36894-69-6

Basic information

• Product Name: Labetalol
• Synonyms: LABETALOL;LABETOLOL;5-[1-HYDROXY-2-[(1-METHYL-3-PHENYLPROPYLAMINO)ETHYL]]SALICYLAMIDE;5-[1-hydroxy-2-[(1-methyl-3-phenylpropylamino)ethyl]saicylamide;Labetalol (base and/or unspecified salts);SeH-15719W;2-hydroxy-5-[(1S)-1-hydroxy-2-{[(2R)-4-phenylbutan-2-yl]aMino}ethyl]benzaMide;Laβlol
• CAS NO: 36894-69-6
• Molecular Formula: C₁₉H₂₄N₂O₃
• Molecular Weight: 328.41
• EINECS: 253-258-3
• Product Categories: API's
• Mol File: 36894-69-6.mol
• Article Data: 9

Chemical Properties

• Melting Point: 188 °C
• Boiling Point: 552.686 °C at 760 mmHg
• Flash Point: 288.054 °C
• Appearance: /
• Density: 1.201 g/cm³
• PKA: pKa 7.41 ± 0.01；9.36± 0.01(H2O,t =25,I=0.15(KCl)，Ar)(Approximate)
• CAS DataBase Reference: Labetalol(CAS DataBase Reference)
• NIST Chemistry Reference: Labetalol(36894-69-6)
• EPA Substance Registry System: Labetalol(36894-69-6)

Safety Data

• Hazardous Substances Data: 36894-69-6(Hazardous Substances Data)

Usage

Use advice

Labetalol is a competitive α1- and β-antagonist which is more active at β- than at α-receptors (1 : 3–1 : 7, depending on route). It may be administered orally or i.v. Intravenous bolus doses range from 50–200mg, with infusion rates between 5–150mgh –1, titrated to effect.

Description

Labetalol is an α-adrenergic and α-1 blocking agent which caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.

Uses

Different sources of media describe the Uses of 36894-69-6 differently. You can refer to the following data:
1. Labetalol is used to treat essential hypertension.
2. Anti-adrenergic (α-receptor); anti-adrenergic (β-receptor).

Definition

ChEBI: A secondary amino compound formally derived from ammonia by replacing two of the hydrogens by 2-(3-carbamoyl-4-hydroxyphenyl)-2-hydroxyethyl and 4-phenylbutan-2-yl groups. It is an adrenergic antagonist used to treat high blood pressure.

Biological Functions

Labetalol (Normodyne, Trandate) possesses both - blocking and β-blocking activity and is approximately one-third as potent as propranolol as a -blocker and one-tenth as potent as phentolamine as an -blocker. The ratio of β- to α-activity is about 3:1 when labetalol is administered orally and about 7: 1 when it is administered intravenously. Thus the drug can be most conveniently thought of as a β -blocker with some -blocking properties.

General Description

Labetalol is a phenylethanolamine derivative, is representative of a classof drugs that act as competitive blockers at α1-, β1-, andβ2-receptors. It is a more potent β-blocker than α-blocker.Because it has two asymmetric carbon atoms (1 and 1' ), it existsas a mixture of four isomers. It is this mixture that is usedclinically in treating hypertension. The different isomers,however, possess different α- and β-blocking activities. The -blocking activity resides solely in the (1R,1 'R) isomer,whereas the 1-blocking activity is seen in the (1S,1 R) and(1S,1'S) isomers, with the (1S,1'R) isomer possessing thegreater therapeutic activity.

Contact allergens

This beta-adrenergic and alpha-1 blocking agent caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.

Mechanism of action

Labetalol produces equilibrium-competitive antagonism at β-receptors but does not exhibit selectivity for β1- or β2-receptors. Like certain other β-blockers (e.g., pindolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial agonism, especially at β2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other β-blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic. Labetalol appears to produce relaxation of vascular smooth muscle not only by α-blockade but also by a partial agonist effect at β2-receptors. In addition, labetalol may produce vascular relaxation by a direct non–receptor-mediated effect. Labetalol can block the neuronal uptake of norepinephrine and other catecholamines. This action, plus its slight intrinsic activity at α-receptors, may account for the seemingly paradoxical, although infrequent, increase in blood pressure seen on its initial administration.

Pharmacokinetics

Labetalol is almost completely absorbed from the gastrointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gastrointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circulation. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates.The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essentially unchanged in patients with impaired renal failure.

Clinical Use

Labetalol is a clinically usefulantihypertensive agent. The rationale for its use in themanagement of hypertension is that its α-receptor–blockingeffects produce vasodilation and its β-receptor–blockingeffects prevent the reflex tachycardia usually associated withvasodilation. Although labetalol is very well absorbed, it undergoesextensive first-pass metabolism.

Side effects

There have been reports of excessive hypotension and paradoxical pressor effects following intravenous administration of labetalol. These latter effects may be due to a labetalol-induced blockade of neuronal amine uptake, which increases the concentrations of norepinephrine in the vicinity of its receptors. Approximately 5% of the patients who receive labetalol complain of side effects typical of noradrenergic nervous system suppression. These include postural hypotension, gastrointestinal distress, tiredness, sexual dysfunction, and tingling of the scalp. Most of these effects are related to α-blockade, although the tingling of the scalp may be due to the drug’s intrinsic activity at α-receptors. Side effects associated with β-blockade, such as induction of bronchospasm and congestive heart failure, may also occur, but generally at a lower frequency than -receptor–associated effects. Skin rashes have been reported, as has an increase in the titer of antinuclear antibodies. Despite the latter observation, the appearance of a systemic lupus syndrome is rare. Labetalol also has been reported to interfere with chemical measurements of catecholamines and metabolites.

Synthesis

Labetalol, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropanol)amino)] ethyl] benzamide (12.1.12) is synthesized by the N-alkylation of N-benzyl-N(4-phenyl-2- butyl)amine 5-bromacetylsalicylamide and forming aminoketone (12.1.11), which is further debenzylated by hydrogen using a palladium–platinum on carbon catalyst into labetalol (12.1.12) [28–30].

InChI:InChI=1/C19H24N2O3/c1-13(7-8-14-5-3-2-4-6-14)21-12-18(23)15-9-10-17(22)16(11-15)19(20)24/h2-6,9-11,13,18,21-23H,7-8,12H2,1H3,(H2,20,24)

Upstream product

• 36894-69-6 labetaol 
• 81579-50-2 2-hydroxy-5-<acetyl>benzamide 
• 73866-23-6 5-(2-bromoacetyl)-2-hydroxybenzamide 
• 2344-70-9 1-phenyl-3-butanol 

Downstream Products

• 83167-32-2 (S,R)-labetalol 
• 83167-24-2 *)>-2-hydroxy-5-<1-hydroxy-2-<(1-methyl-3-phenylpropyl)amino>ethyl>benzamide 
• 75659-07-3 (R,R)-labetalol 
• 83167-31-1 *)>-2-hydroxy-5-<1-hydroxy-2-<(1-methyl-3-phenylpropyl)amino>ethyl>benzamide 
• 264232-40-8 2-Hydroxy-5-[1-hydroxy-2-((R)-1-methyl-3-phenyl-propylamino)-ethyl]-benzamide 
• 36894-69-6 2-Hydroxy-5-[1-hydroxy-2-((S)-1-methyl-3-phenyl-propylamino)-ethyl]-benzamide 
• 636595-43-2 N-(5-{4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]but-2-ynyloxymethyl}-2-hydroxybenzamidomethyl)doxorubicin 
• 636595-71-6 4-[3-(2-{2-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)-ethoxy]-ethoxy}-ethyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile 
• 636595-68-1 4-(3-{2-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)-ethoxy]-ethyl}-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-trifluoromethyl-benzonitrile 
• 636595-74-9 4-{3-[4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)but-2-ynyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile 
• 636595-81-8 5-{4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]-but-2-ynyloxymethyl}-2-hydroxy-benzamide 
• 636595-50-1 2-hydroxy-5-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxymethyl}-benzamide 
• 636595-48-7 2-hydroxy-5-[2-(2-hydroxyethoxy)ethoxymethyl]benzamide 
• 636595-52-3 2-hydroxy-5-(4-hydroxy-but-2-ynyloxymethyl)-benzamide 

Relevant articles and documents

Preparation method of labetalol hydrochloride

The invention provides a preparation method of labetalol hydrochloride, and belongs to the technical field of medicines. The invention provides a preparation method. The method comprises the following steps: carrying out nucleophilic substitution reaction on 5-halogenated acetyl salicylamide serving as an initial raw material and benzylamine, and then carrying out nucleophilic substitution reaction on the obtained product and 3-halogenated butylbenzene (or carrying out amine-ester exchange reaction on the obtained product and an esterification reaction product of 3-hydroxybutylbenzene and p-toluenesulfonyl chloride); and carrying out catalytic hydrogenation reaction and salifying to obtain the labeolol hydrochloride. According to the preparation method provided by the invention, benzylamine is adopted to replace dibenzylamine, so that the raw materials are high in atom utilization rate and environment-friendly, and atom economy of green chemistry is embodied; wherein the amine-ester exchange reaction is high in selectivity, and the obtained product is directly used for the next-step reaction. The one-step method is adopted to remove the protective agent and reduce carbonyl, so that the process route is shortened; meanwhile, the preparation method is simple and convenient to operate, high in stability and controllability, high in production cost, high in yield and suitable for industrial production.

COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE

To characterize the urinary exosome miRNome, microarrays were used to identify the miRNA spectrum present within urinary exosomes from ten individuals that were previously classified for their salt sensitivity status. The present application discloses distinct patterns of selected exosomal miRNA expression that were different between salt-sensitive (SS), salt-resistant (SR), and inverse salt-sensitive (ISS) individuals. These miRNAs can be useful as biomarkers either individually or as panels comprising multiple miRNAs. The present invention provides compositions and methods for identifying, diagnosing, monitoring, and treating subjects with salt sensitivity of blood pressure. The applications discloses panels of miRNAs useful for comparing profiles, and in some cases one or more of the miRNAs in a panel can be used. The miRNAs useful for distinguishing SS and SR or ISS and SR subjects. One or more of the 45 miRNAs can be used. Some of the miRNAs have not been previously reported to be circulating. See those miRNAs with asterisks in FIG. 1 and below. The present invention encompasses the use of one or more of these markers for identifying and diagnosing SR, SS, and ISS subjects.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.