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Acebutolol……..For the management of hypertension and ventricular premature beats in adults.

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Acebutolol

Acebutolol
N-(3-Acetyl-4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl)butanamide
3′-acetyl-4′-(2-hydroxy-3-(isopropylamino)propoxy)butyranilide
(±)-acebutolol
Acetobutolol; Sectral; Prent; Neptal; Acebutololum; Acebutololo; (+-)-Acebutolol; dl-Acebutolol; Acebrutololum

Molecular Formula: C18H28N2O4   Molecular Weight: 336.42592
 
 
CAS Registry Number: 37517-30-9
CAS Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]butanamide
Additional Names: 3¢-acetyl-4¢-[2-hydroxy-3-(isopropylamino)propoxy]butyranilide; 1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane; 5¢-butyramido-2¢-(2-hydroxy-3-isopropylaminopropoxy)acetophenone
Percent Composition: C 64.26%, H 8.39%, N 8.33%, O 19.02%
Melting point: mp 119-123°
 
Derivative Type: Hydrochloride
CAS Registry Number: 34381-68-5
Manufacturers’ Codes: M & B 17803A; IL-17803A
Trademarks: Acecor (SPA); Acetanol (RPR); Neptal (Procter & Gamble); Prent (Bayer); Sectral (RPR)
Molecular Formula: C18H28N2O4.HCl
Molecular Weight: 372.89
Percent Composition: C 57.98%, H 7.84%, N 7.51%, O 17.16%, Cl 9.51%
Properties: Crystals from anhydr methanol-anhydr diethyl ether, mp 141-143°. Freely sol in water. Soly at room temperature (mg/ml): water 200; ethanol 70.
Melting point: mp 141-143°
Therap-Cat: Antihypertensive; antianginal; antiarrhythmic (class II).
 
Acebutolol (trade names SectralPrent) is a beta blocker for the treatment of hypertension and arrhythmias.
A cardioselective beta-adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm as well as weak inherent sympathomimetic action.
 

Brief background information

Salt ATC Formula MM CAS
C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 37517-30-9
(R) be the bases C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 68107-81-3
(S) be the bases C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 68107-82-4
(RS) -monogidrohlorid C07AB04
C07BB04
18 H 28 N 2 O 4 · HCl 372.89 g / mol 34381-68-5
Acebutolol
Acebutolol structure.svg
Acebutolol ball-and-stick.png
Systematic (IUPAC) name
(RS)-N-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}butanamide
Clinical data
Trade names Sectral
AHFS/Drugs.com monograph
MedlinePlus a687003
Licence data US FDA:link
Pregnancy cat. (AU) B (US)
Legal status ℞ Prescription only
Routes oral, iv
Pharmacokinetic data
Bioavailability 40% (range 35 to 50%)
Metabolism Hepatic
Half-life 3-4 hours (parent drug)
8-13 hours (active metabolite)
Excretion Renal: 30%
Biliary: 60%
Identifiers
CAS number 37517-30-9 Yes
ATC code C07AB04
PubChem CID 1978
DrugBank DB01193
ChemSpider 1901 Yes
UNII 67P356D8GH Yes
KEGG D02338 Yes
ChEBI CHEBI:2379 Yes
ChEMBL CHEMBL642 Yes
Chemical data
Formula C18H28N2O4 
Mol. mass 336.426 g/mol
 
 
Physical data
Melt. point 121 °C (250 °F)

 

Application

  • antagonist of β-adrenergic
  • β-blocker

Classes of substances

  • Acetophenones
    • 1-aryloxy-3-amino-2-propanol
      • Butyric acid anilides

Synthesis pathway

Chemical structure for Acebutolol

File:Acebutolol synthesis 01.svg

Synthesis a)


 

Trade Names

Country Trade name Manufacturer
Germany Printemps Bayer
Sali-Printemps – “-
Tredalat – “-
France Sektral Sanofi-Aventis
United Kingdom Sekadreks Aventis
Sektral Aventis
Italy Atsekor SPA
AlOl SIT
Printemps Bayropharm
Sektral Rhône-Poulenc Rorer
Japan Atsetanol Sanofi-Aventis
Chugai
Sektral Organon
USA – “- Wyeth-Ayerst
Ukraine No No

Formulations

  • ampoule 25 mg;
  • Capsules 100 mg, 200 mg;
  • Tablets of 200 mg, 400 mg, 500 mg (as hydrochloride)

Pharmacology

Acebutolol is a cardioselective beta blocker with ISA (intrinsic sympathomimetic activity; see article on pindolol). It is therefore more suitable than non cardioselective beta blockers, if a patient with asthma or chronic obstructive pulmonary disease (COPD) needs treatment with a beta blocker. (For these reasons, it may be a beta-blocker of choice in inclusion in Polypill strategies). In doses lower than 800mg daily its constricting effects on the bronchial system and smooth muscle vessels are only 10% to 30% of those observed under propranolol treatment, but there is experimental evidence that the cardioselective properties diminish at doses of 800mg/day or more.

The drug has lipophilic properties, and therefore crosses the blood–brain barrier. Acebutolol has no negative impact on serum lipids (cholesterol and triglycerides). No HDL decrease has been observed. In this regard, it is unlike many other beta blockers which have this unfavourable property.

The drug works in hypertensive patients with high, normal, or low renin plasma concentrations, although acebutolol may be more efficient in patients with high or normal renin plasma concentrations. In clinically relevant concentrations, a membrane-stabilizing effect does not appear to play an important role.

Pharmacokinetics

Acebutolol is well absorbed from the GI tract, but undergoes substantial first-pass-metabolization, leading to a bioavailability of only 35% to 50%. Peak plasma levels of acebutolol are reached within 2 to 2.5 hours after oral dosing. Peak levels of the main active metabolite, diacetolol, are reached after 4 hours. Acebutolol has a half-life of 3 to 4 hours, and diacetolol a half-life of 8 to 13 hours.

Acebutolol undergoes extensive hepatic metabolization resulting in the desbutyl amine acetolol which is readily converted into diacetolol. Diacetolol is as active as acebutolol (equipotency) and appears to have the same pharmacologic profile. Geriatric patients tend to have higher peak plasma levels of both acebutolol and diacetolol and a slightly prolonged excretion. Excretion is substantially prolonged in patients with renal impairment, and so a dose reduction may be needed. Liver cirrhosis does not seem to alter the pharmacokinetic profile of the parent drug and metabolite.

Indications

Contraindications

  • Stable or Unstable Angina (due to its partial agonist or ISA activity)

Contraindications and Precautions

Further information: Propranolol

Acebutolol may not be suitable in patients with Asthma bronchiale or COPD due to its bronchoconstricting (β2 antagonistic) effects.

Side effects

Further information: Propranolol

The development of anti-nuclear antibodies (ANA) has been found in 10 to 30% of patients under treatment with acebutolol. A systemic disease with arthralgic pain and myalgias has been observed in 1%. A lupus erythematosus-like syndrome with skin rash and multiforme organ involvement is even less frequent. The incidence of both ANA and symptomatic disease under acebutolol is higher than under Propranolol. Female patients are more likely to develop these symptoms than male patients. Some few cases of hepatotoxicity with increased liver enzymes (ALTAST) have been seen. Altogether, 5 to 6% of all patients treated have to discontinue acebutolol due to intolerable side effects. When possible, the treatment should be discontinued gradually in order to avoid a withdrawal syndrome with increased frequency of angina and even precipitation of myocardial infarction.

Dosage

The daily dose is 200mg – 1,200mg in a single dose or in 2 divided doses as dictated by the severity of the condition to be treated. Treatment should be initiated with low doses, and the dose should be increased cautiously according to the response of the patient. Acebutolol is particularly suitable for antihypertensive combination treatment with diuretics, if acebutolol alone proves insufficient. In some countries injectable forms for i.v.-injection with 25mg acebutolol exist, but these are only for cases of emergency under strict clinical monitoring. The initial dose is 12.5 to 25mg, but additional doses may be increased to 75 to 100mg, if needed. If further treatment is required, it should be oral.

Sectral (acebutolol HCl) structural formula illustration

Sectral (acebutolol HCl) is a selective, hydrophilic beta-adrenoreceptor blocking agent with mild intrinsic sympathomimetic activity for use in treating patients with hypertension and ventricular arrhythmias. It is marketed incapsule form for oral administration. Sectral (acebutolol) capsules are provided in two dosage strengths which contain 200 or 400 mg of acebutolol as the hydrochloride salt. The inactive ingredients present are D&C Red 22, FD&C Blue 1, FD&C Yellow 6, gelatin, povidone, starch, stearic acid, and titanium dioxide. The 200 mg dosage strength also contains D&C Red 28 and the 400 mg dosage strength also contains FD&C Red 40. Acebutolol HCl has the following structural formula:

View Enlarged TableAcebutolol HCl is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±)N-[3-Acetyl-4-[2- hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide.

External links

 
US3857952
EXAMPLE 5 5-Butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described in Example (4) was dissolved in anhydrous methanol (50 ml.), and anhydrous diethyl ether (200 ml.) added. A saturated solution of anhydrous hydrogen chloride in anhydrous diethyl ether (25 ml.) was added dropwise with stirring. An oil was precipitated, which crystallized on further stirring. The solid was filtered off and recrystallized from a mixture of anhydrous methanol and anhydrous diethyl ether to give 5-butyramido-2′-(2- hydroxy-3-isopropyl’amino-propoxy)acetophenone hydrochloride (2.5 g.), m.p. l4ll43C.
 

EXAMPLE 4 Crude 5-butyramido-2′-(2,3-epoxypropoxy)acetophenone (16 g), isopropylamine (20 g.) and ethanol (100 ml.) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and theresidual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, theethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallised from a mixture of ethanol and diethyl ether to give 5′-butyramido-2- (2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g.), m.p. 119l23C.

Similarly prepared was cyclohexylamino-2-hydroxypropoxy)acetophenone, m.p. 112113C.

Crude 5-butyramido-2-(2,3-epoxypropoxy)acetophenone used as startingmaterial was prepared as follows:

p-Butyramidophenol (58 g.; prepared according to Fierz-David and Kuster, loc.cit.), acetyl chloride (25.4 g.) and benzene (500 ml.) were heated together under reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene.

The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give pbutyramidophenyl acetate (38 g.) as an off-white solid, mp. 102-l03C. A mixture of p-butyramidophenyl acetate (38 g.), aluminium chloride (80 g.) and 1,l,2,2-tetrachloroethane (250 ml.) was heated at 140C. for 3 hours. The reaction mixture was cooled and treated with iced water. The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were extracted with 2N aqueous sodium hydroxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5′-butyramido-2-hydroxyacetophenone 15.6 g.), m.p. 114l17C. A solution of 5-butyramido-2′- hydroxyacetophenone (15.6 g.) in ethanol (100 ml.) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g.) and ethanol (100 ml.). The resulting solution’was evaporated to dryness under reduced pressure and dimethylformamide (100 ml.) was added to the solid’residue. Ap-

proximately ml. of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin ml.) was added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to’give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5-butyramido- 2-(2,3-epoxypropoxy)acetophenone (16 g.), m.p. 1101 16C.

The crude compound may be purified by recrystallisation from ethyl acetate, after, treatment with decolourizing charcoal, to give pure 5′-butyramido-2′-(2,3- epoxypropoxy)acetophenone, m.p. 136138C.

 

Links

  • GB 1247384 (May & Baker; appl. 22.12.1967).
  • DAS 1,815,808 (May & Baker; appl. 19.12.1968; GB -prior. 22.12.1967, 5/14/1968, 2.8.1968).
  • US 3,726,919 (May & Baker; 10/4/1973; GB -prior. 22.12.1967, 05.14.1968, 2.8.1968).
  • US 3,857,952 (May & Baker; 31.12.1974; GB -prior. 22.12.1967, 14.05.1968, 2.8.1968).
 
Literature References:
Cardioselective b-adrenergic blocker. Prepn: K. R. H. Wooldridge, B. Basil, ZA 6808345eidem, US3857952 (1969, 1974 both to May & Baker).
Pharmacology: Cuthbert, Owusu-Ankomah, Br. J. Pharmacol. 43, 639 (1971); Basil et al., ibid. 48, 198 (1973); Lewis et al., Br. Heart J. 35, 743 (1973).
HPLC determn in plasma and urine: M. Piquette-Miller et al., J. Chromatogr. 526, 129 (1990).
Crystal structure: A. Carpy et al., Acta Crystallogr. B35, 185 (1979).
Review of pharmacology and therapeutic efficacy: B. N. Singh et al., Drugs 29, 531-569 (1985); G. DeBono et al., Am. Heart J. 109, 1211-1223 (1985).
Comprehensive description: R. T. Foster, R. A. Carr, Anal. Profiles Drug Subs. 19, 1-26 (1990).
 
 
Keywords: Adrenergic Blocker,  Antianginal,  Antiarrhythmic, Antihypertensive, Aryloxypropanolamine Derivatives, Acebutolol, β-adrenergic receptor

 
 
 
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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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