- Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids
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Atorvastatin calcium (Lipitor, Sortis) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization/dehydration process in the side chain), treatment with conc. aqueous hydrochloric acid gave a complex, bridged molecule under C–C-bond formation of the lactone moiety with the pyrrole, migration of the isopropyl group and loss of the carboxanilide residue. The novel degradation products were characterized by NMR spectroscopy, HRMS data and X-ray crystal structure analysis.
- Krau?, Jürgen,Klimt, Monika,Luber, Markus,Mayer, Peter,Bracher, Franz
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- HMG-CoA reductase inhibitors and P-glycoprotein modulation
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1. Five 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P-glycoprotein (P-gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over-expresses the multi-drug resistance protein la/b (mdrla/lb). 2. P-gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. 3. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration-dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P-gp and results were comparable for both methods. 4. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P-gp affinity in drug screening that is especially useful for early phases of drug development.
- Bogman, Katrijn,Peyer, Anne-Kathrin,Toeroek, Michael,Kuesters, Ernst,Drewe, Juergen
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- Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
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1. We investigated the structure-activity relationship of 31 kinds of synthesized atorvastatin esters, thioesters, amides and lactone, selected as prodrug models, for metabolic activation by microsomes and hydrolases. 2. The susceptibility to human carboxylesterase 1 (hCES1) was influenced not only by the size of the acyl group and alkoxy group but also by the degree of steric crowding around the alkoxy group. 3. The susceptibility to human carboxylesterase 2 (hCES2) increased with a decrease in electron density around the alkoxy group of the substrate. 4. Lactone was specifically hydrolyzed by paraoxonase 3 (PON3). 5. These findings should be useful in prodrug design for controlling metabolic activation.
- Mizoi, Kenta,Takahashi, Masato,Sakai, Sachiko,Ogihara, Takuo,Haba, Masami,Hosokawa, Masakiyo
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p. 261 - 269
(2019/06/27)
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- NOVEL CLASS OF COMPOUNDS FOR THE TREATMENT OF CARDIOVASCULAR DISEASE
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The present invention relates to the field of medicine, specifically the field of treatment and prevention of cardiovascular diseases.
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Page/Page column 62
(2017/09/05)
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- Multi-substituted pyrroles he the sandbank contains the fluorine derivative and use thereof
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The invention belongs to the field of pharmaceutical chemistry, provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor and particularly provides a polysubstituted pyrimidine statin fluorinated modifier containing a 3-fluoro-caprolactone fragment and 1-fluoro-3-hydroxy pentanoic acid formed after the ring opening of lactone and salts or esters thereof, wherein the polysubstituted pyrimidine statin fluorinated modifier has a structural formula described by a formula shown in the description or a formula shown in the description or a formula shown in the description. Proven by tests, the compound has the effect of inhibiting the activity of the HMG-coA reductase and can serve as a new-generation potential HMG-CoA reductase inhibitor.
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Paragraph 0115; 0116; 0117
(2018/01/19)
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- The total synthesis of calcium atorvastatin
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A practical and convergent asymmetric route to calcium atorvastatin (1) is reported. The synthesis of calcium atorvastatin (1) was performed using the remote 1,5-anti asymmetric induction in the boron-mediated aldol reaction of β-alkoxy methylketone (4) with pyrrolic aldehyde (3) as a key step. Calcium atorvastatin was obtained from aldehyde (3) after 6 steps, with a 41% overall yield.
- Dias, Luiz C.,Vieira, Adriano S.,Barreiro, Eliezer J.
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p. 2291 - 2296
(2016/03/01)
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- An efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol reactions and synthesis of atorvastatin lactone
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An efficient strategy for the synthesis of syn 1,3-diol has been developed, employing an imidazolidinone based chiral auxiliary via stereoselective and sequential double acetate aldol reactions. The syn 1,3-diol subunit was modified to obtain the C-7 carboxylic acid side chain and further subjected to reaction with a suitable 1,4-diketone under Paal-Knorr conditions to obtain atorvastatin lactone.
- Goyal, Sandeep,Patel, Bhautikkumar,Sharma, Ratnesh,Chouhan, Mangilal,Kumar, Kapil,Gangar, Mukesh,Nair, Vipin A.
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supporting information
p. 5409 - 5412
(2015/09/15)
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- A novel strategy towards the atorvastatin lactone
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We describe a novel strategy to the atorvastatin lactone based on a Paal-Knorr synthesis of pyrrole 24 by condensing diketone 23 with primary amine 22. The latter contains the syn-1,3-diol subunit and a benzyl ether function at the other end of the chain. This allowed for manipulations on the pyrrole ring via iodination at C2, metalation with t-BuLi and carboxylation. The obtained acid 26 could be converted via amide formation, debenzylation, oxidation and lactonization to atorvastatin lactone 6. The key building block, 2-((4R,6S)-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethanamine (22) was obtained by two sequential asymmetric transfer hydrogenative carbonyl allylations according to Krische.
- Sawant, Pramod,Maier, Martin E.
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experimental part
p. 9738 - 9744
(2011/02/25)
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- Synthesis and hydroxyapatite binding activity of bisphosphonate-statin conjugates
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To develop a methodology for delivering anabolic agents statins to bone, a bone targeting bisphosphonate was used as a carrier of drugs. Four statin-bisphosphonate conjugates were synthesized and examined for their bone mineral affinity in vitro by hydrox
- Xu, Guangyu,Zuo, Gaolei,Zhong, Shihua,Zhang, Wei
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scheme or table
p. 419 - 423
(2010/04/23)
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- PRODRUG OF ATROVASTATIN BY CHOLESTEROL'S SYNTHESIS INHIBITORS
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The present invention relates to atorvastatin prodrugs or pharmaceutically acceptable salts thereof. The compound of the present invention is hydrolyzed to atorvastatin in a body and allows atorvastatin to be maintained in a concentration effective in inhibiting the production of cholesterol for a long time. Further, the compound of the present invention can reduce side effects caused by an initial high concentration of atorvastatin in blood, thereby improving safety problems remarkably. Therefore, the compound of the present invention is effective in treating or preventing various diseases caused by excessive cholesterol such as hyperlipidemia, etc.
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- A METHOD FOR PRODUCING STATINS IN PURE FORM
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This invention provides a new method for the preparation of statins comprising hydrolyzing a mixture of compounds of the following formulas (Formula III and IV).
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Page/Page column 10
(2009/07/25)
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- Synthesis of some impurities and/or degradation products of atorvastatin
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Synthesis of some impurities and/or degradation products of atorvastatin, calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl) pyrrol-1-yl]-3,5-dihydroxyheptanoate, is described. These include its desfluoro analog, the corresponding (3S,5S)-and (3S,5R)-epimers, atorvastatin lactone, and some other potential impurities. The synthesized compounds as well as the corresponding intermediates were characterized by 1H NMR, 13C NMR and MS.
- Stach, Jan,Havlicek, Jaroslav,Placek, Lukas,Radl, Stanislav
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p. 229 - 246
(2008/12/22)
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- PREPARATION OF AN ATORVASTATIN INTERMEDIATE
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Atorvastatin lactone is prepared by hydrogenating tert-butyl isopropylidene nitrile to tert-butyl isopropylidene amine and condensing the amine with the diketone of atorvastatin to form acetonide ester. The diol protecting acetonide ester is deprotected to form a diol ester by dissolving the acetonide ester in methanol and treating with an acid. The diol ester is saponified to form a sodium salt. Methanol is removed from the reaction mixture by distillation. The sodium salt is reacidified to the free diol acid and atorvastatin lactone is formed from the diol acid. The atorvastatin lactone is directly dried without further purification.
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Page/Page column 6-9; 11
(2008/06/13)
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- A PROCESS FOR SYNTHESIS OF LARGE PARTICLE SIZE STATIN COMPOUNDS.
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This invention discloses a process for synthesis of with large size statin compounds comprising adding solution of desired statin compound either crystalline or amorphous form, optionally obtained from, their intermediates by known methods, in organic solvent to anti-solvent, under stirring, optionally the solvent was being evaporated, isolating the title compound by centrifugation followed by drying under vacuum. Specifically the process was directed to the synthesis of Atorvastatin calcium and Fluvastatin Sodium.
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Page/Page column 17
(2008/06/13)
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- Process for producing atorvastatin hemicalcium
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A process is provided for preparing pharmaceutical grade atorvastatin hemicalcium salt comprising: (a) deesterifying, wherein R is an ester protecting group to (b) extracting R(R*,R*)-3 into an organic solvent or mixture of solvents, (c) adding a base of formula NR1R2R3 wherein R1, R2 and R3 are independently selected from H, substituted or non-substituted C1 to C7 alkyl, C6 to C9 aryl, C8 to C10 aralkyl or aminoalkyl to form atorvastatin base salt, (d) isolating by precipitation of the above atorvastatin base salt and purifying when necessary,
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Page/Page column 9
(2008/06/13)
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- PROCESS AND INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF STATINS, PARTICULARLY ATORVASTATIN
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There is provided a process for the preparation of a compound of formula (7) or salts thereof: wherein R1 represents a hydrogen or a hydrocarbyl group, R2 represents a hydrogen or substituent group, R3 represents a hydrogen or a hydrocarbyl group, and X represents a hydrogen or substituent group which comprises a) cyanating a compound of formula (1): wherein Y represents a halo group, preferably CI or Br; P1 represents hydrogen or a protecting group, and W represents =0 or -OP2, in which P2 represents hydrogen or a protecting group, to give a compound of formula (2): b) reducing the compound of formula (2) to give a compound of formula (3): coupling the compound of formula (3) with a compound of formula (4): to give a compound of formula (5): when W represents -OP2, deprotecting and then oxidising the compound of formula (5) to give a compound of formula (6): and e) subjecting the compound of formula (5) when W represents =O, or compound of formula (6) to ring-opening, and removal of any remaining protecting groups, to give a compound of formula (7) or salts thereof.
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- PROCESS FOR PREPARING 5-(4-FLUOROPHENYL)-1-[2R,4R)-4-HYDROXY-6-OXO-TETRAHYDRO-PYRAN-2-YL)ETHYL]-2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE
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A method for preparing 5-(4-fluorophenyl)-1-[2R,4R)-4- hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.
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- PROCESS FOR PREPARING 5-(4-FLUOROPHENYL)-1-[2-((2R,4R)-4-HYDROXY -6-OXO-TETRAHYDRO-PYRAN-2-YL)ETHYL]-2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE
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A method for preparing 5-(4-fluorophenyl)-I-[2-((2R, 4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.
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- Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
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An improved process for the preparation of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is described where a hydroxy ester derivative is converted in two steps to the desired product, as well as valuable intermediates used in the process.
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- Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6--2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus
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A series of trans-tetrahydro-4-hydroxy-6--2H-pyran-2 ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro.Inhibitory potency was found to increase subtantially when substituents were introduced into positions three and four of the pyrrole ring.A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33, (+)-(4R)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1- -1H-pyrrole-4-carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.
- Roth, B. D.,Blankley, C. J.,Chucholowski, A. W.,Ferguson, E.,Hoefle, M. L.,et al.
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p. 357 - 366
(2007/10/02)
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