138402-11-6 Usage
Uses
Used in Pharmaceutical Industry:
Irbesartan is used as an antihypertensive drug for the treatment of high blood pressure. It acts as an angiotensin II type 1 (AT1) receptor antagonist, helping to lower blood pressure by blocking the effects of angiotensin II, a hormone that constricts blood vessels.
Used in Cardiovascular Applications:
Irbesartan is used as a treatment for hypertension, particularly in patients with type 2 diabetes and hypertension. It is effective in managing blood pressure and has been shown to be particularly useful in patients with diabetic nephropathy, a condition characterized by elevated serum creatinine and proteinuria.
Used in Antidepressant Applications:
Irbesartan has also been found to have potential use as an antidepressant, although this application may be less common compared to its use as an antihypertensive agent.
Used in Congestive Heart Failure Treatment:
Irbesartan is used as a second-line agent in the treatment of congestive heart failure, a condition in which the heart is unable to pump blood effectively. Its role as an angiotensin II receptor antagonist helps to improve heart function and reduce the symptoms of this condition.
Antihypertensives
Irbesartan is an angiotensin Ⅱreceptor inhibitor, angiotensin Ⅱ receptors are divided into AT1, AT2, irbesartan can inhibit AngⅠtransform into AngⅡby selectively blocking the AT1 receptor of AngⅡ, specifically antagonize angiotensin converting enzyme 1 receptor (AT1), the antagonism of AT1 is 8500 times than that of AT2, it can inhibit vasoconstriction and aldosterone release by selectively blocking the binding AngⅡ with AT1 receptor and result in the antihypertensive effect. This product does not inhibit angiotensin converting enzyme (ACE), renin, and other hormone receptors, neither suppress the blood pressure regulation and the balance of sodium ion channels. Irbesartan can also reduce electrical remodeling of the myocardium, thereby reduce the mortality rate of patients with hypertension, it is the most effective drug for treatment of hypertension and cardiovascular disease.
Angiotensin antagonists (ARB) is applied to the clinical treatment of hypertension and diabetic nephropathy. At present, domestic drugs for treating high blood pressure are divided into angiotensin converting enzyme inhibitors (ACEI), calcium channel blockers, beta blockers and so on according to different working parts. By contrast, ARB has better antihypertensive effect, while Irbesartan is a new type of angiotensin antagonist which has clear antihypertensive effect, and has an important role in inhibiting left ventricular hypertrophy and protecting the kidneys.
According to foreign reports, it can quickly absorb by oral and the bioavailability is 60-80%, not affected by food. Plasma tmax is 1-1.5 hours, plasma protein combined rate is 90%, elimination half-life is 11-15 hours, reaching steady state in three days. By aldehyde oxidation acidification or glucose metabolism, vitro studies have shown that mainly oxidation by cytochrome enzymes of P450 and 2C9. This product and its metabolites excrete by biliary tract and kidney.
Irbesartan (Emberd) produced by Sanofi-aventis hangzhou minsheng pharmaceutical co., LTD won the approval of the SFDA used in the treatment of hypertension in type 2 diabetic nephropathy on March 8, 2007, and becomes China's first effective antihypertensive drug.
Telmisartan
Telmisartan is a new type of blood pressure drug, is a kind of specific angiotensin Ⅱ receptor (AT Ⅰ) antagonist, used in the treatment of essential hypertension. To instead of high affinity of angiotensin receptor Ⅱwith AT Ⅰ receptor subtypes (known angiotensin Ⅱ loci). Telmisartan has no effects in the AT Ⅰ receptor agonist sites, selectively combined with ATⅠ receptor and the combined effect is durable. Has no affinity with other receptor (including AT2 and other characteristics of less AT receptors). The other receptor function remains to be seen, excessive receptor stimulation effect due to telmisartan angiotensin Ⅱ level is also not known. Telmisartan is not inhibit human plasma renin, and also don't block the ion channel. Don't inhibit angiotensin converting enzymeⅡ, the enzyme can degrade and enhance adverse reactions caused by the excitation peptide inhibition. 80 mg of telmisartan in the human body is almost completely inhibit angiotensin Ⅱ causing increased blood pressure. Inhibition effect is last for a full of 24 hours and can still be detectable in 48 hours. Antihypertensive effect is obvious in 3 hours after the first dose. At 4 weeks after treatment began to gain maximum antihypertensive effect, and can be maintained in the long-term treatment. If the treatment was interrupted suddenly, the blood pressure returns to the treatment level in just a few days, rather than a resilient high blood pressure. In direct comparison of two kinds of high blood pressure drugs in clinical trials, treatment group was significantly lower than that of patients with dry cough angiotensin converting enzyme inhibitors in treatment group.
The above information is edited by the lookchem of Duan Yalan.
Usage and Dosage
Oral: recommended starting dose of 0.15 g, 1 time a day. It can be increased to 0.3 g according to the condition, 1 time a day. Can be used alone, also can be shared with other anti-hypertensive drugs.
Severe hypertension and not satisfied with drop in blood pressure after the drug increment, can add with small dose of diuretic (such as thiazide) or other antihypertensive drugs.
Drug interaction
It has no obvious interactions with hydrochlorothiazide, digoxin, warfarin, nitrate benzene, pyridine.
It should be paid attention to when shared with diuretics due to insufficient blood volume and low sodium which can cause low blood pressure (hypotension). When shared with potassium diuretics (such as ammonia, benzene with organism), should avoid potassium increasing.
Do not affect each other pharmacokinetics when shared with digitalis drugs such as digoxin, beta blockers such as atenolol, calcium antagonists such as benzene, pyridine nitrate.
Overdose
After an overdose of this product can occur hypotension, tachycardia or bradycardia, vomiting, gastric lavage and support therapy should be adopted.
Side effects
Common adverse reactions: headache, dizziness, palpitation, etc., I have a cough, general degree is slight, the majority of patients continue to drugs are tolerated.
Rare urticaria and angioneurotic oedema.
Literature on this product is: the incidence of adverse reactions to more than 1% of indigestion, stomach burning, diarrhea, skeletal muscle pain, fatigue, and upper respiratory tract infection, but with the blank control group no significant difference. Greater than 1% but less than control group in the incidence of abdominal pain, anxiety, nervousness, nausea, vomiting, chest pain, pharyngitis, skin rashes, tachycardia, etc. Low blood pressure and incidence of orthostatic hypotension is about 0.4%.
Chemical property
Crystallization from 96% ethanol, melting point is 180-181 ℃.
Production Method
Methods 1:
1-(fluorene methoxy carbonyl amino) ring e carboxylic acid (I) benzylamine reaction with 4-(2-phenyl cyano) amidation, product (Ⅲ) and water release N to produce compound (Ⅳ). (Ⅳ) and Triethyl orthobutyrate condensation, cyclization to compound (V), then azide to formation tetrazolium with sodium reaction to obtain Telmisartan.
Methods 2:
1-(fluorene methoxyl carbonyl amino) ring e carboxylic acid (I) condensation with compound(Ⅳ), the product remove N protection based to compound (Ⅷ), reacts with Triethyl orthobutyrate, obtain the product.
Manufacturing Process
1. Synthesis of 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-oneMethod 1:The ethyl ester of 1-aminocyclopentanecarboxylic acid is prepared according
to Adkins and Billica (J. Amer. Chem. Soc., 1948, 70, 3121).Ethyl valerimidate hydrochloride is prepared according to Mac Elvain (J. Amer.
Chem. Soc., 1942, 64, 1825-1827) and then freed from its hydrochloride by
reaction with potassium carbonate and extraction with CH2Cl2.The ethyl ester of 1-aminocyclopentanecarboxylic acid (1.57 g) and ethyl
valerimidate (1.56 g) are dissolved in 12 ml of xylene containing 6 drops of
acetic acid. After refluxing for 6.5 h, the reaction medium is concentrated
under vacuum, the residue is chromatographed on silica gel using a
chloroform/methanol/acetic acid mixture (94/4/2; v/v/v) as the eluent. The
fraction containing the expected product is evaporated several times in the
presence of xylene and then benzene in order to remove the acetic acid. 1.91
g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one are obtained in the
form of a thick oil.Method 2:1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a roundbottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9
ml of water and 3.5 ml of 20% aqueous ammonia is added; finally, 3 g of
cyclopentanone in 3.8 ml of methanol are added to the flask. After stirring for
1.5 h, the mixture is heated at 60°C for 45 min, heating is then stopped,
stirring is continued for 45 min and the mixture is then cooled to 25°C. It is
extracted several times with methylene chloride.The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone,
and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is
added, with stirring. The precipitate of 1-aminocyclopentanenitrile formed is
filtered off.5.1 g of the oxalate obtained in the previous step are treated with 7.65 ml of
concentrated sulfuric acid (d = 1.84) over 45 min, with stirring. The evolution
of a gas is observed and the temperature rises to 100°C. The mixture is
cooled to about 35°C and poured into a mixture of ice and concentrated
aqueous ammonia (10 g/2.8 ml). The suspension formed is extracted with
chloroform containing 5% of methanol. The 1-aminocyclopentanecarboxamide
was obtained.3 g of the compound prepared in the previous step are placed in 70 ml of
anhydrous THF and 3.3 ml of triethylamine, and 3 ml of valeryl chloride in 10
ml of anhydrous THF are added, with stirring. A white suspension is formed.
The intermediate which is formed, but not isolated, is 1-(Nvaleryl)aminocyclopentanecarboxamide. 6 g of potassium hydroxide pellets, 7
ml of water and 16 ml of methanol are added. The mixture is refluxed for 2.5
h and 9 g of ammonium chloride are then added. After stirring for 15 min, the
mixture is concentrated under vacuum. The residue of the 2-n-butyl-4-
spirocyclopentane-2-imidazolin-5-one obtained is taken up in water and
extracted with ethyl acetate.2. Synthesis of 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-
yl)-methyl]-2-imidazolin-5-oneA mixture containing 250 mg of sodium hydride (as an 80% dispersion in
mineral oil) and 5 ml of DMF is prepared under a nitrogen atmosphere and a
solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-
one in 10 ml of DMF is added dropwise. The mixture is stirred for 30 min at
20°C and a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of
DMF is then added. After stirring for 1 h at 20°C, the DMF is evaporated off
under reduced pressure, the residue is then taken up with ethyl acetate,filtered and evaporated. The residue of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-nbutyl-4-spirocyclopentane-2-imidazolin-5-one is purefied by chromatography1.56 g of the previous product, 2.6 g of tributyltin azide and 30 ml of xylene
are refluxed for 66 h. The xylene is then evaporated off and the residue is
dissolved in 20 ml of CH2Cl2 and 5 ml of THF with the addition of 0.8 ml of 10
N sodium hydroxide solution and, after stirring for 30 min, 2.5 g of trityl
chloride, and the mixture is stirred for 26 h. After evaporation of the solvents,
the residue is taken up in ethyl acetate in ethyl acetate, washed with water
and then with a 3% solution of potassium bisulfate and water. It is dried and
evaporated. The residue is chromatographed on alumina using a hexane/ethyl
acetate mixture (9/1; v/v) as the eluent to give 1.97 g of the 2-n-butyl-4-
spirocyclopentane-1-[(2'-(triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-
2-imidazolin-5-one. Melting point 150-152°C.1.96 g of the product prepared in the previous step are dissolved in 10 ml of
methanol and 10 ml of THF. After the reaction medium has been cooled to
5°C, 1.5 ml of 4 N hydrochloric acid are added and the mixture is stirred for 3
h at 20°C and 1 h at 30°C. After evaporation of the solvents, the residue is
taken up in water and the pH is brought to 12 by the addition of 10 N sodium
hydroxide solution. The aqueous phase is extracted with ether, toluene and
ether again. The aqueous phase is acidified to pH 2 by the addition of 1 N
hydrochloric acid and then extracted with ethyl acetate and the extract is
evaporated. The aqueous phase is acidified to pH 2 by the addition of 1 N
hydrochloric acid and then extracted with ethyl acetate and the extract is
dried and evaporated. The white solid obtained is dried at 50°C under 0.05
mm of mercury to give 840 mg of the 2-n-butyl-4-spirocyclopentane-1-[(2'-
(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Melting point 180-
181°C.
Therapeutic Function
Antihypertensive
Biochem/physiol Actions
Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist with antihypertensive activity. It also elicits selective peroxisome proliferator-activated receptor γ (PPARγ)-modulating activity and possesses anti-inflammatory properties. Irbesartan shows protective cardiovascular effects and provides protection against chronic glomerulonephritis.
Clinical Use
Angiotensin-II receptor antagonist:
Hypertension
Diabetic nephropathy
Veterinary Drugs and Treatments
Although experience in veterinary medicine is minimal irbesartan
may be useful in treating canine hypertension associated with renal
insufficiency. It may be effective in treating heart failure when dogs
are unable to tolerate ACE inhibitors, but documentation for this
use is lacking. One study, using very high irbesartan dosages (60
mg/kg PO twice daily) in dogs with subacute mitral regurgitation,
demonstrated no improvement in left ventricular function or prevention
of left ventricular remodeling (Perry, Wei et al. 2002).
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and
increased risk of renal impairment with NSAIDs;
hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia
hypotension and renal impairment with ACE-Is and
aliskiren.
Ciclosporin: increased risk of hyperkalaemia and
nephrotoxicity.
Diuretics: enhanced hypotensive effect;
hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism
of hypotensive effect.
Lithium: reduced excretion (possibility of enhanced
lithium toxicity).
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and
nephrotoxicity.
Metabolism
Following oral or intravenous administration of 14C
irbesartan, 80-85% of the circulating plasma radioactivity
is attributable to unchanged irbesartan. Irbesartan is
metabolised by the liver via glucuronide conjugation and
oxidation. The major circulating metabolite is irbesartan
glucuronide (approximately 6%). In vitro studies indicate
that irbesartan is primarily oxidised by the cytochrome P450
enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.
Irbesartan and its metabolites are eliminated by both
biliary and renal pathways. After either oral or IV
administration of [14C]-irbesartan, about 20% of the
radioactivity is recovered in the urine, and the remainder
in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 138402-11-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,8,4,0 and 2 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 138402-11:
(8*1)+(7*3)+(6*8)+(5*4)+(4*0)+(3*2)+(2*1)+(1*1)=106
106 % 10 = 6
So 138402-11-6 is a valid CAS Registry Number.
InChI:InChI=1/C25H28N6O/c1-2-3-10-22-26-25(15-6-7-16-25)24(32)31(22)17-18-11-13-19(14-12-18)20-8-4-5-9-21(20)23-27-29-30-28-23/h4-5,8-9,11-14H,2-3,6-7,10,15-17H2,1H3,(H,27,28,29,30)
138402-11-6Relevant articles and documents
Improved synthesis of irbesartan, an antihypertensive active pharmaceutical ingredient
Sumalatha, Bollikonda Satyanarayana Yasareni,Venkatraman, Sundram,Reddy, Ghanta Mahesh,Reddy, Padi Pratap
, p. 1979 - 1982 (2005)
An improved synthesis of the antihypertensive drug irbesartan, based on the Suzuki reaction, has been described. Copyright Taylor & Francis, Inc.
Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof
-
Paragraph 0099; 0100; 0101; 0109, (2019/05/28)
The invention discloses a method for treating azide ions in a system and application thereof to the preparation of a compound with a tetrazolium group and without genotoxic impurities. The method is that the azide ions contained in the hydrogen peroxide treatment system are used. The method is used for preparing the compound with the tetrazolium group and comprises the following preparation steps:enabling a compound containing a cyano group to react with an azide, adding hydrogen peroxide after the reaction to quench and remove excessive sodium azide and further obtaining the compound with the tetrazolium group. The compound prepared by the method does not contain the genotoxic impurities. The method is simple in operation, mild in reaction conditions and suitable for industrial production.
Nickel-Catalyzed Denitrogenative ortho-Arylation of Benzotriazinones with Organic Boronic Acids: an Efficient Route to Losartan and Irbesartan Drug Molecules
Thorat, Vijaykumar H.,Upadhyay, Nitinkumar Satyadev,Cheng, Chien-Hong
, p. 4784 - 4789 (2018/11/10)
Denitrogenative ortho-arylation, vinylation and methylation of 1,2,3-benzotriazin-4-(3H)-ones with organic boronic acids catalyzed by nickel complexes to give a wide range of o-substituted benzamides were demonstrated. Further, the catalytic reaction is successfully applied to the synthesis of the popular hypertensive drugs losartan and irbesartan in high yields. (Figure presented.).
One-pot method for preparing irbesartan
-
Paragraph 0026-0034, (2018/12/13)
The invention discloses a one-pot method for preparing irbesartan. The method comprises the following steps: with 2-butyl-1,3-diazaspiro[4,4]non-1-ene-4-one hydrochloride and 2-cyano-4'-bromomethylbiphenyl as raw materials, performing a reaction in an aprotic solvent containing an alkaline solution, performing an alkylation reaction under the action of a phase transfer catalyst to obtain 2-butyl-3-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-1,3-diazaspiro[4,4]non-1-ene-4-one, and performing a cyclization reaction on the 2-butyl-3-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-1,3-diazaspiro[4,4]non-1-ene-4-one and sodium azide under the action of a cyclization catalyst to obtain the irbesartan. The method has the advantages of simple operation, a short reaction time, high yield, high purity and suitability for industrial production.
Syntheses of 5-substituted 1H-tetrazoles catalyzed by reusable Cu(II)-NaY zeolite from nitriles
Sudhakar,Purna Chandra Rao,Prem Kumar,Suresh,Ravi
, p. 864 - 866 (2017/02/10)
Cu(II)-NaY heterogeneous catalyst is used for the synthesis of 5-substituted 1H-tetrazoles by [2+3]-cycloaddition of sodium azide and nitriles. The salient features of this process are low reaction times, mild reaction conditions and high yields. The catalyst is recovered and reused for several cycles with consistent activity.
Preparation method of irbesartan isomer and irbesartan intermediate
-
Paragraph 0031; 0033, (2017/01/02)
The invention relates to a preparation method of an irbesartan isomer and an irbesartan condensation compound isomer as an irbesartan intermediate. The method comprises the following steps: 1) a phase transfer catalyst and an organic solvent are added to an irbesartan ring compound hydrochloride and biphenyl bromide, a sodium hydroxide solution is added, a reaction liquid is filtered after sufficient reaction of the raw materials, a filter cake is subjected to column chromatographic separation, and the irbesartan condensation compound isomer is obtained; 2) triethylamine hydrochloride, sodium azide and an organic solvent A are added to the irbesartan condensation compound isomer, the materials are heated to 100-130 DEG C and reacted, the sodium hydroxide solution and an organic solvent B are added, the mixture is stirred, left to stand and subjected to organic layer removal, hydrochloric acid is added to an aqueous-layer solution to regulate pH to 3.5-6.0, the solution is stirred and filtered, a filter cake is subjected to recrystallization with an organic solvent C or subjected to column chromatographic separation, and the irbesartan isomer is obtained. The irbesartan isomer impurity and the irbesartan intermediate prepared with the method have higher purity and lower energy consumption and cost. Meanwhile, the preparation method is simple to operate and environment-friendly and has important value in irbesartan production and research.
DEPROTECTION METHOD FOR TETRAZOLE COMPOUND
-
, (2015/09/23)
The present invention relates to a method of deprotecting a tetrazole compound, useful as an intermediate for angiotensin II receptor blockers, and provides a novel production method of angiotensin II receptor blockers. Provided is a production method of a compound represented by the formula [3] or [4] or a salt thereof, including (i) reducing a compound represented by the formula [1] or [2] or a salt thereof in the presence of a metal catalyst and an alkaline earth metal salt, or (ii) reacting the compound with a particular amount of Br?nsted acid: wherein each symbol is as defined in the present specification.
COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE
-
, (2015/02/05)
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.
Novel and efficient debenzylation of N-benzyltetrazole derivatives with the rosenmund catalyst
Seki, Masahiko
, p. 3249 - 3255 (2015/01/08)
The Rosenmund catalyst (Pd/BaSO4) was found to efficiently catalyze debenzylation of N-benzyltetrazole derivatives with ammonium formate by catalytic transfer hydrogenation under mild conditions. The protocol has been applied to functionalized substrates to provide various angiotensin II receptor blockers in excellent yields.
AN IMPROVED PROCESS FOR PREPARATION OF IRBESARTAN
-
Page/Page column 9, (2013/12/03)
The present invention relates to an improved process for the preparation of 2-butyl-3-[[2'- (2H-tetrazol5yl[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, the compound of formula I (Irbesartan) comprising reacting 4'-[(2-butyl-4-oxo-1,3- diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile, the compound of formula II (cyano Irbesartan) with sodium azide, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst and triethylamine hydrochloride in an organic solvent at a temperature of 120- 140°C.
