89365-50-4

Basic information

• Product Name: Salmeterol
• Synonyms: 4-HYDROXY-A1-[[[6-(4-PHENYLBUTOXY)HEXYL]AMINO]METHYL]-1,3-BENZENEDIMETHANOL;2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino] ethyl]-phenol;SALMETEROL;(+-)-4-hydroxy-alpha1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-1,3-benzenedi;1,3-benzenedimethanol,4-hydroxy-alpha1-(((6-(4-phenylbutoxy)hexyl)amino)methyl;gr33343x;SalmeterolXenofoate;4-Hydroxy-3-[hydroxymethyl]phenyl-N-[6-phenylbutoxyhexyl]ethanolamine
• CAS NO: 89365-50-4
• Molecular Formula: C₂₅H₃₇NO₄
• Molecular Weight: 415.57
• Product Categories: Aromatic Building Blocks;API
• Mol File: 89365-50-4.mol
• Article Data: 16

Chemical Properties

• Melting Point: 75.5-76.5°
• Boiling Point: 603 °C at 760 mmHg
• Flash Point: 318.5 °C
• Appearance: /
• Density: 1.112 g/cm³
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 9.99±0.31(Predicted)
• CAS DataBase Reference: Salmeterol(CAS DataBase Reference)
• NIST Chemistry Reference: Salmeterol(89365-50-4)
• EPA Substance Registry System: Salmeterol(89365-50-4)

Safety Data

• RTECS: CZ6457000
• Hazardous Substances Data: 89365-50-4(Hazardous Substances Data)

Usage

Asthma curative

Salmeterol is an asthma remedy. It is developed from the molecular structure of salbutamol with only an additional tail part. This part is closely associated with the specific structure of the beta 2 receptor, the external receptor site. This allows the other parts of the molecule to act freely on the beta 2 receptor. And for this reason, this product can continue to stay in the position of action. Salmeterol can be used as a bronchodilator for long-acting beta 2 receptor agonists in daily control of asthma symptoms. It can be used for long-term treatment of asthma (including nocturnal asthma and exercise-induced asthma), reversible airway obstruction in chronic bronchitis and emphysema, and is not suitable for acute attack of asthma.

Antiasthmatic medicine

Antiasthmatic drugs are the drugs that can act on the different links of the asthma attack in order to relieve or prevent the attack of asthma. Salmeterol is a new long-acting beta 2 agonist antiasthmatic drug, derived from salbutamol, and closely linked to beta 2 receptor, resulting in more durable activation. Its chemical name is hydroxy naphthalate, which is white or white like powder with bitter taste. It was first developed by the British GlaxoSmithKline Co and was first listed in the UK in 1990. Its commodity name is Serevent, Salmeterol　Xinafoate　Aerosol,Sertindole and Salmeterol. It can inhibit the release of hypersensitivity mediators from the mast cells in the lung. It can inhibit the early and late phase reaction induced by inhalation antigen and reduce the hyperresponsiveness of the trachea. Clinical trials show that is salmeterol stronger than salbutamol. It has a longer duration effect to protect asthma caused by histamine induced bronchoconstriction and movement. It features long duration, small extrapulmonary effect and good tolerance. It is an ideal drug for the treatment of nocturnal attack and asthma. The pharmacokinetic study has indicated that this dose of this product twice a day, 50μg each time. 5～15 min after 1 inhalation of 50 and 400μg, the highest plasma concentration will be 0.1 to 0.2μg /L and 1 ~ μg/L respectively. This product is strongly metabolizing by hydrolysis, and most of the dosage is eliminated in 72h. The doses of 23% and 57% in 168h can be found in urine and feces respectively. In addition, salmeterol has a controlled effect on histamine, leukotrienes and prostaglandins. It is worth notice that this product can not be used with non selective beta blockers for the treatment of asthma, and it should be prudent for patients with asthma with heart disease. Salmeterol 's common adverse reactions include hypokalemia, abnormal bronchospasm, tremor, headache, and palpitations. Its common beta agonists include: ephedrine, isoproterenol, salbutamol, terbutaline, clenbuterol, clorprenaline, tulobuterol, clenbuterol, procaterol, salmeterol, bambuterol, methoxyphenamine, rimiterol, bitolterol, sonarin, butero, fenoterol etc..

Clinical evaluation

It has been proved that this product dose is 50μg, inhaled 2 twice a day, and is effective for mild to moderate asthma. In patients with moderate asthma, it will be more efficient to take a dose of 100μg by inhalation twice a day. The effect is longer and up to 12 h. It has been proved that the dose of 5050μg by inhaling twice a day will be more effectivethan the dose of 200μg salbutamol by inhaling 4 times a day in improving lung function and lightening the day and night respiratory syndrome. Salmeterol aerosol should used in adult bronchial asthma, 50μg each time, twice a day (morning, before bedtime), and the longest medication time is 71 weeks. The results shows an obvious tendency to improve compared with the pre medication. The improvement in the fourth week after administration is 15%. The moderate improvement is 50%, and the mild improvement is 72.5%. The improvement rate of long-term medication is 15%, 68.2% and 88.6%, respectively. 18 patients with bronchial asthma have been given aerosol 25μg and inhalation powder 25μg each time. The results have indicated that FEV10, PEFR, MMEF, V50 and V25 begin to be improved after 25 min, and their effects have maintained for 8h. The results of lung function examination after inhalation of 4h are the same. Both the total improvement and the moderate improvement are both 81.8%, and the effectis completely equal. For the patients with asthma at night, inhalation of 50μg and 100μg every day for twice can obviously improve the expiratory flow rate throughout the night and increase the percentage of sleep in patients with nocturnal asthma. These indexes are superior to placebo. Most studies have shown that this product improves the quality of sleep in the subjects.

Uses

Salmeterol is a β2-Adrenergic agonist used for relief and control of asthma symptoms.

Definition

ChEBI: A phenol having a hydroxymethyl group at C-2 and a 1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl group at C-4; derivative of phenylethanolamine.

General Description

Salmeterol has an N-phenylbutoxyhexyl substituent incombination with a β-OH group and a salicyl phenyl ring foroptimal direct-acting β2-receptor selectivity and potency. Ithas a potency similar to that of ISO. This drug associateswith the β2-receptor slowly resulting in slow onset of actionand dissociates from the receptor at an even slower rate. It is resistant to both MAO and COMT and highly lipophilic(log P=3.88). It is thus very long acting (12 hours), aneffect also attributed to the highly lipophilic phenylalkylsubstituent on the nitrogen atom, which is believed to interactwith a site outside but adjacent to the active site.

Hazard

A poison by inhalation.

Biological Activity

Potent and selective β 2 -adrenoceptor agonist (EC 50 = 5.3 nM); bronchodilator. Unlike other β 2 agonists, binds to exo-site domain of β 2 receptors, producing a slow onset of action and prolonged activation. Also available as part of the β -Adrenoceptor Agonist Tocriset? .

Mechanism of action

A β2-agonist with a slow onset and extended duration of action is salmeterol. Salmeterol has the same phenyl ring substitution R3 as albuterol but also an unusually long and lipophilic group R1 on the nitrogen. The octanol–water partition coefficient, log P, for salmeterol is 3.88, compared with 0.66 for albuterol. Salmeterol is approximately 50-fold more selective than albuterol for the β2-receptor. Substantial evidence indicates that its long duration of action results from a specific binding interaction (“anchoring”) of the phenyl group at the end of the extended lipophilic side chain with a specific region of the β2-receptor, affording salmeterol a unique binding mechanism.

Clinical Use

Salmeterol usually is prescribed for severe persistent asthma following previous treatment with a short-acting β-agonist, such as albuterol. The noticeable differences between salmeterol and albuterol are the onset of action and their duration of action (Table 13.6). When used regularly every day as prescribed, inhaled albuterol decreases the number and severity of asthma attacks. It is not used, however, for relieving an asthma attack that has already started.

InChI:InChI=1/C25H37NO4/c27-20-23-18-22(13-14-24(23)28)25(29)19-26-15-7-1-2-8-16-30-17-9-6-12-21-10-4-3-5-11-21/h3-5,10-11,13-14,18,25-29H,1-2,6-9,12,15-17,19-20H2

Upstream product

• 444809-36-3 6-oxiranyl-4H-benzo[1,3]dioxine 
• 497063-91-9 5-(2-{Benzyl-[6-(4-phenyl-butoxy)-hexyl]-amino}-acetyl)-2-hydroxy-benzoic acid methyl ester 
• 36256-45-8 3-carbomethoxy-4-hydroxy-α-bromoacetophenone 

Downstream Products

• 135271-49-7 salmeterol xinafoate 
• 135271-47-5 (S)-Salmeterol 
• 135271-47-5 (R)-(-)-salmeterol 

Relevant articles and documents

Structural isomers of saligenin-based β2-agonists: Synthesis and insight into the reaction mechanism

Salmeterol and albuterol are well-known β2-adenoreceptor agonists widely used in the treatment of inflammatory respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease. Here we report the preparation of structural isomers of salmeterol and albuterol, which can be obtained from the same starting material as the corresponding β2-agonists, depending on the synthetic approach employed. Using 1D and various 2D NMR measurements, we determined that the structure of prepared isomers holds the β-aryl-β-aminoethanol moiety, in contrast to the α-aryl-β-aminoethanol moiety found in salmeterol and albuterol. We investigated the reaction of β-halohydrin and amines responsible for the formation of β-aryl-β-amino alcohol-both experimentally and using computational methods. The structure of β-halohydrin with the methyl salicylate moiety imposes the course of the reaction. The solvent plays a relevant, yet ambiguous role in the direction of the reaction, while the strength of the base influences the reaction yield and isomer ratio in a more evident way. Using computational methods, we have shown that the most probable reaction intermediate responsible for the formation of the unexpected isomer is the corresponding para-quinone methide, which can be formed due to phenol present in the methyl salicylate moiety. After successful preparation of albuterol and salmeterol isomers, we tested their inhibition potency to human acetylcholinesterase (AChE) and usual and atypical butyrylcholinesterase (BChE). Kinetic studies revealed that both isomers are low-potency reversible inhibitors of human cholinesterases.

Preparation method of salmeterol base

The invention discloses a preparation method of salmeterol. The method includes the following steps: carrying out a condensation reaction on a compound 2 and a compound 3 under an alkaline condition to obtain an intermediate 4; carrying out acidic hydrolysis to obtain an intermediate 5, and reducing the intermediate 5 to obtain an intermediate 6; and removing a benzyl group from the intermediate 6 by using palladium on carbon (Pd/C) to obtain a salmeterol base. The preparation method has the advantages of mild reaction conditions, simple post-treatment, low cost, high yield high product purity, and easiness in realization of industrialization.

An efficient and practical synthesis of salmeterol

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