52-53-9

Usage

Chemical Description

Verapamil is a calcium channel blocker that has been shown to increase the cellular accumulation of vincristine.

Uses

Used in Pharmaceutical Industry:
Verapamil is used as a vasodilator for coronary applications, helping to reduce systemic vascular resistance and mean blood pressure with minor effects on cardiac output.
Used in Cardiology:
Verapamil is used as an antiarrhythmic agent for treating ventricular arrhythmias. However, it is gradually being replaced by adenosine in this application.
Used in Cardiovascular Medicine:
Verapamil is utilized for preventing angina pectoris attacks, arterial hypertension, and treating and preventing supraventricular arrhythmia, which includes paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, and extrasystole.

Mechanism of action

Verapamil is used as an antiarrythmic drug in treating supraventricular arrythmia such as paroxysmal atrial tachycardia, and for controlling atrial fibrillation. By blocking entrance of Ca2+ in the cell, verapamil exhibits a negative inotropic effect, and therefore it cannot be combined with β-adrenoblockers or cynidine since that would lead to an increased inotropic effect.

Clinical Use

Verapamil (Isoptin, Covera), in addition to its use as an antiarrhythmic agent, has been employed extensively in the management of variant (Prinzmetal’s) angina and effort-induced angina pectoris. It selectively inhibits the voltage-gated calcium channel that is vital for action potential genesis in slowresponse myocytes, such as those found in the sinoatrial and A-V nodes. Verapamil is useful for slowing the ventricular response to atrial tachyarrhythmias, such as atrial flutter and fibrillation. Verapamil is also effective in arrhythmias supported by enhanced automaticity, such as ectopic atrial tachycardia and idiopathic left ventricular tachycardia.

Side effects

Orally administered verapamil is well tolerated by most patients. Most complaints are of constipation and gastric discomfort. Other complaints include vertigo, headache, nervousness, and pruritus.

Synthesis

Verapamil, 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl) isopropylvaleronitrile (19.3.15), is synthesized by a scheme using 3,4- dimethoxyphenylacetonitrile as the initial substance. The synthesis of the final product (19.3.15) is accomplished by alkylating 2-(3.4-dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) with N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-3-(chloropropyl)-N-methylamine (19.3.14). The initial 2-(3.4-dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) is synthesized by alkylating 3,4-dimethoxyphenylacetonitrile with isopropyl chloride in the presence of sodium amide. The alkylating agent, N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-3- (chloropropyl)-N-methylamine (19.3.14), is also synthesized from 3,4-dimethoxyphenylacetonitrile followed by reduction into 3,4-dimethoxyphenylethylamine (19.3.12), with subsequent methylation into N-methyl-N-3,4-dimethoxyphenylethylamine (19.3.13). Next, the resulting N-[2-(3,4-dimethoxyphenyl)-ethyl] -N-methylamine (19.3.12) is alkylated by 1-chloro-3-bromopropane into the desired N-[2-(3,4-dimethoxyphenyl)- ethyl]-N-3-(chloropropyl)-N-methylamine (19.3.14), which is alkylated by 2-(3.4- dimethoxyphenyl)-3-methylbutyronitrile (19.3.11) to give the final product, verapamil(19.3.15).

Precautions

Verapamil must be used with extreme caution or not at all in patients who are receiving -adrenoceptor blocking agents. Normally, the negative chronotropic effect of verapamil will in part be overcome by an increase in reflex sympathetic tone. The latter is be prevented by simultaneous administration of a β-adrenoceptor blocking agent, which exaggerates the depressant effects of verapamil on heart rate, A-V node conduction, and myocardial contractility. The use of verapamil in children less than 1 year of age is controversial.

InChI:InChI=1/C27H37N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,7-8,13-16H2,1-6H3

Upstream product

• 871703-17-2 2-(3,4-dimethoxyphenyl)-2-(2-[1,3]dioxolan-2-yl-ethyl)-3-methyl-butyronitrile 
• 3490-06-0 N-methylhomoveratrylamine 
• 625-28-5 Isovaleronitrile 
• 128776-24-9 2-(2-[1,3]dioxolan-2-yl-ethyl)-3-methyl-butyronitrile 
• 102201-30-9 4-(3 4-dimethoxyphenyl)-4-cyano-5-methylcapronitrile 
• 36770-74-8 N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine 
• 20850-49-1 2-(3,4-dimethoxyphenyl)-3-methylbutyronitrile 

Downstream Products

• 38321-02-7 dexverapamil 
• 36622-29-4 (S)-verapamil 
• 1038742-04-9 C₂₆H₃₆N₂O₅ 
• 351009-37-5 C₂₇H₃₈N₂O₅ 
• 34245-14-2 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-methylamino-pentanenitrile 
• 71539-09-8 PR 22 
• 67018-85-3 norverapamil 
• 71539-08-7 PR 25 
• 27487-66-7 D 620 
• 102852-52-8 (+/-)-5-<(3,4-dimethoxyphenethyl)methylamino>-2-(3,4-dimethoxyphenyl)-2-isopropylpentylamine 
• 1369794-58-0 2-(3,4-dihydroxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]methylamino}-2-isopropylpentanenitrile 
• 1376616-12-4 N-(5-((3,4-dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentyl)acetamide 
• 23313-68-0 verapamil hydrochloride 

Relevant academic research and scientific papers

A PROCESS FOR THE PREPARATION OF VERAPAMIL HYDROCHLORIDE

The present invention relates to a process for the preparation of 5-(3,4-dimethoxyphenylethyl) methyl-amino-2-(3,4-dimethoxyphenyl)-2-isopropyl valeronitrile, which is known as Verapamil. The present invention also relates to a process for improving the purity of verapamil and therefore of its hydrochloride represented as the compound of formula I, by efficient removal of the impurities formed, affording a product of purity greater than 99 %. The process of the present invention is simple, efficient, cost-effective and industrially feasible.

Floating pharmaceutical composition comprising an active phase and a non-active phase

The invention concerns a floating pharmaceutical composition consisting of at least a first phase comprising at least a high dose active principle combined with one or several carriers and at least a second phase comprising at least a gas-generating system. The invention also concerns tablets comprising such a pharmaceutical composition and a method for preparing such tablets.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

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.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, 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.

Mild palladium-catalyzed selective monoarylation of nitriles

Two new palladium-catalyzed procedures for the arylation of nitriles under less basic conditions than previously reported have been developed. The selective monoarylation of acetonitrile and primary nitriles has been achieved using α-silyl nitriles in the presence of ZnF2. This procedure is compatible with a variety of functional groups, including cyano, keto, nitro, and ester groups, on the aryl bromide. The arylation of secondary nitriles occurred in high yield by conducting reactions with zinc cyanoalkyl reagents. These reaction conditions tolerated base-sensitive functional groups, such as ketones and esters. The combination of these two methods, one with a-silyl nitriles and one with zinc cyanoalkyl reagents, provides a catalytic route to a variety of benzylic nitriles, which have not only biological significance but utility as synthetic intermediates. The utility of these new coupling reactions has been demonstrated by a synthesis of verapamil, a clinically used drug for the treatment of heart disease, by a three-step route from commercial materials that allows convenient variation of the aryl group.

Method of using deuterated calcium channel blockers

Therapeutic methods and compositions using deuterated enriched 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester and other deuterated dihydropyridine compounds are described. The deuterated compounds exhibit enhanced efficacy in blocking calcium channels over non-deuterated dihydropyridines.

Enhancement of the efficacy of nifedipine by deuteration

A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.

Substituted 1H-imidazoles

New substituted 1H-imidazoles and their salts, processes for the preparation thereof and pharmaceutical compositions. These compounds have the formula STR1 wherein R1, R2, R3 and R5 =hydrogen or C1 -C4 -alkyl; R4 =hydrogen, C1 -C4 -alkyl or C1 -C4 -alkoxy; Y1 =hydrogen and Y2 =OZ2 or the reverse; Z1 =Z2 =hydrogen or C1 -C4 -alkyl or Z1 and Z2 =--CH2 -- or --C(CH3)2 --. These compounds are prepared either by reducing a corresponding imidazole compound having a hydroxyl or alkoxy group on the methyl bridge between the imidazole and phenyl rings, or by hydrolyzing a 4-[[2,2-dimethyl-4H-1,3-benzodioxin-6(or 8)-yl]methyl]-1H-imidazole, or yet by reducing an alkyl 3-[(1H-imidazol-4-yl)methyl]-2-hydroxybenzoate. These compounds have cardiac, cerebral and tissular anti-ischemic activities.

Process for the preparation of basically substituted phenylacetonitriles

A simplified process for the preparation of basically substituted phenylacetonitriles, in particular of verapamil, is described. This process is carried out with fewer stages and higher yields than the known processes according to the state of the art.