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Arotinolol

Arotinolol structure

CAS No:
68377-92-4
Formula:
C15H21N3O2S3
Chemical Name:
Arotinolol
Synonyms:
2-Thiophenecarboxamide,5-[2-[[3-[(1,1-dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-;2-Thiophenecarboxamide,5-[2-[[3-[(1,1-dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-,(±)-;5-[2-[[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-2-thiophenecarboxamide;Arotinolol;(±)-Arotinolol;2-(3-tert-Butylamino-2-hydroxypropylthio)-4-(5-carbamoyl-2-thienyl)thiazole;NSC 317940;52560-77-7
Categories:
Organic Chemistry > Amides

Description

Arotinolol is a nonselective α/β-adrenergic receptor blocker and a vasodilating β-blocker. Arotinolol is an antihypertensive agent for the treatment of a variety of cardiovascular pathologies as well as non-cardiovascular diseases[1].

Arotinolol is a member of thiophenes and an aromatic amide.|Arotinolol is an alpha- and beta-receptor blocker developed in Japan. It is a thiopropanolamine with a tertiary butyl moiety. It has been studied for its potential to be an antihypertensive therapy. Artinolol is being developed by Sumitomo Pharmaceutical Co., Ltd. and it is currently under clinical trials.

Arotinolol Basic Attributes

Molecular Weight：

371.54

Exact Mass：

371.54

NSC Number：

317940

DSSTox ID：

DTXSID3022619

Characteristics

PSA：

170

XLogP3：

2.3

Appearance：

White solid

Density：

1.35

Melting Point：

148-149 °C

Boiling Point：

599ºC at 760 mmHg

Flash Point：

316.6±32.9 °C

Refractive Index：

1.646

Water Solubility：

Slightly soluble

Toxicity

Toxicity Summary：

The major toxic effects reported for arotinolol-like drugs are the presence of central nervous system depression.

Protein Binding：

The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. Arotinolol is highly bound to serum proteins reaching a ratio of the original dose of 95.3% in the form of the R-enantiomer and 84.5% of the S-enantiomer. The presented stereospecificity is thought to be related to the α1-acid glycoprotein.

Drug Information

Drug Indication：

Artinolol was introduced to be used as an antihypertensive agent since 1986. It has been studied for other functions like tremor control for patients with Parkinson disease and it is currently in clinical trials for its use in the control of blood pressure and heart rate.

Pharmacology：

Preclinical studies showed a lack of intrinsic sympathomimetic activities or membrane-establishing properties. It is confirmed that arotinolol presents vasorelaxant activity. This characteristic is also proved to be mainly mediated by its α1-blocking property. In preclinical hypertension trials, there is a specific acute bradycardiac and antihypertensive activity with a pronounced reduction in heart rate. Some reports indicate a delayed development of hypertension when arotinolol is administered daily. Arotinolol has a dose-dependent decrease in cardiac contractility and coronary blood flow as well as an increase in total peripheral resistance. The effects of arotinolol have been confirmed in clinical trials where this drug was able to decrease cardiac index and thus, blood pressure.

MeSH：

Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. (See all compounds classified as Adrenergic beta-Antagonists.)|Drugs that bind to but do not activate alpha-adrenergic receptors thereby blocking the actions of endogenous or exogenous adrenergic agonists. Adrenergic alpha-antagonists are used in the treatment of hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma. (See all compounds classified as Adrenergic alpha-Antagonists.)

Absorption：

Arotinolol gets rapidly absorbed and distributed in the plasma. The plasma concentration peaks 2 hours after initial administration.|The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. Both of the enantiomers were found in urine, suggesting this as the major elimination pathway. It is possible to find arotinolol in urine 2-4 hours after initial administration.|The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. The S-enantiomer is highly retained in red blood cells. The distribution studies have shown that arotinolol is mainly distributed from the plasma to the liver followed by the lungs and lastly in the heart. The distribution in the liver was independent on the stereochemistry of the molecules.

Metabolism/Metabolites：

The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. The R-enantiomer remains unchanged and it is eliminated from the organism by urine in this form while the S-enantiomer is metabolized.

Biological Half-Life：

The reported half-life of arotinolol is 7.2 hours.

Mechanism of Action：

Arotinolol binds to the β1-, β2- and α1- adrenergic receptor sites with a very high affinity. Radioligand studies have shown that arotinolol presents a higher affinity to the β-receptor compared to the α-receptor. The elucidated mechanism of action seems to be the result of a reduction in the cardiac output via the β-blockade and an additional inhibition of the counter-regulatory increase in peripheral resistance mediated by the α-blockade.

MeSH Entry Terms：

2-(3'-tert-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole hydrochloride

Arotinolol Use and Manufacturing

A suitable beta-adrenergic receptor blocker can illustratively be selected from the following list: AC 623 acebutolol alprenolol atenolol amosulalol arotinolol atenolol befunolol betaxolol bevantolol ...A suitable alpha-1-adrenergic receptor blocker can illustratively be selected from the following list: amosulalol arotinolol carvedilol dapiprazole doxazosin fenspiride idazoxan indoramin labetalol ...In a three-necked flask, 850 g of anhydrous ethanol and tert-butylamine (265.7 g, 3.68 mol) were added, and the mixture was stirred and dissolved uniformly to add intermediate (III) 5-(2, 3-epoxypropyl-2-indenyl-4-thiazole). 2-Thiophenecarboxamide (110.0 g, 0.37 mol), stirring and heating and keeping the micro reflux reaction. The reaction was monitored by HPLC for about 12 hours. The solvent was concentrated and the absolute ethanol and excess tert-butylamine were exhausted to obtain the intermediate (IV). , Add 3300g of purified water slightly, stir and heat to reflux at 110C, dissolve transparent, cool to room temperature, adjust pH 0.5 to 1 with 36% hydrochloric acid, wash 3 times with 50g of toluene, discard organic layer, and add ethanol to water layer 1700g , Continue stirring and heating to dissolve transparent, cooling and cooling to 0 ~ 5 C Stir crystallization for more than 4 hours, filtered to obtain crude alpholol (dry-off: 128.5g, molar yield 84.0%, HPLC purity 99.7%);In a three-necked flask, 850 g of anhydrous ethanol and tert-butylamine (265.7 g, 3.68 mol) were added, and the mixture was stirred and dissolved uniformly to add intermediate (III) 5-(2, 3-epoxypropyl-2-indenyl-4-thiazole). 2-Thiophenecarboxamide (110.0 g, 0.37 mol), stirring and heating and keeping the micro reflux reaction. The reaction was monitored by HPLC for about 12 hours. The solvent was concentrated and the absolute ethanol and excess tert-butylamine were exhausted to obtain the intermediate (IV). , Add 3300g of purified water slightly, stir and heat to reflux at 110C, dissolve transparent, cool to room temperature, adjust pH 0.5 to 1 with 36% hydrochloric acid, wash 3 times with 50g of toluene, discard organic layer, and add ethanol to water layer 1700g , Continue stirring and heating to dissolve transparent, cooling and cooling to 0 ~ 5 C Stir crystallization for more than 4 hours, filtered to obtain crude alpholol (dry-off: 128.5g, molar yield 84.0%, HPLC purity 99.7%);In a 3 L reaction flask, add ethyl acetate 1100 ml, methanol 220 ml, purified water 550 ml, EXAMPLE 37 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole. To a solution of 2-mercapto-4-(5'-carbamoyl-2'-thienyl)thiazole, 3.2 g. in 20 ml. of 0.3 % aqueous sodium hydroxide solution, 1-chloro-3-t-butylaminopropanol, 12.64 g. in 20 ml. of methanol was added, while the temperature was maintained at 20C. The reaction solution was stirred at room temperature for 4 hours, and then condensed to a half volume in vacuo. The residual solution, added with 100 ml. of water, was extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue, 4.8 g., which was recrystallized from chloroform-light petroleum to yield 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole; needles, m.p. 148 - 149C. According to Example 37, the following compounds were synthesised.

Computed Properties

Molecular Weight:371.5
XLogP3:2.3
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:8
Exact Mass:371.07959044
Monoisotopic Mass:371.07959044
Topological Polar Surface Area:170
Heavy Atom Count:23
Complexity:406
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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Arotinolol

CAS No.: 68377-92-4

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