Saturday 8 March 2014

Zotarolimus

File:Zotarolimus.png

Zotarolimus

A 179578; ABT 578; Resolute; 42-(1-Tetrazolyl)rapamycin; (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)rapamycin
Molecular Formula: C52H79N5O12
Molecular Weight: 966.21
A tetrazole-containing Rapamycin analog as immunomodulator and useful in the treatment of restenosis and immune and autoimmune diseases.
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-3-{(1R)-2-[(1S,3R,4S)-3-methoxy-4-(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl)-6,8,12,14,20,26-hexamethyl-4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-heptadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone, cas no 221877-54-9
zotarolimus in  U.S. Patent Nos. 6,015,815 and 6,329,386 ,  and PCT Application No. WO 1999/015530
Zotarolimus (INN, codenamed ABT-578) is an immunosuppressant. It is a semi-synthetic derivative of rapamycin. It was designed for use in stents with phosphorylcholine as a carrier. Coronary stents reduce early complications and improve late clinical outcomes in patients needing interventional cardiology.[1] The first human coronary stent implantation was first performed in 1986 by Puel et al.[1][2] However, there are complications associated with stent use, development of thrombosis which impedes the efficiency of coronary stents, haemorrhagic and restenosis complications are problems associated with stents.[1]
These complications have prompted the development of drug-eluting stents. Stents are bound by a membrane consisting of polymers which not only slowly release zotarolimus and its derivatives into the surrounding tissues but also do not invoke an inflammatory response by the body.
Medtronic are using zotarolimus as the anti-proliferative agent in the polymer coating of their Endeavor and Resolute products.[3]
The inherent growth inhibitory properties of many anti-cancer agents make these drugs ideal candidates for the prevention of restenosis. However, these same properties are often associated with cytotoxicity at doses which block cell proliferation. Therefore, the unique cytostatic nature of the immunosuppressant rapamycin was the basis for the development of zotarolimus by Johnson and Johnson. Rapamycin was originally approved for the prevention of renal transplant rejection in 1999. More recently, Abbott Laboratories developed a compound from the same class, zotarolimus (formerly ABT-578), as the first cytostatic agent to be used solely for delivery from drug-eluting stents to prevent restenosis.[4]
Drug-eluting stents
Drug-eluting stents have revolutionized the field of interventional cardiology and have provided a significant innovation for preventing coronary artery restenosis. Polymer coatings that deliver anti-proliferative drugs to the vessel wall are key components of these revolutionary medical devices. The development of stents which elute the potent anti-proliferative agent, zotarolimus, from a synthetic phosphorylcholine-based polymer known for its biocompatible profile. Zotarolimus is the first drug developed specifically for local delivery from stents for the prevention of restenosis and has been tested extensively to support this indication. Clinical experience with the PC polymer is also extensive, since more than 120,000 patients have been implanted to date with stents containing this non-thrombogenic coating.[4]
Structure and properties
Figure US07700614-20100420-C00014
Zotarolimus is a analog made by substituting a tetrazole ring in place of the native hydroxyl group at position 42 in rapamycin that is isolated and purified as a natural product from fermentation. This site of modification was found to be the most tolerant position to introduce novel structural changes without impairing biologic activity. The compound is extremely lipophilic, with a very high octanol:water partition coefficient, and therefore has limited water solubility. These properties are highly advantageous for designing a drug-loaded stent containing zotarolimus in order to obtain a slow sustained release of drug from the stent directly into the wall of coronary vessels. The poor water solubility prevents rapid release into the circulation, since elution of drug from the stent will be partly dissolution rate-limited. The slow rate of release and subsequent diffusion of the molecule facilitates the maintenance of therapeutic drug levels eluting from the stent. In addition, its lipophilic character favors crossing cell membranes to inhibit neointimal proliferation of target tissue. The octanol:water partition coefficients of a number of compounds, recently obtained in a comparative study, indicate that zotarolimus is the most lipophilic of all DES drugs [4]
Stents are used to treat serious decreases in vessel or duct diameter due to a variety of diseases and conditions, especially atherosclerotic diseases, and are often used after angioplasty. While frequently used in arteries, stents are also used in other structures, including veins, bile ducts, esophagus, trachea, large bronchi, ureters, and urethras. Stents are the innovation of the English dentist Charles Stent (1845-1901).
While effective in treating deleterious lumen narrowing, vascular stents in an instance of medical irony, also risk re-creating the condition that they were used to treat. Stents can incur the development of thick endothelial tissue inside the lumen—the neointima. While the degree of development varies, the neointima can grow to occlude the vessel lumen, a type of restenosis.
Figure US20100204466A1-20100812-C00001
Figure US20100204466A1-20100812-C00002
Figure US20100204466A1-20100812-C00003
Previous Syntheses of Zotarolimus
Mollison presented several methods to generate zotarolimus from sirolimus (Mollison, 2000). For example, C-40 hydroxyl of sirolimus is activated with the formation of triflate, and the triflate is then purified by column chromatography. During triflate purification, some of the activated intermediate reverts to sirolimus and its epimer, epi-sirolimus, due to presence of the water during chromatography. The purified triflate is then reacted in a second step with tetrazole to produce the 40-epi-tetrazole derivative of sirolimus, that is, zotarolimus. The crude product is then purified by column chromatography. However, even with this purification, the end product could contain sirolimus and epi-sirolimus impurities.
ISOMERS
ABT-578 [40-epi-(1-tetrazolyl)-rapamycin], known better today as zotarolimus, is a semi-synthetic macrolide triene antibiotic derived from rapamycin. Zotarolimus' structure is shown in Formula D.
...........................
 zotarolimus having one of the following structures:
Figure US08257724-20120904-C00008


A representative procedure is shown in Scheme 1.
Figure US08257724-20120904-C00007
As shown in Scheme 1, conversion of the C-42 hydroxyl of rapamycin to a trifluoromethanesulfonate or fluorosulfonate leaving group provided A. Displacement of the leaving group with tetrazole in the presence of a hindered, non-nucleophilic base, such as 2,6-lutidine, or, preferably, diisopropylethyl amine provided epimers B and C, which were separated and purified by flash column chromatography.
Synthetic Methods
The foregoing may be better understood by reference to the following examples which illustrate the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention as defined in the appended claims.
Example 1 42-Epi-(tetrazolyl)-rapamycin (less polar isomer) Example 1AA solution of rapamycin (100 mg, 0.11 mmol) in dichloromethane (0.6 mL) at −78° C. under a nitrogen atmosphere was treated sequentially with 2,6-lutidine (53 uL, 0.46 mmol, 4.3 eq.) and trifluoromethanesulfonic anhydride (37 uL, 0.22 mmol), and stirred thereafter for 15 minutes, warmed to room temperature and eluted through a pad of silica gel (6 mL) with diethyl ether. Fractions containing the triflate were pooled and concentrated to provide the designated compound as an amber foam.
Example 1B 42-Epi-(tetrazolyl)-rapamycin (less polar isomer)A solution of Example 1A in isopropyl acetate (0.3 mL) was treated sequentially with diisopropylethylamine (87 L, 0.5 mmol) and 1H-tetrazole (35 mg, 0.5 mmol), and thereafter stirred for 18 hours. This mixture was partitioned between water (10 mL) and ether (10 mL). The organics were washed with brine (10 mL) and dried (Na2SO4). Concentration of the organics provided a sticky yellow solid which was purified by chromatography on silica gel (3.5 g, 70-230 mesh) eluting with hexane (10 mL), hexane:ether (4:1(10 mL), 3:1(10 mL), 2:1(10 mL), 1:1(10 mL)), ether (30 mL), hexane:acetone (1:1(30 mL)). One of the isomers was collected in the ether fractions.
MS (ESI) m/e 966 (M);
Example 2 42-Epi-(tetrazolyl)-rapamycin (more polar isomer) Example 2A 42-Epi-(tetrazolyl)-rapamycin (more polar isomer)Collection of the slower moving band from the chromatography column using the hexane:acetone (1:1) mobile phase in Example 1B provided the designated compound.
MS (ESI) m/e 966 (M).
..........................................................
sirolimus (commercially available or produced as described ((Paiva et al., 1991; Sehgal et al., 1975; Vezina et al., 1975) is dissolved in DCM:toluene (such as 1:2) 100. The reaction mixture is concentrated to dryness 105, and the azeo-drying process 105 is repeated 1-5 times more, more preferably 2-4 times, most preferably twice, preferably with DCM:toluene. The resulting foamy solid is dissolved in IPAc 110, and then 2,6-Lutidine is added 115. The solution is cooled to −30° C. 115. Triflic anhydride is then slowly added to the solution 115. After stirring the reaction mixture, the solution is filtered under nitrogen. The recovered salts 120 are washed with IPAc 125.
To the salts is added 1-H-tetrazole and DIEA 130. The reaction mixture is stirred at room temperature (e.g., 22-25° C.) 135and then concentrated. The crude reaction mixture is purified, using for example, a silica gel column and using, e.g., 1:1 THF:heptane to elute 140. The fractions are monitored for the N-1 isomer (which elutes more slowly than the N-2 isomer), pooled and concentrated, forming an oil. The oil is dissolved in minimum DCM and the solution loaded on a silica gel column packed in, for example, 65:35 heptane:acetone 145. The column is eluted with, for example, 65:35 heptane:acetone, the fractions monitored for the pure product, pooled and concentrated 150.
Figure US20100204466A1-20100812-C00012
Figure US20100204466A1-20100812-C00013
The purified product is then dissolved in t-BME, and then n-heptane is slowly added to form a precipitate while vigorously stirring the solution 150. The precipitated solids are stirred at 5-10° C., filtered, washed again with heptane, and dried on the funnel with nitrogen. The product is dissolved in acetone and treated with BHT 155. The solution is concentrated, dissolved in acetone, and then concentrated to dryness. The product is then dried under vacuum at 47° C. 160.
EXAMPLES
Example 1 Dichloromethane-Toluene Isopropylacetate One-Pot Process with Filtration (1)
In this example, zotarolimus was prepared from rapamycin in a one-pot process using dichloromethane, toluene and isopropylacetate; the preparation was then purified, concentrated, and dried. The purified product was then characterized by its 1H, 13C NMR resonances from COSY, ROESY, TOCSY, HSQC, and HMBC spectra.
Rapamycin (10 g) was dissolved in dichloromethane (DCM, 25 ml) and toluene (50 ml). The reaction mixture was concentrated to dryness. This azeo-drying process was repeated twice with DCM/toluene. The foamy solid was dissolved in isopropylacetate (IPAc, 65 ml), and 2,6-Lutidine (3.2 ml) was added. The solution was cooled to −30° C. acetonitrile-dry ice bath, and triflic anhydride (2.8 ml) was added slowly in 10 minutes. The reaction mixture was stirred for 30 minutes, and then filtered under nitrogen atmosphere. The salts were washed with IPAc (10 ml). 1-H-tetrazole (2.3 g), followed by diisopropylethylamine (DIEA, 7.4 ml) were added. The reaction mixture was stirred for 6 hours at room temperature, and then concentrated. The crude reaction mixture was purified on a silica gel column (350 g) eluting with 1:1 THF/heptane. The fractions containing product that eluted later (predominantly N-1 isomer) were collected and concentrated. The concentrated oil was dissolved in minimum DCM and loaded on a silica gel column packed in 65:35 heptane:acetone. The column was eluted with 65:35 heptane:acetone, and fractions containing pure product were concentrated.
The purified product was then dissolved in t-butylmethyl ether (t-BME, 13.5 g), and n-heptane (53 g) was added slowly with vigorous stirring. The precipitated solids were stirred at 5-10° C. for 2 hours, filtered, washed with heptane and dried on the funnel with nitrogen to give 3.2 g wet product. The solids (1.0 g) were dissolved in acetone (10 ml) and treated with 2,6-di-tert-butyl-4-ethylphenol (DEP, 0.2%). The solution was concentrated, dissolved in acetone (10 ml) and concentrated to dryness. The product was dried under vacuum for 18 hours at 47° C., yielding 0.83 g of zotarolimus. The product was characterized by its 1H, 13C NMR resonances from its COSY, ROESY, TOCSY, HSQC, and HMBC spectra.
1H-NMR (DMSO-d6, position in bracket): ppm 0.73 (Me, 43); 0.81 (Me, 49); 0.84 (Me, 46); 0.89 (Me, 48); 0.98 (Me, 45); 1.41, 1.05 (CH2, 24); 1.18, 1.10 (CH2, 36); 1.52 (CH, 37); 1.53 (CH2, 12 & 42); 1.59, 1.30 (CH2, 5); 1.41, 1.67 (CH2, 4); 1.11, 1.73 (CH2, 38); 1.21, 1.83 (CH2, 15); 1.21, 1.83 (CH2, 13); 1.62 (Me, 44); 1.73 (Me, 47); 1.76 (CH, 35); 1.60, 2.09 (CH2, 3); 1.93, 2.21 (CH2, 41); 2.05 (CH, 11); 2.22 (CH, 23); 2.47 (CH, 25); 2.40, 2.77 (CH2, 33); 3.06 (OCH3, 50); 3.16 (OCH3, 51); 3.22, 3.44 (CH2, 6); 3.29 (OCH2, 52); 3.29 (CH, 31); 3.60 (CH, 39), 3.62 (CH, 16); 3.89 (CH, 27); 4.01 (CH, 14); 4.02 (CH, 28); 4.95 (CH, 2); 5.02 (CH, 34); 5.10 (═CH, 30); 5.17 (CH, 40); 5.24 (OH, 28); 5.46 (═CH, 22); 6.09 (═CH, 18); 6.15 (═CH, 21); 6.21 (═CH, 20); 6.42 (═CH, 19); 6.42 (OH, 10), 9.30 (CH, 53).
13C NMR (DMSO-d6, position in bracket): ppm 10.4 (Me, 44); 13.1 (Me, 47); 13.6 (Me, 46); 14.5 (Me, 49); 15.5 (Me, 43 & 48); 20.3 (CH2, 4); 21.6 (Me, 45); 24.4 (CH2, 4); 26.2 (CH2, 12); 26.4 (CH2, 3); 26.8 (CH2, 41); 27.2 (CH2, 42); 29.6 (CH2, 13); 31.6 (CH2, 38), 31.7 (CH, 37); 32.9 (CH, 35); 34.8 (CH, 11); 35.2 (CH, 23); 38.2 (CH2, 36); 39.1 (CH, 25); 39.4 (CH2, 33); 39.6 (CH2, 24), 40.0 (CH2, 15); 43.4 (CH2, 6); 45.2 (CH, 31); 50.6 (CH, 2); 55.4 (OCH3, 50); 55.8 (OCH3, 52); 57.0 (OCH3, 52); 55.9 (CH, 40); 66.2 (CH, 14); 73.4 (CH, 34); 75.6 (CH, 28); 77.4 (CH, 39); 82.3 (CH, 16); 85.7 (CH, 27); 99.0 (CH, 10); 125.3 (═CH, 30); 127.0 (═CH, 18 & 19); 130.4 (═CH, 21); 132.2 (═CH, 20); 137.2 (═CMe, 29); 137.7 (═CMe, 17); 139.2 (═CH, 22); 144.6 (CH, 53); 167.0 (C═O, 8); 169.1 (C═O, 1); 199.0 (C═O, 9); 207.5 (C═O, 32); 210.7 (C═O, 26).
Example 2 Dichloromethane-Isopropylacetate One-Pot Process (2)
In this example, zotarolimus was prepared from rapamycin in a one-pot process using dichloromethane and isopropylacetate. The compound was then purified, concentrated, and dried.
Rapamycin (10 g) was dissolved in dichloromethane (DCM, 100 g). 2,6-Lutidine (2.92 g) was added. The solution was cooled to −30° C. in acetonitrile-dry ice bath, and triflic anhydride (4.62 g) was added slowly in 10 minutes. The reaction mixture was stirred for 20 minutes, and then warmed to 10° C. within 15 minutes. The reaction solution was then concentrated. The residue was dissolved in IPAc (55 g). 1-H-tetrazole (2.68 g), followed by diisopropylethylamine (DIEA, 7.08 g) were then added. The reaction mixture was stirred for 6 hours at room temperature and then concentrated. The crude reaction mixture was purified on a silica gel column (360 g), eluting with 1:1 THF:heptane. The fractions containing product that eluted later (principally N-1) were collected and concentrated. The concentrated oil was dissolved in minimum DCM and loaded on a silica gel column (180 g) that was packed in 65:35 heptane:acetone. The column was then eluted with 65:35 heptane:acetone, and fractions containing pure product were concentrated.
The purified product was dissolved in t-butylmethyl ether (t-BME, 23 g) and added slowly to n-heptane (80 g) with vigorous stirring. The precipitated solids were stirred at 5-10° C. for not longer than 1 hour, filtered, washed with heptane and dried on the funnel with nitrogen. BHT (0.015 g) was added to the solids. The solids were dissolved in acetone (20 g), passed through a filter, and concentrated. The residue was treated with acetone two times (20 g), and concentrated each time to dryness. The product was then dried under vacuum for 18 h at not more than 50° C. to give 2.9 g of zotarolimus.
Example 3 Dichloromethane One Pot Process (3)
In this example, zotarolimus was prepared from rapamycin in a one-pot process using dichloromethane. The compound was then purified, concentrated, and dried as described in Example 2.
Rapamycin (7.5 g) was dissolved in DCM (30 g). 2,6-Lutidine (1.76 g) was added. The solution was cooled to −30° C. in acetonitrile-dry ice bath, and triflic anhydride (2.89 g) was added slowly in 10 minutes. The reaction mixture was stirred for 20 minutes, and then assayed for the presence of rapamycin to determine consumption in the reaction. 1-H-tetrazole (1.44 g), followed by DIEA (5.29 g) was added. The reaction mixture was stirred for 6 hours at room temperature, and then directly loaded on a silica gel (270 g) column prepared in 1:1 THF:n-heptane (v/v). The crude reaction mixture was purified with 1:1 THF:n-heptane. The fractions containing product that elute later were collected and concentrated. The concentrated solids were dissolved in minimum DCM and loaded on a silica gel column (135 g) packed in 70:30 n-heptane:acetone. The column was eluted with 70:30 n-heptane:acetone, and fractions containing pure product, as identified by thin-layer chromatography (TLC), were concentrated.
The purified product was dissolved in t-BME (9 g), and added slowly to n-heptane (36 g) with vigorous stirring at 10±10° C. The precipitated solids were stirred at 5-10° C. for not longer than 1 hour, filtered, washed with n-heptane and dried on the funnel with nitrogen. BHT (0.006 g) was added to the solids. The solids were dissolved in acetone (20 g), passed through a filter, and concentrated. The residue was treated with acetone twice (20 g each) and concentrated each time to dryness. The product was dried under vacuum for not longer than 18 hours at not more than 50° C. to give 2.5 g of zotarolimus.
The above process, when carried out with rapamycin presence of 2,6-di-tert-butylpyridine or 2,4,6-collidine (2,3,5-trimethylpyridine) as a non-nucleophilic in step 1a gave zotarolimus of acceptable purity, but a lower yield.
Example 4 High-Pressure Liquid Chromatography HPLC Purification of Zotarolimus Prepared by the One-Pot Synthesis Method
In this example, zotarolimus was made from rapamycin using a one-pot synthesis method of the invention (using DCM), and then subjected to an additional round of purification using HPLC.
Rapamycin (3.75 g) was dissolved in dichloromethane (DCM, 15 g). 2,6-Lutidine (0.88 g) was then added. The solution was cooled to −30° C. in acetonitrile-dry ice bath, and triflic anhydride (1.45 g) was added slowly in 10 minutes. The reaction mixture was stirred for 20 minutes, and then 1-H-tetrazole (0.72 g), followed by DIEA (2.65 g) was added. The reaction mixture was stirred for 6 hours at 25° C., and then directly loaded on a silica gel (115 g) column prepared in 70:30 n-heptane:acetone. The crude reaction mixture was purified with 70:30 n-heptane:acetone. The fractions containing product were collected, and concentrated.
The concentrated solids were dissolved in acetonitrile-water and loaded on a C-18 TechniKrom column (5 cm×25 cm), and eluted with 64:36 acetonitrile-water containing 0.1% BHT. Fractions were analyzed by reverse phase (RP)—HPLC, and product fractions pooled and concentrated to remove acetonitrile. The product was extracted with ethyl acetate or isopropyl acetate, dried (sodium sulfate) and concentrated.
The purified product was dissolved in t-BME (4.5 g), and added slowly to n-heptane (18 g) with vigorous stirring at −10° C. The precipitated solids were stirred at 5-10° C. for not longer than 1 hour, filtered, washed with n-heptane and dried on the funnel with nitrogen. BHT (0.005 g) was added to the solids. The solids were dissolved in acetone (20 g), passed through a filter, and concentrated. The residue was treated with acetone twice (20 g), and concentrated each time to dryness. The product was dried under vacuum for not longer than 18 hours at not more than 50° C. to give 1.2 g of high quality zotarolimus.
  1. Braunwald E, Zipes D, Libby P, ed. (2001). Heart diseases: a textbook of cardiovascular disease (6th ed.). Philadelphia: Saunders Elsevier.
  2.  Sigwart, U; Puel, J; Mirkovitch, V; Joffre, F; Kappenberger, L (1987). "Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty". The New England journal of medicine 316 (12): 701–6. doi:10.1056/NEJM198703193161201PMID 2950322.
  3. "Medtronic Receives FDA Approval for Endeavor Zotarolimus-Eluting Coronary Stent System".
  4.  Burke, Sandra E.; Kuntz, Richard E.; Schwartz, Lewis B. (2006). "Zotarolimus (ABT-578) eluting stents". Advanced Drug Delivery Reviews 58 (3): 437–46.doi:10.1016/j.addr.2006.01.021PMID 16581153.
  5.  Heitman, J; Movva, NR; Hall, MN (1991). "Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast". Science 253 (5022): 905–9. PMID 1715094.
AspirinWorks
The FDA has approved the zotarolimus-eluting stent (Medtronic).
US81291273-7-2012ASSAY FOR IMMUNOSUPPRESSANT DRUGS
US81295213-7-2012ONE POT SYNTHESIS OF TETRAZOLE DERIVATIVES OF RAPAMYCIN
US20111716627-15-2011NON-DENATURING LYSIS REAGENT
US20110919974-22-2011IMMUNOSUPPRESSANT DRUG EXTRACTION REAGENT FOR IMMUNOASSAYS
US79149993-30-2011NON-DENATURING LYSIS REAGENT
US782081210-27-2010METHODS OF MANUFACTURING CRYSTALLINE FORMS OF RAPAMYCIN ANALOGS
US781203210-13-2010CRYSTALLINE FORMS OF RAPAMYCIN ANALOGS
US77006144-21-2010One pot synthesis of tetrazole derivatives of rapamycin
US200925805410-16-2009Heparin Prodrugs and Drug Delivery Stents Formed Therefrom
US20090473232-20-2009Medical Devices Containing Rapamycin Analogs
   
US20090473242-20-2009Medical Devices Containing Rapamycin Analogs
US745585311-26-2008Medical devices containing rapamycin analogs
US200828767511-21-2008CASCADE SYSTEM
US20082132789-5-2008Method Of Treating Disorders Using Compositions Comprising Zotarolimus And Paclitaxel
US20081758847-25-2008Medical Devices Containing Rapamycin Analogs
US73994807-16-2008Methods of administering tetrazole-containing rapamycin analogs with other therapeutic substances using medical devices
US20081537906-27-2008Medical Devices Containing Rapamycin Analogs
US20061988679-8-2006COMPOSITIONS AND METHODS OF ADMINISTERING RAPAMYCIN ANALOGS USING MEDICAL DEVICES FOR LONG-TERM EFFICACY
WO2001087372A1 *Apr 25, 2001Nov 22, 2001Cordis CorpDrug combinations useful for prevention of restenosis
EP1826211A1 *Feb 20, 2007Aug 29, 2007Cordis CorporationIsomers and 42-Epimers of rapamycin alkyl ether analogs, methods of making and using the same
US5151413 *Nov 6, 1991Sep 29, 1992American Home Products CorporationRapamycin acetals as immunosuppressant and antifungal agents
US5362718 *Apr 18, 1994Nov 8, 1994American Home Products CorporationRapamycin hydroxyesters
US7193078Mar 1, 2005Mar 20, 2007Terumo Kabushiki KaishaProcess for production of O-alkylated rapamycin derivatives
US7220755Nov 12, 2003May 22, 2007Biosensors International Group, Ltd.42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
US7279571Dec 1, 2005Oct 9, 2007Teva Gyógyszergyár Zártkörüen Müködö RészvénytársaságMethods of preparing pimecrolimus
US7812155Nov 26, 2007Oct 12, 2010Terumo Kabushiki KaishaProcess for preparing an o-alkylated rapamycin derivative and o-alkylated rapamycin derivative
US7872122May 8, 2009Jan 18, 2011Chunghwa Chemical Synthesis & Biotech Co., Ltd.Process for making Biolimus A9
US20050101624 *Nov 12, 2003May 12, 2005Betts Ronald E.42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
US20090209572Nov 19, 2008Aug 20, 2009Biotica Technology Limited36-Des(3-Methoxy-4-Hydroxycyclohexyl) 36-(3-Hydroxycycloheptyl) Derivatives of Rapamycin for the Treatment of Cancer and Other Disorders
US20100204466Feb 23, 2010Aug 12, 2010Abbott LaboratoriesOne pot synthesis of tetrazole derivatives of rapamycin
US20100249415Mar 29, 2010Sep 30, 2010Kwang-Chung LeeProcess for preparation of temsirolimus
READ
ANONYMOUS: "Randomised comparison of zotarolimus eluting and sirolimus-eluting stents in patients with coronary artery disease (ENDEAVOUR III)" JOURNAL OF AMERICAN COLLEGE OF CARDIOLOGY, vol. 46, no. 11, 6 December 2005 (2005-12-06), pages CS5-CS6, XP009089338

No comments:

Post a Comment