147526-32-7 Usage
Uses
Used in Pharmaceutical Industry:
Pitavastatin calcium is used as an antilipemic agent for the treatment of hypercholesterolemia. It works by competitively inhibiting HMG-CoA reductase, leading to a reduction in plasma cholesterol levels. This makes it a valuable medication for patients who are unable to lower their cholesterol levels through diet and exercise alone.
Used in Cardiovascular Health:
Pitavastatin calcium is used as a cholesterol-lowering agent to help prevent cardiovascular diseases. By reducing LDL-cholesterol levels, it contributes to the overall management of cardiovascular health and reduces the risk of heart attacks and strokes.
Used in Clinical Studies:
Pitavastatin calcium is used in clinical studies to evaluate its efficacy and safety in comparison with other statin medications. In a 12-week double-blind comparative study, pitavastatin (2 mg/day) was found to be more effective than pravastatin (10 mg/day) in reducing LDL-cholesterol levels, with both agents producing similar increases in HDL-cholesterol.
Used in Drug Formulation:
Pitavastatin calcium is used as an active pharmaceutical ingredient in the formulation of Livalo, a brand-name medication for the treatment of hypercholesterolemia. Its chemical properties, such as being a white to off-white powder, make it suitable for incorporation into various drug formulations.
Statin lipid-lowering drugs
Pitavastatin calcium is jointly developed by two companies Nissan Chemical and Kowa Co.it is the first total synthesis HMG-CoA reductase inhibitor, it belongs to statin drugs ,it reduces the ability of the liver to manufacture cholesterol mainly through inhibition of some liver enzymes called HMGCo-A reductase , thus it improves the elevated blood cholesterol levels, it is primarily used for the treatment of hypercholesterolemia and familial hypercholesterolemia patients,its lipid-lowering effect is very good, it is the most potent lipid-lowering drug so far.
Pharmacological effects
Inhibition of HMG-CoA reductase: pitavastatin calcium has a strongly antagonistic inhibition effect on HMG-CoA enzyme , IC50 value is 6.8 nmol/L, and its intensity is 24 times of simvastatin, while it is 68 times of fluvastatin.
It Hinders the synthesis of cholesterol: the ability to effectively inhibit the process of generating cholesterol in human hepatocytes HepG2 , IC50 value is 5.8nmol/L, and its intensity is 29 times of simvastatin, it is 57 times that of atorvastatin. But pitavastatin calcium inhibition effect on each enzyme in cholesterol generation after generation of mevalonate is very weak.
It Increases LDL receptor density: pitavastatin induces the synthesis of LDS receptor mRNA in the ultra-low concentration of 1μmol/L, it can increase the number of LDS receptor mRNA , it results in the increasing of LDL receptor density , thereby it promotes clearance of LDL , so that plasma LDL-plasma total cholesterol concentration and triglyceride concentration decrease.
The above information is edited by the lookchem of Tian Ye.
Pharmacokinetics
The main parts of its absorption after oral administration are the duodenum and colon,its rate of binding plasma protein in the body is 96%and it is more selectively distributed in the liver after absorption , the drug concentration in body tissues is lower than that in the plasma or the same as that in the plasma . Pitavastatin calcium is mainly metabolized in the liver, kidney, lung, heart, muscle , metabolite concentrations are lower than the concentration of drug prototype, it is excreted through feces,there is also a small amount of drug excretion through urine , total excretion rate is almost 100%.
A healthy male adult oral pitavastatin is 0.5~8mg, t1/2 is about 10h,the cmax and AUC of the prototype drug in plasma increase with increasing dose , repeatedly taking does not result in medication savings.
Toxicity
Acute toxicity: rats and dogs oral,study its acute toxicity. Pitavastatin calcium median lethal dose on the rats are about male 500~1000mg/kg, female 250~500 mg/kg, dogs lethal dose is about 50~100mg/kg.
Long term toxicity: respectively, rats, dogs and monkeys are administered a long-term experiment. From the experimental results, the safe dose of pitavastatin calcium are rats 1 mg/kg · d-1 (6 months), canine 0.3mg/kg · d-1 (12 months), monkey 3mg/kg · d-1 (6 months). No central nervous system, reproductive system, and myocardial dysfunction is observed which is common while taking other statins during administration.
Carcinogenicity, mutagenicity: mouse oral 1,12,30, 75mg/kg dose, the incidence of cancer has no significant increase than in the control group .in Chromosome abnormality tests, at the highest concentration of 625μg/ml,the result is positive, but at the same concentration, gene mutation recovery tests, micronucleus test s(in vivo) and UDS test s(in vivo) are negative.
Clinical Study
In the therapeutic effect, statins is the first In the lipid-lowering drugs in which pitavastatin effect is very obvious, pitavastatin calcium is a third generation statins anti-hyperlipidemia drug, and Russell atorvastatin (rosuvastatin ) while being called "super statin", is one of the better statins which are current international clinical application of the treatment of hypercholesterolemia, familial hypercholesterolemia , because its clinically effective dose is 1-2mg/day, significantly lower than other marketed statins, with high efficiency, and security features, it has a good tolerability. clinical trail phase I results show that pitavastatin calcium in 1,2,4 mg dose has clinical significance in patients with high blood cholesterol.
Results of clinical trail phase Ⅱ determine that the best dosage of the pitavastatin calcium for the treatment of hyperlipidemia is 2mg/d.
clinical trail phaseⅢ comparison of experimental results show that the efficacy of pitavastatin calcium on reducing Tc and LDL-c is better than the effect of fluvastatin, and there is no significant difference in safety. Multi-center long-term administration tests carried out in Japan show that the dosage in 1~4mg/d range can effectively control blood lipid levels. The above test results demonstrate the effectiveness of pitavastatin calcium in treatment of hyperlipidemia on clinic.
Originator
Nissan (Japan)
Hazard
A poison by ingestion.
Safety Profile
A poison by ingestion.Experimental reproductive effects. When heated todecomposition it emits toxic vapors of NOx and Fí.
Synthesis
The convergent synthesis was
achieved by cross-coupling of aryl halide 149 with (E)-
alkenyl borane 155 which was derived from terminal
acetylene 154 by via hydroboration. Anthranilic acid
(143) was treated with TsCl and sodium carbonate in hot
water to give N-tosylated intermediate in 78% yield, which
was converted to the corresponding acid chloride 144 with
PCl5 in o-dichlorobenzene at 85°C. Intermediate 144,
without isolation, was reacted with fluorobenzene in the
presence of AlCl3 at 80°C to give the Friedel-Crafts product
which was then hydrolyzed in hot water to give
fluorobenzophenone free aniline 145 in 64% yield from the
N-tosyl anthranilic acid. Acetyl cyclopropane (146) was
reacted with diethyl carbonate to give the corresponding
ethyl ester 147. The quinoline core structure was obtained by
condensing fluorobenzophenone 145 with 147 under acidic
conditions with a Dean-Stark trap to give quinoline-3-
carboxylic ethyl ester 148 in 90% yield. Ester 148 was
hydrolyzed with potassium hydroxide, and the free
carboxylic acid thus obtained was subsequently photoiododecarboxylated
with iodine and PhI(OAc)2 to give aryl iodide 149 in 74% yield. 3-Trimethylsilylpropynal (150)
was used as the starting material to prepare the chiral side
chain. Compound 150 was reacted with di-anion 151 in
THF at low temperature to give the corresponding diol ester
which was first reacted with Et2BOMe and then reduced to
acetylene with sodium borohydride. The free diol was
protected as ketal with 2,2-dimethoxypropane in the presence
of TsOH to give dimethylketal acetylene 152 in 99% yield.
The ester functionality was hydrolyzed with sodium
hydroxide to give the acid in 92% yield. The racemic free
acid was resolved with (R)-(1-naphthyl)ethylamine to give
the pure diastereomeric salt 153 which crystallized out in
31% yield and 97% e.e. Esterification of the free carboxylic
acid liberated from the crystalline salt with ethyl iodide gave
optically pure acetylene 154 in 70% yield. Hydroboration of
acetylene 154 with disiamylborane gave (E)-alkenyldisiamylborane
155 and the excess borane reagent was
quenched with sodium ethoxide in ethanol. After
evaporation of all volatile material, the residue was directly
subjected to the cross-coupling reaction. Palladium (II)
chloride and aryl iodide 149 were mixed in acetonitrile to
give coupling product 156 in 99% yield. After the ketal in
156 was hydrolyzed under acid conditions and the ester was
hydrolyzed with sodium hydroxide, the resulting carboxylic
sodium salt was reacted with calcium chloride to yield
pitavastatin calcium (XIX) with 99% e.e.
Check Digit Verification of cas no
The CAS Registry Mumber 147526-32-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,7,5,2 and 6 respectively; the second part has 2 digits, 3 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 147526-32:
(8*1)+(7*4)+(6*7)+(5*5)+(4*2)+(3*6)+(2*3)+(1*2)=137
137 % 10 = 7
So 147526-32-7 is a valid CAS Registry Number.
InChI:InChI=1/2C25H25FNO4.Ca/c2*26-17-9-7-15(8-10-17)24-20-3-1-2-4-22(20)27-25(16-5-6-16)21(24)12-11-18(28)13-19(29)14-23(30)31;/h2*1-4,7-12,16,18-19,23,28-30H,5-6,13-14H2;/q2*-1;+2/b2*12-11+;/t2*18-,19-,23+;/m11./s1
147526-32-7Relevant articles and documents
Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound
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Paragraph 0031-0033, (2020/05/14)
The invention discloses a method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound. (4R, 6S)-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methanesulfonyl)amino]-5-pyrimidine] vinyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and (4R, 6S)-6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl] vinyl]-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate are respectivelytaken as starting materials of rosuvastatin and pitavastatin, deprotection and a hydrolyzation one-step method is adopted to prepare statin acid, then the statin acid is taken as a reaction substratefor dehydration and substitution two-step reaction to prepare the 2, 5-diene heptanoate compound. The preparation and synthesis routes of rosuvastatin and pitavastatin 2, 5-diene heptanoate involved in the invention are short and feasible, the operation is simple and convenient, the product yield is high, and the rosuvastatin and pitavastatin 2, 5-diene heptanoate is more suitable for large-scaleindustrial production.
Palladium-Catalyzed Stereoselective Cyclization of in Situ Formed Allenyl Hemiacetals: Synthesis of Rosuvastatin and Pitavastatin
Spreider, Pierre A.,Breit, Bernhard
, p. 3286 - 3290 (2018/06/11)
A diastereoselective palladium-catalyzed cyclization of allenyl hemiacetals is described. It permits the selective synthesis of 1,3-dioxane derivatives, precursors for syn-configured 1,3-diols which make an appearance in all of the statin representatives. The reaction allows the total synthesis of Rosuvastatin and Pitavastatin in a straightforward fashion.
New crystal form of pitavastatin hemicalcium salt and preparation method thereof
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Paragraph 0052-0061, (2019/01/08)
The invention provides a new crystal form of a pitavastatin hemicalcium salt. The new crystal form is named as a crystal form I. In an X-ray powder diffraction spectrum measured by using a Cu-K alpharay, the new crystal form of the pitavastatin hemicalciu
Multi-substituted dihydroisoquinolines he the sandbank contains the fluorine derivative and use thereof
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Paragraph 0135; 0136, (2018/06/04)
The invention belongs to the field of pharmaceutical chemistry, and provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is a polysubstituted miazine statin fluorine-containing modifier of 1-fluoro-3-hydroxypentanoic acid and its salt or ester formed after ring opening of 3-fluoro-caprolactone fragment and its lactone. The structural formula of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is shown in the specification. A result of test of like compounds shows that the compounds have an HMG-CoA reductase activity inhibition effect, and can be used as a new-generation latent HMG-CoA reductase inhibitor.
For production of the precursor [...]
-
, (2018/03/23)
PROBLEM TO BE SOLVED: To provide a precursor compound of pitavastatin calcium excellent in safety and cost with high yield and high selectivity in a mild condition.SOLUTION: A method for producing a precursor compound of pitavastatin calcium of formula 1 is characterized by reacting a compound of formula 2 with a compound of formula 3 in the presence of an alkali metal salt selected from alkali metal carbonate, alkali metal acetate, and alkali metal propionate. (In the formulae, Ris a C-Calkyl group, and Ris an aryl group, an aralkyl group, or an alkyl group.)
Method for preparing statin raw material drug intermediate by use of improved Julia olefination as key step
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Paragraph 0045; 0046; 0047; 0048, (2017/08/28)
The invention relates to a method for preparing a statin raw material drug intermediate by use of improved Julia olefination as a key step, and mainly solves the problems of high construction cost of a chiral center for preparing of the statin raw materia
Method for preparing pitavastatin lactone impurity
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Paragraph 0007, (2016/11/17)
The invention discloses a method for preparing pitavastatin lactone impurity. 4-(1-(4-chlorobenzoyl))-6-imino-3-methyl-1,4,6,7-tetrahydropyrazolo[3,4-D][1,3]thiazol-4-yl)-2-methoxyphenol is one main impurity during production of pitavastatin calcium. The impurity can be prepared through dehydration condensation of a compound (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3R,5S-dihydroxy-6-heptenoic acid. The condensation reaction conditions are mild, the product purity is high, and research demand on pitavastatin calcium quality is satisfied.
Pitavastatin calcium method for the preparation of
-
, (2017/03/14)
The invention relates to a preparation method of a cholesterol reduction drug, particularly relates to a preparation method of pitavastatin calcium as a crude drug of the cholesterol reduction drug, and aims at the problems that the pitavastatin calcium synthetic technology in the prior art is long in steps and complicated in operation, and uses strongly corrosive reagents which is environmentally unfriendly, causes serious corrosion to equipment, and may not facilitate industrial production. The invention provides the new preparation method of the pitavastatin calcium, the new preparation method is as follows: 3-bromomethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline is prepared from 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde by a one step reaction, and then reacts with an organophosphorus reagent to obtain pitavastatin calcium intermediate phosphorus ylide, on the basis of improving of the yield to 80%, the reaction steps are reduced, and the reaction difficulty is reduced, and hydroxylamine hydrochloride is selected as a deprotection reagent, so that the new preparation method is mild in reaction conditions, environmentally friendly, high in yield, and beneficial to industrial production.
3,5-dihydroxyhept-6-enoic acid derivative preparation method
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, (2017/04/19)
The invention relates to a preparation method of 3, 5-dihydroxy-6-heptenoic acid derivatives. The preparation method comprises the steps of hydrolyzing crude statin ester to form a water-soluble alkali metal salt, extracting by using a solvent to remove impurities which cannot be dissolved into water, and converting at high yield to form ester with relatively high purity; then, purifying the ester by using a recrystallization way to obtain pure statin ester; and finally, converting the pure statin ester at high yield to form statin calcium, namely the 3, 5-dihydroxy-6-heptenoic acid derivatives. The 3, 5-dihydroxy-6-heptenoic acid derivatives, namely rosuvastatin calcium and pitavastatin calcium, synthesized by using the preparation method are high in purity and total yield, relatively low in cost and beneficial to mass production.
The synthesis of [18F]pitavastatin as a tracer for hOATP using the Suzuki coupling
Yagi, Yusuke,Kimura, Hiroyuki,Arimitsu, Kenji,Ono, Masahiro,Maeda, Kazuya,Kusuhara, Hiroyuki,Kajimoto, Tetsuya,Sugiyama, Yuichi,Saji, Hideo
, p. 1113 - 1121 (2015/02/19)
Fluorine-18 labeled radiotracers, such as [18F]fluorodeoxyglucose, can be used as practical diagnostic agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be enhanced significantly by the introduction of fluorine groups into their original structures, and significant progress has been made during the last three decades towards the development of practical procedures for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with radioactive 18F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life sciences because it can act as an antihyperlipidemic agent as well as a substrate for hepatic organic anion transporting polypeptides (hOATP). With this in mind, it was envisaged that [18F]pitavastatin would be used as an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent. Herein, we report a practical method for the synthesis of [18F]pitavastatin by the Suzuki coupling reaction of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a radiochemical yield of 12 ± 3% (decay corrected from [18F]fluoride ions, n = 3). This journal is
