144701-48-4 Usage
Description
Telmisartan, a member of the benzimidazole class, is an angiotensin II receptor antagonist used widely in the treatment of hypertension. It is a white or off-white crystalline powder, odorless and tasteless, with specific chemical properties that allow it to be soluble in chloroform, slightly soluble in methanol, very slightly soluble in acetone, and practically insoluble in water. Telmisartan was launched in the US for the treatment of hypertension and is the sixth of its class to be marketed after the lead compound Losartan. It is known for its long-lasting effect (24-hour half-life) and does not require transformation into an active metabolite for its activity. Telmisartan is a potent competitive antagonist of AT1 receptors, which mediate most of the important effects of angiotensin II, while lacking affinity for the AT2 subtypes or other receptors involved in cardiovascular regulation.
Uses
1. Cardiotonic Applications:
Telmisartan is used as a cardiotonic agent for the treatment of congestive heart failure.
2. Antihypertensive Applications:
Telmisartan is used alone or in combination with other classes of antihypertensives for the treatment of hypertension.
3. Anti-cancer Applications:
Telmisartan is used as an anti-cancer agent, although its specific role and mechanism in cancer treatment are not detailed in the provided materials.
4. Diabetic Nephropathy Treatment:
Telmisartan is used in the treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus.
5. Hypertension Treatment:
Telmisartan is used as an angiotensin II receptor antagonist for the treatment of hypertension, providing effective and sustained blood-pressure lowering effects with a low incidence of side effects.
Used in Pharmaceutical Industry:
Telmisartan is used as an active pharmaceutical ingredient for the development of drugs targeting hypertension, congestive heart failure, and diabetic nephropathy.
Used in Clinical Studies:
Telmisartan is used in clinical studies to evaluate its efficacy and safety in treating various cardiovascular conditions, including hypertension and heart failure.
Mechanisms of Action
80mg of telmisartan for the human body will practically completely counter the high blood pressure caused by angiotension II. Effects will last for 24 and can still be detected within 48 hours. Blood pressure-lowering effects should gradually become apparent within 3 hours after the initial dose. If treatment is suddenly interrupted, blood pressure will return to the same level as before treatment in a matter of days, and there will be no rebound high blood pressure. In a clinical trial that compared two kinds of antihypertensive drugs, patients in the treatment group experienced lower rates of coughing than those in the group treated by angiotensin converting enzyme inhibitors.
Telmisartan has a half-life of 18～24 hours, and will take effect 1～4 hours after taken. Medicinal effects can last for as long as 35 hours, with a high (T/P) ratio and outstanding effects in controlling morning blood pressure. Thus, this medicine can effectively control blood pressure for 24 hours, and it meets the once-daily medicinal standard (40～80mg, qd).
Clinical effects and characteristics:
Pharmacokinetics show: Rapid effects (0.3h), long duration (35.4h), little effect on heart rate when lowering blood pressure.
Compared to Enalapril: Stronger antihypertensive effects than Enalapril; when both are used in combination with diuretics, Telmisartan still appears to be superior and results in a lower coughing rate.
Compared to Lisinopril: More apparent antihypertensive effects (for both systolic and diastolic blood pressure), coughing rate for Telmisartan (16%) is drastically lower than that of Lisinopril (60%).
Compared to Atenolol: Similar antihypertensive effects, lower rate of side effects (impotence and fatigue).
Compared to Amlodipine: The Telmisartan group experienced noticeably lower heart rates four hours after ingestion and from six a.m. to twelve p.m.
Overall, Telmisartan has the following characteristics in comparison with other antihypertensive medicine: specific receptor effects, noticeable hypertensive effects, good diuretic effects, improvement of myocardial stenosis, safe usage, good tolerance, and convenient daily dosage.
Side Effects
In the placebo control experiment, the incidence rate of negative events for the Telmisartan group (41.4%) was similar to that of the placebo group (43.9%). Negative events were unrelated to dosage, sex, age, or race.
The following lists negative reactions were accumulated via the 5788 hypertensive patients that were treated with Telmisartan in the clinical trial.
Negative effects are categorized by incident rate as:
Very common (>1/10); common (>1/100, <1/10=); uncommon (>1/1000, <1/100=); rare (>1/10000, <1/1000=); very rare (<1/100000=)
Bodily reaction: Common: Back pain (e.g. sciatica), chest pain, flu-like symptoms, infection symptoms (e.g. urinary tract infection including cystitis). Uncommon: sight abnormality, sweating.
Central and peripheral nervous system: Common: vertigo.
Digestive system: Common: stomach pain, diarrhea, indigestion, gastrointestinal disorders. Rare: dry mouth, bloating.
Muscle skeletal system: Common: joint pain, leg cramps or leg pain, muscle pain. Rare: Tenosensitis symptoms.
Nervous system: Rare: anxiety.
Respiratory system: Common: upper respiratory tract infection, including pharyngitis and rhinitis.
Skin and accessory system: Common: Skin abnormalities such as eczema.
Additionally, since Telmisartan entered the market, there have been individual cases of erythema, itching, syncope, insomnia, depression, stomach discomfort, vomiting, hypotension, bradycardia, tachycardia, dyspnea, eosinophilia, thrombocytopenia, weakness, and reduced work efficiency. Similar to other angiotensin II receptor blockers, very few cases have reported vascular edema, nettles, and other negative reactions.
The laboratory found: compared to the placebo, the Telmisartan group occasionally exhibited lowered hemoglobin or raised uric acid. Any increase in serum creatinine or liver enzymes in the Telmisartan group was similar or lower than that of the placebo group.
Patent
Telmisartan was originally formulated by the German pharmaceutical company Boehringer Ingelheim; it earned the German patent EP502,314 in 1991, was first approved to enter the American market in November 1998, and then entered German, Philippines, Australian, Belgium, British, and other markets.
Originator
Boehringer Ingelheim (Germany)
Manufacturing Process
A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate
dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of
phosphorus oxychloride is refluxed for 2 h. Then about 80 ml of phosphorus
oxychloride are distilled off and the residue is mixed with about 150 ml of
water. The oily crude product precipitated is extracted three times with 50 ml
of ethyl acetate and after evaporation purified by column chromatography
(600 g of silica gel; eluant:methylene chloride/methanol (30:1)). Yield of
methyl-2-n-propyl-benzimidazole-5-carboxylate: 15.0 g of oil (69%).A solution of 15.0 g (73 mmol) of methyl 2-n-propyl-benzimidazole-5-
carboxylate and 8 g (200 mMol) of sodium hydroxide in 200 ml of water and
400 ml of ethanol is refluxed for 2 h. Then the alcohol is distilled off, the
aqueous solution is acidified with dilute sulphuric acid (pH 4-5) and
evaporated using a rotary evaporator. The product crystallising out is suction filtered, washed with 50 ml of acetone and 50 ml of diethylether and dried.
Yield of 2-n-propyl-benzimidazole-5-carboxylic acid-hemisulphate: 9.1 g
(61%), melting point: >220°C.A solution of 6.7 g (25 mMol) of 2-n-propyl-benzimidazole-5-carboxylic acidhemisulphate
and 4.9 g (25 mMol) of 2-methylaminoaniline dihydrochloride in
200 g of polyphosphoric acid is stirred for 5 h at 150°C, then poured onto 600
ml of water and made alkaline with concentrated ammonia whilst cooling with
ice. The resulting solution is extracted three times with 200 ml of ethyl
acetate, the crude product thus obtained is purified by column
chromatography (300 g of silica gel; eluant:methylene chloride/methanol =
15:1). Yield of 2-n-propy1-5-(1-methylbenzimidazol-2-yl)-benzimidazole: 2.8
g of oil (39%).A solution of 2.0 g (6.9 mMol) of 2-n-propyl-5-(1-methylbenzimidazol-2-yl)-
benzimidazole and 0.91 g (7.5 mmol) of potassium tert-butoxide in 50 ml of
dimethylsulfoxide is stirred for 90 min at room temperature, then 2.6 g (7.5
mMol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and the
mixture is stirred for a further 15 h at room temperature. The mixture is then
poured onto 300 ml of water and extracted three times with 50 ml of ethyl
acetate. The crude product obtained after evaporation of the organic phase is
purified by column chromatography (300 g silica gel; eluant:methylene
chloride/methanol = 30:1). In this way, 2.7 g (70%) of an isomer mixture are
obtained (by NMR spectroscopy), contains about 1.18 g of tert-butyl-4'-[(2-npropyl-
5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-
carboxylate and about 1.52 g of tert-butyl 4'-[(2-n-propyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate).2.70 g of the isomer mixture obtained above are dissolved in 100 ml of
methylene chloride, mixed with 40 ml of trifluoroacetic acid and stirred for 4 h
at room temperature. The mixture is then evaporated to dryness in vacuo, the
residue is dissolved in 100 ml of 2 N sodium hydroxide solution, the solution
is washed with 50 ml of diethylether and the product mixture is precipitated
by acidifying the aqueous phase with acetic acid. By column chromatography
(400 g of silica gel, eluant:methylene chloride/methanol = 15:1) of the solid
thus obtained 0.9 g (74%) of 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate, melting point 217°-218°C.
Therapeutic Function
Antihypertensive
Biochem/physiol Actions
Telmisartan is a non-peptide AT1 angiotensin receptor antagonist.
Clinical Use
Angiotensin-II antagonist:
Hypertension
Prevention of cardiovascular events
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.
Cardiac glycosides: concentration of digoxin
increased.
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
Telmisartan is metabolised by conjugation to the
glucuronide of the parent compound. No pharmacological
activity has been shown for the conjugate.
Telmisartan is excreted almost entirely in the faeces via
bile, mainly as unchanged drug.
Check Digit Verification of cas no
The CAS Registry Mumber 144701-48-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,4,7,0 and 1 respectively; the second part has 2 digits, 4 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 144701-48:
(8*1)+(7*4)+(6*4)+(5*7)+(4*0)+(3*1)+(2*4)+(1*8)=114
114 % 10 = 4
So 144701-48-4 is a valid CAS Registry Number.
InChI:InChI=1/C33H30N4O2/c1-7-12-33-39-34-24(2)21-27(35-38-30-15-10-11-16-31(30)40(35)6)22-32(34)41(33)23-25-17-19-26(20-18-25)28-13-8-9-14-29(28)36(42)43-37(3,4)5/h8-11,13-22H,7,12,23H2,1-6H3
144701-48-4Relevant articles and documents
Improved one-pot synthesis of telmisartan
Rao, Challa Nageswar,Naresh, Tondepu,Satyanarayana, Komati,Reddy, Bojja Ramachandra,Reddy, Ghanta Mahesh
, p. 530 - 534 (2010)
Cost-effective and improved one-pot synthesis for telmisartan (1) is described that minimizes the reaction time and gives high-purity material. Copyright Taylor & Francis Group, LLC.
A convergent approach to the total synthesis of telmisartan via a Suzuki cross-coupling reaction between two functionalized benzimidazoles
Martin, Alex D.,Siamaki, Ali R.,Belecki, Katherine,Gupton, B. Frank
, p. 1915 - 1919 (2015)
A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.
MANUFACTURING METHOD OF BIPHENYL-2-CARBOXYLIC ACID METHYL ESTER
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Paragraph 0071-0076, (2019/12/25)
PROBLEM TO BE SOLVED: To provide a manufacturing method of 4'-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}biphenyl-2-carboxylic acid methyl ester, capable of improving yield and quality, and enhancing efficiency of workability in an industrial scale. SOLUTION: There is provided a manufacturing method of 4'-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}biphenyl-2-carboxylic acid methyl ester by adding water to a reaction mixture containing an organic polar solvent and 4'-{[4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl]methyl}biphenyl-2-carboxylic acid methyl ester generated by mixing a mixture obtained by adding 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole and a base to an organic polar solvent, and 4'-bromomethyl biphenyl-2-carboxylic acid methyl ester, to crystallize the methyl ester. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
Solid dispersions comprising Telmisartan and the preparation method thereof
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Paragraph 0111; 0114; 0118, (2018/05/15)
The solid dispersions comprising telmisartan and a manufacturing method thereof, according to the present invention, unlike conventional methods requiring a low yield, can manufacture telmisartan of a high yield through simple and short steps by using a relatively inexpensive raw material, can secure excellent quality through reduction of generation of decomposition products, and can manufacture the solid dispersions on a mass production basis to be commercially available. Therefore, the solid dispersions of novel crystalline polymorph of the telmisartan of the present invention has improved storage stability and solubility, and can be synthesized at a high yield, thereby being expected to be very useful in the manufacture of pharmaceuticals.COPYRIGHT KIPO 2018
