- Synthesis process for temsirolimus
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The invention discloses a synthesis process for temsirolimus. The synthesis process comprises the following steps: step 1, preparing 2,2,5-trimethyl-5-carboxyl-1, 3-dioxane; step 2, preparing anhydride; step 3, carrying out esterification reaction; step 4, carrying out hydrolysis reaction and finally obtaining the target product, temsirolimus. According to the synthesis process disclosed by the invention, in the reaction of the step 2, DIPEA (diisopropanolamine) is selected as alkali and methylene chloride is selected as a solvent so that anhydride reaction liquid can be directly used in the reaction in the step 3, and technological operation is reduced; the selectivity of the direct esterification reaction is achieved by lowering the temperature and controlling the usage amount of DMAP (dimethylaminopyridine) and the usage amount of anhydride, and the by-products of 31-esterification are reduced; the esterification selectivity is improved greatly, and the reaction route is simplified; and by selecting an ethylene glycol, para-toluenesulfonic acid and tetrahydrofuran deprotection system, the reaction time is reduced greatly, and the yield is improved.
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Paragraph 0009; 0010
(2016/12/26)
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- Therapeutic Targets for Alzheimer's Disease
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The present invention relates to novel methods for the prevention, treatment and diagnosis of Alzheimer's disease. In addition, the invention relates to methods for assessing an individual's susceptibility or pre-disposition to Alzheimer's disease. The methods of the present invention involve the use of therapeutic targets and diagnostic and/or predictive markers within the mTOR signalling pathway. The methods also involve screening subjects for genetic polymorphisms associated with rapamycin-sensitive genes.
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Page/Page column
(2015/05/26)
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- DRUG DELIVERY MEDICAL DEVICE
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A medical device that releases a pharmaceutical agent to a target site is disclosed. The medical device includes a balloon, and a coating on at least a portion of the balloon. Each particle of the particles of the pharmaceutical agent is at least partially encapsulated in a polymer layer. The method includes the steps of providing a device including a balloon, and a coating on at least a portion of the balloon, the coating including particles of a pharmaceutical agent, and each particle of the pharmaceutical agent is at least partially encapsulated in a polymer layer; positioning the device to allow the balloon to reach the target site; and inflating the balloon of the device.
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Page/Page column
(2015/01/06)
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- METHOD FOR PREPARING 42-(DIMETHYLPHOSPHINATE) RAPAMYCIN
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A method for preparing 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I) is provided, which has advantages of high conversion rate and no 31,42-bis(dimethyl phosphinate) Rapamycin (III) generated. In the method of the present invention, Rapamycin (II) is firstly reacted with triethyl chlorosilane in a base condition to form 31,42-bis(triethylsilylether) Rapamycin (IV-b), followed by a selective deprotection process to obtain 31-triethylsilylether Rapamycin (V-b). Next, a phosphorylation reaction is performed by using dimethylphosphinic chloride under a base solution to obtain a crude product. Finally, a deprotection reaction is performed in a diluted sulfuric acid solution to obtain a crude product of Ridaforolimus (I). Since the conversion rate of each step of the method of the present invention is higher than 98%, it indicates that the method of the present invention is suitable for industrial production.
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- MANUFACTURE, METHOD AND USE OF DRUG-ELUTING MEDICAL DEVICES FOR PERMANENTLY KEEPING BLOOD VESSELS OPEN
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The invention relates to stents and catheter balloons having optimized coatings for eluting rapamycin as well as methods for manufacturing these coatings.
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- LIGHT MEDIATED REGULATION OF PROTEIN DIMERIZATION
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The present invention relates to photoactivatable rapamycin compounds. The invention further relates to the use of photoactivatable rapamycin compounds to regulate the dimerization and/or activity of polypeptides in a light dependent manner.
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Page/Page column 39
(2012/03/11)
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- MANUFACTURE, METHOD AND USE OF ACTIVE SUBSTANCE-RELEASING MEDICAL PRODUCTS FOR PERMANENTLY KEEPING BLOOD VESSELS OPEN
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The invention relates to stents and catheter balloons having optimized coatings for eluting rapamycin as well as methods for manufacturing these coatings.
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- Total Synthesis of rapamycin
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For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.
- Ley, Steven V.,Tackett, Miles N.,Maddess, Matthew L.,Anderson, James C.,Brennan, Paul E.,Cappi, Michael W.,Heer, Jag P.,Helgen, Celine,Kori, Masakuni,Kouklovsky, Cyrille,Marsden, Stephen P.,Norman, Joanne,Osborn, David P.,Palomero, Maria A.,Pavey, John B. J.,Pinel, Catherine,Robinson, Lesley A.,Schnaubelt, Juergen,Scott, James S.,Spilling, Christopher D.,Watanabe, Hidenori,Wesson, Kieron E.,Willis, Michael C.
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experimental part
p. 2874 - 2914
(2009/12/25)
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- A PURE FORM OF RAPAMYCIN AND A PROCESS FOR RECOVERY AND PURIFICATION THEREOF
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The present invention relates to a pure form of rapamycin with a total impurity content less than 1.2% ; a process for recovery and purification of rapamycin comprising steps of (a) treating the fermentation broth, extracts or solutions containing rapamycin with water immiscible solvent and concentration; (b) addition of a water miscible solvent to effect separation of impurities present; (c) optionally, binding of the solvent containing the product from step (b) to an inert solid, washing the solid with a base and acid, followed by elution; (d) subjecting the elute from step (c) or the solvent containing the product from step (b) to silica gel chromatography; (e) crystallization of the product obtained from step (d); (f) subjecting a solution of the product from step (e) to hydrophobic interaction or reversed phase chromatography; and (g) re-crystallization to afford rapamycin in substantially pure form.
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Page/Page column 9
(2008/12/05)
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- Total synthesis of rapamycin
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Rapamycin synthesis all wrapped up: A new convergent synthesis of rapamycin (1) is reported that involves a macroetherification/catechol tethering strategy for construction of the macrocyclic core of this intriguing natural product. Other studies on this commercialized potent immunosuppressant delineate new cell signaling pathways of relevance to cancer chemotherapy. (Chemical Equation Presented).
- Maddess, Matthew L.,Tackett, Miles N.,Watanabe, Hidenori,Brennan, Paul E.,Spilling, Christopher D.,Scott, James S.,Osborn, David P.,Ley, Steven V.
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p. 591 - 597
(2008/02/01)
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- Purification of rapamycin
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Purified rapamycin and a chemical process for obtaining the purified rapamycin are described.
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Page/Page column 4-5
(2008/06/13)
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- A PROCESS FOR THE RECOVERY OF SUBSTANTIALLY PURE TRICYCLIC MACROLIDE
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Process for the recovery of a macrolide in substantially pure form comprising: a) treating the macrolide with water immiscible solvent followed by concentration, b) mixing with water, water miscible solvent or mixture thereof, c) performing hydrophobic interaction chromatography and collecting the fractions, d)extracting the fraction containing macrolide with water immiscible solvent followed by concentration, e) adding water miscible solvent to effect separation of impurities from the macrolide compound, f) performing silica gel chromatography and collecting the fractions, g) isolating the macrolide compound in substantially pure form. The macrolide is preferably rapamycin, tacrolimus or immunomycin.
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Page/Page column 7-8
(2008/06/13)
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- METHOD OF PURIFYING MACROLIDES
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Provided is a method of purifying a macrolide, especially tacrolimus, that includes loading macrolide onto a bed of sorption resin and elting with a suitable eluent such as a combination of water and tetrahydrofuran.
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- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
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The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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- 28-EPIRAPALOGS
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Methods and materials involving 28-epirapamycin analogs are disclosed.
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- O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders
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The present invention relates to methods of alleviating and inhibiting a lymphoproliferative disorder in a mammal, the method comprising administering one or more rapamycin derivatives (including rapamycin) to the mammal. Further, the invention provides a method for identifying agents which are useful for alleviating and inhibiting a lymphoproliferative disorders, as well as a method for identifying agents which are capable of inhibiting metastasis of lymphatic tumors in a mammal.
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- Medical devices incorporating deuterated rapamycin for controlled delivery thereof
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Deuterated rapaymcin can be controllably introduced target locations within the patient's body by using an implantable medical device having a structure incorporated with a therapeutic agent comprising a deuterated rapamycin. Representative deuterated rapamycins include epi-7-deuteromthyl rapamycin, 7,43-d6 rapamycin, 7-deuteromethyl rapamycin and 31,42-d2-rapamycin and isomers thereof, and mixtures thereof. The deuterated rapamycin can also be glycosylated.
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- Selective epimerization of rapamycin via a retroaldol/aldol mechanism mediated by titanium tetraisopropoxide.
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We describe the efficient and selective epimerization of the immunosuppressant rapamycin to 28-epirapamycin under mild conditions. The mechanism of epimerization involves an equilibrium of the four C28/C29 diastereomers through a two-step retroaldol/aldol (macrocycle ring-opening/ring-closing) sequence. This retroaldol/aldol equilibration is not restricted to rapamycin but is also applicable to acyclic beta-hydroxyketones. A potentially useful extension of the method--the use of beta-hydroxyketones as enolate synthons for effecting inter- or intramolecular aldol reactions under neutral conditions--is demonstrated.
- Yang,Digits,Hatada,Narula,Rozamus,Huestis,Wong,Dalgarno,Holt
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p. 2033 - 2035
(2008/02/11)
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- A unified total synthesis of the immunomodulators (-)-rapamycin and (-)-27-demethoxyrapamycin: Assembly of the common C(1-20) perimeter and final elaboration
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The potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-demethoxyrapamycin (2) have been synthesized via a unified and highly convergent strategy. In the preceding paper we discussed the construction of common building blocks A-C and their linkage to provide the C(21-42) segments of 1 and 2. Herein we describe model studies of triene generation and hydroxyl deprotection, the preparation and coupling of building blocks D and E, a two-step protocol for macrocycle formation via union of the ABC and DE subtargets, and completion of the total syntheses. The synthesis of 27-demethoxyrapamycin (2) confirmed the assigned structure.
- Smith III, Amos B.,Condon, Stephen M.,McCauley, John A.,Leazer Jr., Johnnie L.,Leahy, James W.,Maleczka Jr., Robert E.
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p. 962 - 973
(2007/10/03)
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- Rapamycin derivatives
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Rapamycin derivatives; pharmaceutical compositions comprising such rapamycin derivatives and pharmaceutically acceptable carriers or diluents; and methods of using such derivatives to inhibit pathogenic fungi growth, inhibit immunosuppression or treat carcinogenic tumors are disclosed.
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- New extractive process for the recovery of naturally occurring macrolides
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This invention relates to a process of recovering a neutral macrolide antibiotic, especially a tricyclic macrolide such as rapamycin from concentrates of fermentation broth extracts or mother liquors whereby acidic and/or basic components formed in the fermentation process are removed by utilizing aqueous base or acid extraction procedures from a water-immiscible solution of said concentrate and non-polar components are separated from the neutral macrolide by selective solubility.
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- Total Synthesis of Rapamycin
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Details of the total synthesis of rapamycin (1) are reported.The synthesis required the preparation of intermediates 4-9 in nonracemic form; key coupling reactions included a chromium-mediated addition of vinyl iodide 8 to aldehyde 7 and an Evans aldol reaction to couple fragments 62 and 9.Intermediates 4 and 6 were joined through an amide bond formation to afford advanced intermediate 71.Swern oxidation of the diol in 71 was followed by a selective removal of the TES groups and a second Swern oxidation.Finally, removal of the remaining silyl protecting groups provided fully deprotected, penultimate intermediate 2 in which all carbons were in their proper oxidation state.Macrocyclization was achived through a tandem inter/intramolecular palladium-mediated Stille coupling reaction between distannylethene 3 and bis(vinyl iodide) 2.This latter process accomplished in one step the installation of the remaining two carbons of the natural product and the completion of its total synthesis. - Keywords: rapamycin, stannylethenes, Stille coupling, vinyl iodides
- Nicolaou, K. C.,Piscopio, Anthony D.,Bertinato, Peter,Chakraborty, Tushar K.,Minowa, Nobuto,Koide, Kazunori
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p. 318 - 333
(2007/10/02)
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- Gem-distributed esters of rapamycin
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Compounds of the structure STR1 R and R1 are each, independently, hydrogen, or STR2 R2 and R3 are each, independently, alkyl, arylalkyl, or may be taken together to form a cycloalkyl ring; R4 and R5 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a saturated heterocycle wherein the heterocyclic ring may be optionally mono-, di-, or tri-substituted; m=0-1; and n=0-6; with the proviso that R and R1 are not both hydrogen, or a pharmaceutically acceptable salt thereof, and STR3 R1 is STR4 R2 and R3 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a cycloalkyl ring; R4 and R5 are each, independently, hydrogen, alkyl, arylalkyl, or may be taken together to form a saturated heterocycle wherein the heterocyclic ring may be optionally mono-, di-, or tri-substituted; m=0-1; and n=0-6; or a pharmaceutically acceptable salt thereof which are useful as immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agents.
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- Lipase mediated hydrolysis of rapamycin 42-hemisuccinate benzyl and methyl esters
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Benzyl and methyl esters of rapamycin 42-hemisuccinate were hydrolyzed under very mild conditions to the rapamycin hemisuccinate using lipase from Pseudomonas sp. This selective deprotection was performed on a ≥100 mg scale for both esters resulting in 50% isolated yield from the methyl ester and 29% from the benzyl ester of the desired acid.
- Adamczyk, Maciej,Gebler, John C.,Mattingly, Phillip G.
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p. 1019 - 1022
(2007/10/02)
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- 42-oxorapamycin
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This invention provides an oxidized derivative of rapamycin in which the hydroxyl at the 42-position has been oxidized to the corresponding ketone or a pharmaceutically acceptable salt thereof, which by virtue of its immunosuppressive and antifungal activity is useful in treating transplantation rejection, host vs. graft disease, autoimmune diseases, diseases of inflammation, and fungal infections and a process for the preparation of this oxidized derivative of rapamycin. STR1
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- Rapamycin and process of preparation
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Antibiotic rapamycin is producible by culturing Streptomyces hygroscopicus NRRL 5491 in an aqueous nutrient medium. Rapamycin has antifungal properties. Methods for its preparation and use are disclosed.
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