19216-56-9

Usage

Uses

Used in Cardiovascular Medicine:
Prazosin is used as an antihypertensive agent for treating mid-to-moderate hypertension. It effectively reduces blood pressure without causing significant changes in cardiac function indicators such as heart rate, coronary flow, or cardiac output. This selective action on blood pressure makes it a valuable treatment option for patients with average or moderate hypertension.

Originator

Hypovase, Pfizer, UK,1974

Manufacturing Process

Preparation of 2-Chloro-4-Amino-6,7-Dimethoxyquinazoline: To 800 ml of a solution of anhydrous ammonia in tetrahydrofuran at room temperature is added 30 g of 2,4-dichloro-6,7-dimethoxyquinazoline [F.H.S. Curd et al., J. Chem. Soc., p 1759 (1948)]. The mixture is stirred for 44 hours. The precipitate (29 g, MP 267° to 268°C) is filtered and recrystallized from methanol to yield 19 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, MP 302°C (dec.).Preparation of 2-(1-Piperazinyl)-4-Amino-6,7-Dimethoxyquinazoline: To 5 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, is added 20 g of a 25% solution of piperazine in ethanol. The mixture is heated at 160°C for 16 hours in a pressure bottle. The solvent is then evaporated and the residue is recrystallized from methanol/water.Preparation of 2[4-(2-Furoyl)-Piperazinyl]-4-Amino-6,7-Dimethoxyquinazoline: To 0.10 mol 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline in 300 ml methanol is added with vigorous stirring, 0.10 mol 2-furoyl chloride. After addition is complete, the mixture is stirred for 3 hours at room temperature. The solids are filtered to give the desired product, MP 278° to 280°C.

Therapeutic Function

Antihypertensive

Clinical Use

Prazosin is effective in reducing all grades of hypertension. The drug can be administered alone in mild and (in some instances) moderate hypertension.When the hypertension is moderate or severe, prazosin generally is given in combination with a thiazide diuretic and a -blocker. The antihypertensive actions of prazosin are considerably potentiated by coadministration of thiazides or other types of antihypertensive drugs. Prazosin may be particularly useful when patients cannot tolerate other classes of antihypertensive drugs or when blood pressure is not well controlled by other drugs. Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by diabetes mellitus or gout. Prazosin and other -antagonists find use in the management of benign prostatic obstruction, especially in patients who are not candidates for surgery. Blockade of -adrenoceptors in the base of the bladder and in the prostate apparently reduces the symptoms of obstruction and the urinary urgency that occurs at night.

Side effects

Although less of a problem than with phenoxybenzamine or phentolamine, symptoms of postural hypotension, such as dizziness and light-headedness, are the most commonly reported side effects associated with prazosin therapy. These effects occur most frequently during initial treatment and when the dosage is sharply increased. Postural hypotension seems to be more pronounced during Na deficiency, as may occur in patients on a low-salt diet or being treated with diuretics, - blockers, or both.

Synthesis

Prazosin, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)-piperazine (12.2.12), is synthesized from 2-amino-4,5-dimethoxybenzoic acid, which upon reaction with sodium cyanate undergoes heterocyclation into 2,4-dihydroxy-6,7-dimethoxyquinazoline (12.2.9). Substituting hydroxyl groups of Prazosin with chlorine atoms by reaction with thionyl chloride, or a mixture of phosphorous oxychloride with phosphorous pentachloride gives 2,4-dichloro-6,7-dimethoxyquinazoline (12.2.10). Upon subsequent reaction with ammonia, the chlorine atom at C4 of the pyrimidine ring is replaced with an amino group, which leads to the formation of 4-amino-2-chloro-6,7-dimethoxyquinazoline (12.2.11). Introducing this into a reaction with 1-(2-furoyl)piperazine gives prazosin (12.2.12) [38–47].

Veterinary Drugs and Treatments

Prazosin is less well studied in dogs than hydralazine, and its capsule dosage form makes it less convenient for dosing. Prazosin, however, appears to have fewer problems with causing tachycardia, and its venous dilation effects may be an advantage over hydralazine when preload reduction is desired. It could be considered for therapy for the adjunctive treatment of CHF, particularly when secondary to mitral or aortic valve insufficiency when hydralazine is ineffective or not tolerated. Prazosin may also be used for the treatment of systemic hypertension or pulmonary hypertension in dogs.

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Antidepressants: enhanced hypotensive effect with MAOIs. Avanafil, vardenafil, sildenafil and tadalafil: enhanced hypotensive effect - avoid. Beta-blockers: enhanced hypotensive effect, increased risk of first dose hypotensive effect. Calcium-channel blockers: enhanced hypotensive effect, increased risk of first dose hypotensive effect. Diuretics: enhanced hypotensive effect, increased risk of first dose hypotensive effect. Moxisylyte: possibly severe postural hypotension when used in combination.

Metabolism

Prazosin is extensively metabolised in the liver, mainly by demethylation and conjugation; some of the metabolites have antihypertensive activity. It is excreted as metabolites and 5-11% as unchanged prazosin mainly in the faeces via the bile.

InChI:InChI=1/C19H21N5O4/c1-26-15-10-12-13(11-16(15)27-2)21-19(22-17(12)20)24-7-5-23(6-8-24)18(25)14-4-3-9-28-14/h3-4,9-11H,5-8H2,1-2H3,(H2,20,21,22)

Upstream product

• 527-69-5 2-furancarbonyl chloride 
• 60547-97-9 4-amino-6,7-dimethoxy-2-piperazin-1-ylquinazoline 
• 57200-93-8 ethyl 4-(2-furoyl)piperazin-1-ylformimidate hydrochloride 
• 26961-27-3 2-amino-4,5-dimethoxybenzonitrile 
• 34065-01-5 1-cyanopiperazine 
• 120-43-4 4-ethoxycarbonylpiperazine 
• 23680-84-4 2-chloro-6,7-dimethoxyquinazolin-4-amine 
• 88-14-2 2-furanoic acid 
• 65679-30-3 4-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-6,7-dimethoxy-quinazoline 
• 65679-29-0 4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazine-1-carbonitrile 
• 108-86-1 bromobenzene 
• 1260939-66-9 4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester 

Related news

The effects of Prazosin (cas 19216-56-9) on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis07/30/2019

Nightmares are a highly prevalent and distressing feature of post-traumatic stress disorder (PTSD). Previous studies have reached mixed conclusions regarding the effects of prazosin on nightmares, sleep quality and overall PTSD symptoms in patients with PTSD. MEDLINE, EMBASE, all EBM databases, ...detailed

Relevant academic research and scientific papers

PEPTIDE AND SMALL MOLECULE AGONISTS OF EPHA AND THEIR USES

A method of treating cancer in a subject includes administering to the subject a therapeutically effective amount of a compound, the small molecule having a general formula: A-L-X-Z (I).

Design and synthesis of small molecule agonists of EphA2 receptor

Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure?activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor.

Targeting Influenza A Virus RNA Promoter

The emergence of drug-resistant strains of influenza virus makes exploring new classes of inhibitors that target universally conserved viral targets a highly important goal. The influenza A viral genome is made up of eight single-stranded RNA-negative segments. The RNA promoter, consisting of the conserved sequences at the 3′ and 5′ end of each RNA genomic segment, is universally conserved among influenza A virus strains and in all segments. Previously, we reported on the identification and NMR structure of DPQ (6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine) (compound 1) in complex with the RNA promoter. Here, we report on additional screening and SAR studies with compound 1, including ex vivo anti-influenza activity assays, resulted in improved cellular activity against influenza A virus in the micromolar range.

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.

Parallel synthesis of N-arylpiperazines using polymer-assisted reactions

A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleophilic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.

Novel crystalline forms of prazosin hydrochloride

The invention relates to novel and valuable crystalline forms of the hypotensive agent prazosin hydrochloride. The anhydrous α-form is preferred because it is relatively non-hygroscopic and hence possesses important advantages in handling and formulation. The polyhydrate form of prazosin hydrochloride is preferred because of its low, uniform rate of dissolution.

Process for preparing hypotensive 2-(4-aroylpiperazin-1-yl)-amino-6,7-dimethoxyquinazolines

Certain 2-(4-aroylpiperazin-1-yl)-4-amino-6,7-dimethoxyquinazolines are prepared by a novel process wherein certain 2-(4-substituted-piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline intermediates wherein said substituent is cyano, certain carbon-oxygen double bond containing groups or certain carbon-nitrogen double bond containing groups, are reacted with certain metalloaryl compounds followed by hydrolysis. The products are known hypotensive agents. Certain of the process intermediates are novel compounds.

Synthesis and identification of the major metabolites of prazosin formed in dog and rat

The 6 O demethyl and 7 O demethyl analogues of the new antihypertensive drug prazosin [2 [4 (2 furoyl) piperazin 1 yl] 4 amino 6,7 dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate ten step reaction sequences starting from isovanillin and vanillin, respectively. The 6 O demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7 O demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2 (1 piperazinyl) 4 amino 6,7 dimethoxyquinazoline and 2,4 diamino 6,7 dimethoxyquinazoline, are also described. All four metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.