Labetalol
ラベタロール;
- Molecular FormulaC19H24N2O3
- Average mass328.405 Da
Labetalol hydrochloride, AH-5158A, Sch-15719W, Amipress, Trandate, Normodyne
Labetalol was granted FDA approval on 1 August 1984
Presolol; (RS)-2-Hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide; 5-[1-Hydroxy-2-[(1-methyl-3-phenyl propyl)amino]ethyl]salicylamide
A salicylamide derivative that is a non-cardioselective blocker of BETA-ADRENERGIC RECEPTORS and ALPHA-1 ADRENERGIC RECEPTORS.
- AH 5158
- Albetol
- EC 253-258-3
- EINECS 253-258-3
- HSDB 6537
- Ibidomide
- Labetalol
- Labetalolum
- Labetalolum [INN-Latin]
- Labetolol
- SCH 15719W
- UNII-R5H8897N95
Labetalol hydrochloride
- CAS Number 32780-64-6,
- Empirical Formula (Hill Notation) C19H24N2O3 · HCl,
- Molecular Weight 364.87
REF https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/74787_Labetalol%20Hydrochloride_Chemr.pdf
RR
CAS 75659-07-3
- (R,R)-Labetalol
- Dilevalol
- Dilevalolum
- Dilevalolum [Latin]
- UNII-P6629XE33T
Labetalol is a racemic mixture of 2 diastereoisomers where dilevalol, the R,R’ stereoisomer, makes up 25% of the mixture.8 Labetalol is formulated as an injection or tablets to treat hypertension
Labetalol is a medication used to treat high blood pressure and in long term management of angina.[1][2] This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy.[2] In essential hypertension it is generally less preferred than a number of other blood pressure medications.[1] It can be given by mouth or by injection into a vein.[1]
Common side effects include low blood pressure with standing, dizziness, feeling tired, and nausea.[1] Serious side effects may include low blood pressure, liver problems, heart failure, and bronchospasm.[1] Use appears safe in the latter part of pregnancy and it is not expected to cause problems during breastfeeding.[2][3] It works by blocking the activation of β-receptors and α-receptors.[1]
Labetalol was patented in 1966 and came into medical use in 1977.[4] It is available as a generic medication.[2] A month supply in the United Kingdom costs the NHS about 8 £ as of 2019.[2] In the United States the wholesale cost of this amount is about US$12.[5] In 2016 it was the 233rd most prescribed medication in the United States with more than 2
Medical uses
Labetalol is effective in the management of hypertensive emergencies, postoperative hypertension, pheochromocytoma-associated hypertension, and rebound hypertension from beta blocker withdrawal. [7]
It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia. [8]
It is also used as an alternative in the treatment of severe hypertension.[7]
Special populations
Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women.[9]
Nursing: breast milk has been shown to contain small amounts of labetalol (0.004% original dose). Prescribers should be cautious in the use of labetalol for nursing mothers.[9]
Pediatric: no studies have established safety or usefulness in this population.[9]
Geriatric: the elderly are more likely to experience dizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect.[9]
Side effects
Common
- Neurologic: headache (2%), dizziness (11%) [9]
- Gastrointestinal: nausea (6%), dyspepsia (3%) [9]
- Cholinergic: nasal congestion (3%), ejaculation failure (2%) [9]
- Respiratory: dyspnea (2%) [9]
- Other: fatigue (5%), vertigo (2%), orthostatic hypotension [9]
Low blood pressure with standing is more severe and more common with IV formulation (58% vs 1%[9]) and is often the reason larger doses of the oral formulation cannot be used.[10]
Rare
- Fever [9]
- Muscle cramps [9]
- Dry eyes [9]
- Heart block [9]
- Hyperkalemia [9]
- Hepatotoxicity [9]
- Drug eruption similar to lichen planus[11]
- Hypersensitivity – which may result in a lethal respiratory distress[9]
Contraindications
Labetalol is contraindicated in people with overt cardiac failure, greater-than-first-degree heart block, severe bradycardia, cardiogenic shock, severe hypotension, anyone with a history of obstructive airway disease including asthma, and those with hypersensitivity to the drug.[12]
Chemistry
The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons.[13] This configuration results in strong agonist activity. As the size of the substituent attached to the amine becomes greater, particularly with respect to a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is, therefore, an antagonist.[13] Labetalol, with its 1-methyl-3-phenylpropyl substituted amine, is greater in size relative to a t-butyl group and therefore acts predominantly as an antagonist. The overall structure of labetalol is very polar. This was created by substituting the isopropyl group in the standard beta-blocker structure with an aralkyl group, including a carboxamide group on the meta position, and by adding a hydroxyl group on the para position.[14]
Labetalol has two chiral carbons and consequently exists as four stereoisomers.[15] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1 blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed nonselective β blocker and selective α1 blocker.[14] Labetalol is typically given as a racemic mixture to achieve both alpha and beta receptor blocking activity.[16]
Stereoisomers of labetalol | |
---|---|
(R,R)-Labetalol CAS number: 75659-07-3 |
(S,S)-Labetalol CAS number: 83167-24-2 |
(R,S)-Labetalol CAS number: 83167-32-2 |
(S,R)-Labetalol CAS number: 83167-31-1 |
Labetalol acts by blocking alpha and beta adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output.
The β:α antagonism of labetalol is approximately 3:1.[17][18]
It is chemically designated in International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride.[16][19]
Pharmacology
Mechanism of action
Labetalol’s dual alpha and beta adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasing systemic vascular resistance with little effect on stroke volume, heart rate and cardiac output.[20] During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume.[21]
Labetalol is a dual alpha (α1) and beta (β1/β2) adrenergic receptor blocker and competes with other Catecholamines for binding to these sites.[22] Its action on these receptors are potent and reversible.[12] Labetalol is highly selective for postsynaptic alpha1- adrenergic, and non-selective for beta-adrenergic receptors. It is about equipotent in blocking both beta1- and beta2- receptors.[14]
The amount of alpha to beta blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of alpha to β blockade is 1:3. Intravenously, alpha to β blockade ratio is 1:7.[14][12] Thus, the labetalol can be thought to be a beta-blocker with some alpha-blocking effects.[12][22][23] By comparison, labetalol is a weaker β-blocker than propranolol, and has a weaker affinity for alpha-receptors compared to Phentolamine.[14][22]
Labetalol possesses intrinsic sympathomimetic activity.[23] In particular, it is a partial agonist at beta2- receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial beta2- agonism and through alpha1- blockade.[23][24] Overall, this vasodilatory effect can decrease blood pressure.[25]
Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity.[23][26] By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity.[27]
Physiological action
The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking beta1- receptors should decrease heart rate, but labetalol does not. When labetalol is given in acute situations, it decreases the peripheral vascular resistance and systemic blood pressure while having little effect on the heart rate, cardiac output and stroke volume, despite its alpha1-, beta1- and beta2- blocking mechanism.[20][21] These effects are mainly seen when the person is in the upright position.[25]
Long term labetalol use also has different effects from other beta-blocking drugs. Other beta-blockers, such as propranolol, persistently reduce cardiac output during exercise. The peripheral vascular resistance decreases when labetalol is first administered. Continuous labetalol use further decreases peripheral vascular resistance. However, during exercise, cardiac output remains the same due to a compensatory mechanism that increases stroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume.[21]
Pharmacokinetics
Labetalol, in animal models, was found to cross the blood-brain-barrier in only negligible amounts.[28]
History
Labetalol was the first drug created that combined both alpha- and beta- adrenergic receptor blocking properties. It was created to potentially fix the compensatory reflex issue that occurred when blocking a single receptor subtype, i.e. vasoconstriction after blocking beta-receptors or tachycardia after blocking alpha receptors. Because the reflex from blocking the single receptor subtypes acted to prevent the lowering of blood pressure, it was postulated that weak blocking of both alpha- and beta- receptors could work together to decrease blood pressure.[14][21]
Syn 1
Drugs Fut 1976,1(3),125
DE 1643224; FR 1557677; FR 8010M; GB 1200886; US 3642896; US 3644353; US 3705233
Condensation of 5-bromoacetylsalicylamide (I) with N-benzyl-N-(1-methyl-3-phenylpropyl)amine (II) in refluxing butanone to 5-(N-benzyl-N-(1-methyl-3-phenylpropyl) glycyl)salicylamide hydrochloride (III), m.p. 139-141 C, which is reduced with H2 over Pt-Pd/C in ethanol.
SYN 2
Reductocondensation of 5-(N,N-dibenzylglycyl)salicylamide (IV) and benzylace-tone (V) with H2 over Pd-Pt/C in methanol – acetic acid.
SYN 3
Reaction of methyl 5-(2-amino-1-hydroxyethyl)salicylate hydrochloride (VI) with NH3 to 5-(2-amino-1-hydroxyethyl)salicylamide hydrochloride (VII), m.p. >360 C, which is finally condensed with benzylacetone (V) and reduced with H2 over Pd-Pt/C in methanol.
SYN 4
SYN 5
2-hydroxy-5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)-, monohydrochloride, could be produced through many synthetic methods.
Following is one of the synthesis routes: 5-Bromoacetylsalicylamide (I) with N-benzyl-N-(1-methyl-3-phenylpropyl)amine (II) is condensed in the presence of refluxing butanone to produce 5-(N-benzyl-N-(1-methyl-3-phenylpropyl) glycyl)salicylamide hydrochloride (III), m.p. 139-141 C, and next the yielding compound is reduced with H2 over Pt-Pd/C in ethanol.
SYN 6
https://patents.google.com/patent/WO2017098520A1/en
aration of Labetaiol Hydrochloride of
Scheme -I illustrates the process for preparation of Labetaiol Hydrochloride of formula (I).
30% NaOH
Step – Sodium borohydride
Pure Labetaiol Hydrochloride (I)
aration of Labetaiol Hydrochloride of
Scheme -I illustrates the process for preparation of Labetaiol Hydrochloride of formula (I).
30% NaOH
Step – Sodium borohydride
Pure Labetaiol Hydrochloride (I)
SYN
https://patents.google.com/patent/EP0009702A1/en
-
The substance labetalol is known from British patent specification 1,266,058 and U.S.P. 4,012,444. Its pharmacological properties are discussed by Farmer et. al. in British Journal of Pharmacology, 45: 660-675 (1972), who designate it AH5158; it is shown to block a- and β-adrenergic receptors, suggesting that it would be useful in the treatment of arrhythmia, hypertension and angina pectoris.
- [0003]
The unique pharmacological properties of labetalol and its use as an antihypertensive agent are said to be largely a function of the exquisite balance of its a- and a-blocking activities. The file history of U.S.P. 4,012,444 indeed indicates that slight changes in the chemical structure of labetalol deleteriously affect this balance, and, even in the few analogous compounds where the balance is retained, the absolute potencies of these compounds are shown to be too low for them to be useful antihypertensive agents. Therefore, in the treatment of hypertension, labetalol is the compound of choice among those disclosed in British patent specification 1,266,058 and U.S.P. 4,012,444.
- [0004]
Labetalol has two asymmetrically substituted carbon atoms and therefore can exist as two diastereoisomers and four optical isomers. Indeed, British patent specification 1,266,058 and U.S.P. 4,012,444 disclose that compounds such as labetalol have optically active forms, but give no example of an optically active form. These patent specifications .teach that “the racemic mixtures may be resolved by conventional methods, for example by salt formation with an optically active acid, followed by fractional crystallization”, but give no method of resolution. Example 14 of each specifi– cation does indeed describe the separation of labetalol into two diastereoisomers “1” and “2”, using benzoic acid, but this is not an optical resolution. In British patent specifications 1,541,932 and 1,541,933, “isomer 1” is designated “diastereoisomer A” and is characterised as that diastereoisomer whose hydrochloride salt has the higher melting point. These two British patent specifications also disclose that diastereoisomer A is a valuable antiarrhythmic agent since it has strongly reduced β-adrenergic blocking activity and is therefore useful in the treatment of people who have suffered myocardial infarction.
- [0005]
We have now discovered that diastereoisomer A is composed of the (S,R) and (R,S) optical isomers of labetalol, whereas diastereoisomer B is composed of the (S,S) and (R,R) optical isomers. We have also-surprisingly found that the novel (R,R) optical isomer of labetalol exhibits, in comparison with labetalol itself, both an unexpectedly high increase in β-adrenergic blocking potency and a decrease in a-adrenergic blocking potency. Thus, when the (R,R) optical isomer is compared with labetalol, the ratio of the β-adrenergic blocking potency to the a-adrenergic blocking potency is found to be greatly and unexpectedly increased. In particular, animal tests have indicated that the (R,R) optical isomer has about twelve times the β-blocking potency of labetalol, but only about one third of the a-blocking potency of labetalol. These. properties could in no way have been predicted theoretically, especially as the β-blocking potency of diastereoisomer B is not significantly different from that of labetalol and the a-blocking potency of diastereoisomer B is half that of labetalol. Indeed, it is clear, when the activities of the four optical isomers of labetalol are compared, that the activities of the diastereoisomers A and B and indeed of labetalol itself cannot be calculated from the activities of their components. One can put this the other way around by saying that the α-and β-blocking activities of the four optical isomers of labetalol do not merely average to give the a- and β-blocking activites of labetalol and of its diastereoisomers A and B. Some of the activities are much greater than could ever have been expected on a simple basis of mathematical proportions, in particular the high β-blocking activity of the (R,R) optical isomer: this activity is much higher than the β-blocking activity of diastereoisomer B so that antagonism evidently exists between the (S,S) and (R,R) optical isomers with respect to the β-blocking activity. This degree of antagonism could in no way have been foreseen. In the absence of this antagonism, the (R,R) optical isomer shows a balance of properties that make it the optical isomer of choice in the treatment of hypertension. In particular, the (R,R) optical isomer possesses potent antihypertensive activity and rapid onset of activity while substantially lacking the undesirable side-effects usually associated with a-blockade, e.g. postural hypotension.
-
The following Table shows the relationships between labetalol, its diastereoisomersA and B and the four pure optical isomers; below each compound are given its potencies as an a-blocking and then as a β-blocking agent, all relative to the values for labetalol (assigned values 1.0 for each blocking activity):
This table clearly shows the unexpectedly high β-blocking activity and ratio of β-:α-blocking activities possessed by the (R,R)-optical isomer. Additionally, the (R,R)–optical isomer has been found to possess greater direct peripheral vasodilation activity than labetalol, and this also contributes to its anti-hypertensive activity. Moreover, the (R,R)-optical isomer is substantially non-toxic at therapeutic doses.
- [0007]
According to the invention therefore we provide the (R,R)-optical isomer of labetalol, namely 5- {(R)–1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl} salicylamide, which can be characterised by means of its hydrochloride salt which is dimorphic with m.pts. of about 133-134°C. and about 192-193.5°C. and an [α]D 26 of about -30.6° (conc. 1 mg./ml., ethanol), said (R,R) optical isomer being substantially free of the corresponding (R,S), (S,R) and (S,S) optical isomers
reaction scheme:
- E. (-)-5- { (R)-l-Hydroxy-2-[(R)-(l-methyl-3-phenylpropyl)-amino]ethyl} salicylamide hydrochloride salt (9)
- [0032]
Treat a solution of 3.0 g. (0.0059 mol.) of 2-0-benzyl-5-{(R) -1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)benzylamino]ethyl} salicylamide in 30 ml. of ethyl ether with 2N ethereal hydrogen chloride until no further precipitation occurs. Wash the precipitated 2-0-benzyl-5-{(R)-1-hydroxy-2-[(R)-(1-methyl–3-phenylpropyl)benzylamino]ethyl} salicylamide hydrochloride with ether to remove excess hydrogen chloride and dissolve it in 100 ml. ethanol. To the ethanol solution add 300 mg. of a 20% palladium hydroxide on carbon catalyst and hydrogenate (3 atm.; 3.1 kg. cm.-2) in a Paar apparatus with shaking at room temperature for 3 hours. Filter off the catalyst, evaporate, and triturate the solid residue with isopropanol. Dissolve the solid in 11 ml. of 1N sodium hydroxide, adjust the pH to about 8 and precipitate the free base by bubbling in carbon dioxide. Collect the free base, wash it with water and dry it in vacuo at 40°C. Chromatograph the free base on 450 g. of silica gel and dissolve the pure product in 20 ml. of boiling acetonitrile. Cool the solution and carefully acidify with 2N ethereal HC1 to about pH2. Solidify the gum which precipitates by refluxing the mixture for 10 minutes, filter off the solid, wash it with ethyl ether and recrystallize it from ethanol to obtain analytically pure product (9), m.p. 192-193.5°C.(dec.), [α]D26 = -30.6° (c=1.0, ethanol).
Dilevalol
Synonyms:(R,R)-Labetalol
ATC:C02CB
- MW:328.41 g/mol
- CAS-RN:75659-07-3
- LD50:1719 mg/kg (M, p.o.);
1228 mg/kg (R, p.o.)
Derivatives
Monohydrochloride
- Formula:C19H24N2O3 • HCl
- MW:364.87 g/mol
- CAS-RN:75659-08-4
- LD50:1079 mg/kg (M, p.o.);
82 mg/kg (R, i.v.); 1026 mg/kg (R, p.o.)
Synthesis Path
Clinical data | |
---|---|
Pronunciation | /ləˈbɛtəlɔːl/ |
Trade names | Normodyne, Trandate, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a685034 |
Pregnancy category |
|
Routes of administration |
By mouth, intravenous |
ATC code | |
Legal status | |
Legal status |
|
Pharmacokinetic data | |
Bioavailability | 25% |
Protein binding | 50% |
Metabolism | Liver pass metabolism, |
Elimination half-life | Tablet: 6-8 hours; IV: 5.5 hours |
Excretion | Excreted in urine, not removed by hemodialysis |
Identifiers | |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.048.401 |
Chemical and physical data | |
Formula | C19H24N2O3 |
Molar mass | 328.412 g·mol−1 |
3D model (JSmol) | |
Chirality | Racemic mixture |
References
- ^ Jump up to:a b c d e f “Labetalol Hydrochloride Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
- ^ Jump up to:a b c d e British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 147–148. ISBN 9780857113382.
- ^ “Labetalol Use During Pregnancy”. Drugs.com. Retrieved 11 March 2019.
- ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 463. ISBN 9783527607495.
- ^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
- ^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018.
- ^ Jump up to:a b Koda-Kimble, Mary A.; Alldredge, Brian K. (2013). “21”. Koda-Kimble and Young’s Applied Therapeutic: The Clinical Use of Drugs. Philadelphia: Philadelphia: Lippincott Williams & Wilkins. ISBN 978-1-60913-713-7.
- ^ Arulkumaran, N; Lightstone, L (December 2013). “Severe pre-eclampsia and hypertensive crises”. Best Practice & Research. Clinical Obstetrics & Gynaecology. 27 (6): 877–84. doi:10.1016/j.bpobgyn.2013.07.003. PMID 23962474.
- ^ Jump up to:a b c d e f g h i j k l m n o p q “Trandate” (PDF). Prometheus Laboratories Inc. November 2010. Retrieved 3 November 2015.
- ^ “Labetalol hydrochloride” (PDF). Hospira. May 2015. Retrieved 3 November 2015.
- ^ Shiohara T, Kano Y (2007). “Lichen planus and lichenoid dermatoses”. In Bolognia JL (ed.). Dermatology. St. Louis: Mosby. p. 161. ISBN 978-1-4160-2999-1.
- ^ Jump up to:a b c d “Labetalol [package insert]. Spring Valley, NY: Par Pharmaceutical; 2011” (PDF). Retrieved 2015-11-03.
- ^ Jump up to:a b Medicinal Chemistry of Adrenergics and Cholinergics
- ^ Jump up to:a b c d e f Louis, W.J.; McNeill, JJ; Drummer, OH (1988). Doyle, AE (ed.). Labetalol and other vasodilator/Beta-blocking drugs. IN: Handbook of Hypertension. Amsterdam, Netherlands: Elsevier Sciences Publishing Co. pp. 246–273. ISBN 978-0-444-90469-0.
- ^ Riva E, Mennini T, Latini R (December 1991). “The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers”. Br. J. Pharmacol. 104 (4): 823–8. doi:10.1111/j.1476-5381.1991.tb12513.x. PMC 1908821. PMID 1687367.
- ^ Jump up to:a b Robertson D, Biaggioni, I. Adrenoceptor Antagonist Drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. San Francisco, CA: McGraw Hill Lange Medical; 2012: 151-168. ISBN 978-0-07-176401-8.
- ^ Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical. p. 170. ISBN 978-0-07-145153-6.
- ^ D A Richards; J Tuckman; B N Prichard (October 1976). “Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol”. Br J Clin Pharmacol. 3 (5): 849–855. doi:10.1111/j.1365-2125.1976.tb00637.x. PMC 1428931. PMID 9968.
- ^ “labetalol | C19H24N2O3 – PubChem”. pubchem.ncbi.nlm.nih.gov. Retrieved 2015-11-04.
- ^ Jump up to:a b MacCarthy, E. P.; Bloomfield, S. S. (1983-08-01). “Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects”. Pharmacotherapy. 3(4): 193–219. doi:10.1002/j.1875-9114.1983.tb03252.x. ISSN 0277-0008. PMID 6310529.
- ^ Jump up to:a b c d Louis, W. J.; McNeil, J. J.; Drummer, O. H. (1984-01-01). “Pharmacology of combined alpha-beta-blockade. I”. Drugs. 28 Suppl 2: 16–34. doi:10.2165/00003495-198400282-00003. ISSN 0012-6667. PMID 6151889.
- ^ Jump up to:a b c Robertson, D; Biaggioni, I (2012). Katzung, BG (ed.). Adrenoceptor Antagonist Drugs IN: Basic & Clinical Pharmacology (12 ed.). San Francisco: McGraw Hill Lange Medical. pp. 151–168. ISBN 978-0-07-176401-8.
- ^ Jump up to:a b c d Westfall, David P (2004). Craig, Charles R (ed.). Adrenoreceptor Antagonists IN: Modern Pharmacology with Clinical Applications (6th ed.). Baltimore, MD: Lippincott Williams & Wilkins. pp. 109–117. ISBN 978-0781737623.
- ^ Lund-Johansen, P. (1988-01-01). “Hemodynamic effects of beta-blocking compounds possessing vasodilating activity: a review of labetalol, prizidilol, and dilevalol”. Journal of Cardiovascular Pharmacology. 11 Suppl 2: S12–17. doi:10.1097/00005344-198800000-00004. ISSN 0160-2446. PMID 2464093.
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External links
References
-
- EP 9 702 (Schering Corp.; appl. 17.9.1979; USA-prior. 20.9.1978).
-
Improvement of diastereomer separation:
- DOS 2 616 403 (Scherico; appl. 14.4.1976; USA-prior. 17.4.1975).
- US 4 173 583 (Schering Corp.; 6.11.1979; appl. 21.9.1978; prior. 17.4.1975).
-
Synthesis without chromatographic purification:
- EP 92 787 (Schering Corp.; appl. 20.4.1983; USA-prior. 26.4.1982).
-
Chiral reduction of IV:
- Clifton, J.E. et al.: J. Med. Chem. (JMCMAR) 25, 670 (1982).
- Gold, E.H. et al.: J. Med. Chem. (JMCMAR) 25, 1363 (1982).
- EP 382 157 (Schering Corp.; appl. 6.2.1990; USA-prior. 10.2.1989, 26.9.1989).
- US 4 948 732 (Schering Corp.; 14.8.1990; prior. 26.9.1989, 10.2.1989).