roflumilast material. The preparation method comprises the following steps: mixing 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid SM-1, thionyl chloride, dimethyl formamide with toluene, and carrying out an acylating chlorination reaction to obtain a midbody 1; mixing 3,5-dichloro-4-aminopyridine SM-2, tetrahydrofuran with potassium tert-butoxide and carrying out a salt forming reaction to obtain tetrahydrofuran solution of a midbody 2; and then mixing the midbody 1 and the midbody 2 with tetrahydrofuran, carrying out amidation to obtain a crude product of roflumilast, and refining the crude product of roflumilast to prepare the roflumilast material. Aiming to overcome the shortage of the prior art, the preparation process of the roflumilast material is optimized, so that the curative effect for treating diseases such as chronic obstructive pulmonary disease (COPD) is more remarkable; and besides, a systematic, complete and effective composition identifying and content measuring method is provided, so that the quality of the medicine can be effectively controlled, and the clinical effect is ensured.
Synthesis method of roflumilast
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Paragraph 0044; 0045; 0046; 0047; 0048; 0049; 0050-0059, (2017/07/26)
The invention provides a synthetic method for roflumilast. The method comprises the following steps: (a), in an organic solvent, producing an exchange reaction of a compound (I) and magnesium or a Grignard reagent under the backflow condition to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 0-50 DEG C to obtain a compound (II); or in the organic solvent, reacting the compound (I) with n-butyl lithium at 90 DEG C below zero to 70 DEG C below zero to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 90 DEG C below zero to 70 DEG C below zero to obtain a compound (II); (b) in the organic solvent, reacting the compound (II) obtained in the step (a) with pivaloyl chloride or sulfonyl chloride at 0-50 DEG C in the presence of alkali to generate a mixed anhydride intermediate, and reacting the mixed anhydride intermediate with 3,5-dichloro-4-aminopyridine at 0-70 DEG C to obtain a compound (III) which is roflumilast. The method is short in process route, low in raw material and reagent costs, high in total yield, mild in reaction condition and suitable for industrialized production. The synthetic route of the method is as shown in the descriptions.