US20010039338A1 - Regioselective synthesis of rapamycin derivatives - Google Patents

Regioselective synthesis of rapamycin derivatives Download PDF

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US20010039338A1
US20010039338A1 US09/876,251 US87625101A US2001039338A1 US 20010039338 A1 US20010039338 A1 US 20010039338A1 US 87625101 A US87625101 A US 87625101A US 2001039338 A1 US2001039338 A1 US 2001039338A1
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rapamycin
ether
acid
silyl ether
process according
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Chia-Cheng Shaw
John Sellstedt
Razzak Noureldin
Gloria Cheal
Genevieve Fortier
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Wyeth LLC
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

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  • This invention relates to the regioselective synthesis of derivatives of rapamycin at the 42-position, which are useful for inducing immunosuppression, and in the treatment of transplantation rejection, graft vs. host disease, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders.
  • Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus , which was found to have antifungal activity, particularly against Candida albicans , both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749].
  • Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity.
  • R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
  • Rapamycin has also been shown to be useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No. 5,321,009], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. No. 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], and ocular inflammation [U.S. Pat. No. 5,387,589].
  • rapamycin 42-derivatives are known, typically being esters (carbon and sulfur based) or ethers of the 42-hydroxyl group of rapamycin, that are produced by esterification or etherification of the 42-position. Esterification of rapamycin at the 42-position was commonly prepared by directly reacting rapamycin with acylating agents in order to afford the desired product. The chemistry appeared to be rather simple. However, as rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoacylated product, posed a difficult challenge.
  • This invention provides a regioselective method for the preparation of a 42-ester or ether rapamycin having the structure
  • R is an ester or ether, which comprises:
  • Preferred 42-esters and ethers of rapamycin which can be prepared by the method provided by this invention are disclosed in the following patents, which are all hereby incorporated by reference: alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S. Pat. No. 5,118,677); carbamate esters (U.S. Pat. No. 5,118,678); silyl ethers (U.S. Pat. No. 5,120,842); aminoesters (U.S. Pat. No.
  • the crude product [B] after work-up contains the desired product [B], 31,42-bisester by-product and unreacted rapamycin.
  • the reaction was allowed to proceed for a longer period with negative consequences, the quantity of the 31,42-bisester increased significantly.
  • the resulting crude product [B] is contaminated with unreacted rapamycin and 31,42-bisester, and subsequent column chromatography purification effort has proved to be difficult as the 42,31-bisester has a very close retention time with product [B].
  • the major obstacle in large-scale production of compound [B] appears to be the non-regiospecificity that is further complicated by purification difficulties.
  • This invention overcomes these difficulties by providing a regioselective synthesis of 42-esters or ethers of rapamycin by selectively protecting the 31-hydroxyl group as a silyl ether (i.e., compound [D]), leaving the 42-position hydroxyl accessible for regioselective esterification or etherification to produce 31-O-silyl, 42-esters or ethers (i.e., compound [E]). The 31-hydroxyl group can then be deprotected under mild acidic conditions (i.e., compound [B]).
  • the 31, and 42-hydroxyl groups are protected as trialkyl silyl ethers.
  • the 42-silyl protected hydroxyl group of the 31,42-bis-silylated rapamycin can be selectively cleaved under mildly acidic conditions to provide 31-silyl rapamycin.
  • the silylating agents used for this transformation are common, commercially available chloroalkylsilanes, such as chlorotrimethylsilane, chlorotriethylsilane or chlorotripropylsilane.
  • chloroalkylsilanes such as chlorotrimethylsilane, chlorotriethylsilane or chlorotripropylsilane.
  • the bulkier the trialkylsilane the more time is needed to deprotect in acid media during the penultimate chemical step to regenerate the 31-hydroxyl group.
  • chlorotrimethylsilane, chlorotriethylsilane or chlorotripropylsilane can be used for the preparation of rapamycin 31-O-trialkylsilyl ethers
  • chlorotrimethylsilane is the preferred silylating agent.
  • the trimethylsilyl group is more acid labile and therefore easier to de-protect during the transformation and in effect, this minimizes the formation of degradation products.
  • the preparation of 31-O-trimethylsilyl rapamycin [D] is described in Example 1. Rapamycin is treated with excess chlorotrimethylsilane in ethyl acetate at 0-5° C.
  • rapamycin 31,42-bis-O-trimethylsilyl ether in quantitative yield.
  • the common organic bases such as imidazole, 1-methylimidazole, triethylamine and N,N-diisopropylethylamine can be used for the general silylation reaction.
  • imidazole is found to be the preferred base for the silylation of rapamycin as the reaction is completed within 30 minutes.
  • the esterification or etherification of the 31-protected rapamycin can be carried out under conditions described in the patents listed above.
  • the acylation of rapamycin 31-trimethylsilyl ether was accomplished using 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid in the presence of 4-dimethylaminopyridine or a similar reagent.
  • 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride was also found to be an effective acylation agent in this invention in the presence of 4-dimethylaminopyridine or a similar reagent.
  • acylation conditions methylene chloride is the preferred solvent rather than tetrahydrofuran which was described in the prior art.
  • lower reaction temperature of less than 0° C., with ⁇ 20 to ⁇ 15° C. or lower being more preferred, provides better results than the room temperature acylation described in U.S. Pat. No. 5,362,718.
  • the acylation products, 31-O-TMS, 42-(protected-hydroxy) esters (compound [E]) can be further treated with diluted acid to convert them to 42-(protected-hydroxy) esters (compound [B]) or used directly to make final product 42-hydroxyesters (final product [C]).
  • This methodology can be used to prepare other esters or ethers of rapamycin, by simply varying the esterfiying or etherifying agent used.
  • the synthetic route disclosed in this invention provides several distinct advantages over the synthetic methodology which has been published for the preparation of rapamycin esters or ethers; mainly in the yield and ease of purification of the desired 42-esters or ethers. As this is a regioselective synthesis, the overall yields of the desired 42-esters or ethers is dramatically improved.
  • the synthetic methodology taught in U.S. Pat. No. 5,362,718 provides compound [B] in a 35% yield, whereas, the synthesis of [B] is accomplished in 85% yield using the methodology disclosed herein.
  • rapamycin 31-O-trimethylsilyl ether can be treated with, for example, 2-(t-butyldimethylsilyl)oxyethyl triflate) to provide 31-O-trimethylsilyl, 42-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin.
  • Removal of the silyl protecting groups from the 31-hydroxyl group of rapamycin and from the 42-hydroxyethyl moiety can be accomplished under mildly acidic conditions, such as dilute sulfuric acid to provide 42-O-(2-hydroxy)ethyl rapamycin.
  • This invention also covers 31-silyl ethers of rapamycin, which are useful in the preparation of the 42-esters and ethers of rapamycin, as disclosed herein.
  • the silicon moiety as represented by —SiR′R′′R′′′ contains 3 groups which can be the same or different.
  • Typical silyl ethers of this invention contain R′, R′′, or R′′′ moieties which are alkyl of 1-6 carbon atoms, phenyl, or benzyl groups.
  • the alkyl groups can be branched or straight chain. It is preferred that R′, R′′, and R′′′ be alkyl groups, and more preferred that R′, R′′, and R′′′ are methyl or ethyl. It is still more preferred that the 31-silyl ether is rapamycin 31-O-trimethylsilyl ether.
  • rapamycin 31-O-trimethylsilyl ether 28.50 g, crude, made from 25.28 mmol of rapamycin
  • 120 mL methylene chloride 120 mL methylene chloride
  • a solution of 4-dimethylaminopyridine (11.68 g, 95.60 mmol) in 110 mL methylene chloride was added dropwise over a 2 h period.
  • the reaction mixture was further stirred for 16 h at ⁇ 15 to ⁇ 16° C.
  • the reaction mixture was quenched with 100 mL water and the organic layer was separated and washed with 0.5 N sulfuric acid (180 mL), followed by brine (100 mL), saturated sodium bicarbonate solution (100 mL), water (100 mL ⁇ 2), brine (100 mL) to pH 6-7.
  • the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound (33.18 g) as a beige color foam.
  • reaction mixture was quenched with 100 mL brine and the organic layer was separated and washed with cold 0.5 N sulfuric acid (100 mL), brine (100 mL), saturated sodium bicarbonate solution (100 mL) water (100 mL), brine (100 mL) to pH 6-7.
  • the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford product (12.15 g) as a yellow foam.
  • the aqueous layer was extracted once with 120 mL of ethyl acetate and the organic extracts were combined and washed with saturated sodium bicarbonate solution (120 mL), water (200 mL ⁇ 2) and brine (120 mL) to pH 6-7.
  • the organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure at room temperature to obtain product (28.42 g), as a beige color foam.
  • the crude product was chromatographed on a silica gel column and eluted with 30% acetone in heptane to give 18.06 g of pure product, a white solid (69.4% overall from rapamycin).
  • the 1 H NMR of the product is identical to the product described in U.S. Pat. No. 5,362,718 example 11.
  • the aqueous layer was extracted once with 100 mL of ethyl acetate and the organic extracts were combined and washed with saturated sodium bicarbonate solution (80 mL), water (80 mL ⁇ 2) and brine (100 mL) to pH 6-7.
  • the organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure at room temperature to afford product (22.48 g), a beige color foam.
  • the crude product was chromatographed on a silica gel column and eluted with 30% acetone in heptane to give 16.50 g of pure product as a white solid (78.4% overall from rapamycin).
  • the 1 H NMR of the product is identical to the product described in U.S. Pat. No. 5,362,718 example 11.
  • a solution of rapamycin (5.00 g, 92.7% strength; 5.07 mmol) in 75 mL ethyl acetate was cooled to 0-5° C.; 1.50 g (22.03 mmol) of imidazole was added and stirred to form a solution.
  • 3.05 g (20.23 mmol) of chlorotriethylsilane was added dropwise over a 10 minutes period. The mixture was stirred for 30 min at 0-5° C., then stirred at room temperature overnight to complete the formation of rapamycin 31,42-bis-O-triethylsilyl ether.
  • the reaction mixture was diluted with 80 mL of ethyl acetate and successively washed with brine (60 mL ⁇ 2), saturated sodium bicarbonate solution (40 mL), water (60 mL ⁇ 2), brine (60 mL) to pH 6-7.
  • the filtrate was evaporated under reduced pressure at room temperature to remove most of the solvent and the residual solution was dissolved in 60 mL acetone.
  • a 15 mL quantity of 0.25 N of sulfuric acid was added and the mixture was stirred for 45 h at 0-5° C.; the rapamycin 31,42-bis-O-tripropylsilyl ether disappeared at this stage.
  • the reaction mixture was diluted with 100 mL of ethyl acetate, and successively washed with brine (40 mL ⁇ 2), saturated sodium bicarbonate solution (40 mL), water (40 mL ⁇ 2), and brine (50 mL) to pH 6-7.

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Abstract

This invention provides a regioselective process for preparing a 42-ester or ether of rapamycin, and 31-silyl ether intermediates.

Description

  • This application claims the benefit of U.S. Provisional Application No. Not Yet Known, which was converted from U.S. patent application No. 09/408,830, filed Sep. 29, 1999, pursuant to a petition filed under 37 C.F.R. 1.53(c)(2)(i).[0001]
    • BACKGROUND OF THE INVENTION
  • This invention relates to the regioselective synthesis of derivatives of rapamycin at the 42-position, which are useful for inducing immunosuppression, and in the treatment of transplantation rejection, graft vs. host disease, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders. [0002]
  • Rapamycin is a macrocyclic triene antibiotic produced by [0003] Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749].
  • Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies. [0004]
  • The immunosuppressive effects of rapamycin have been disclosed in FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet 1183 (1978); and U.S. Pat. No. 5,100,899]. [0005]
  • Rapamycin has also been shown to be useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No. 5,321,009], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. No. 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], and ocular inflammation [U.S. Pat. No. 5,387,589]. [0006]
  • Numerous rapamycin 42-derivatives are known, typically being esters (carbon and sulfur based) or ethers of the 42-hydroxyl group of rapamycin, that are produced by esterification or etherification of the 42-position. Esterification of rapamycin at the 42-position was commonly prepared by directly reacting rapamycin with acylating agents in order to afford the desired product. The chemistry appeared to be rather simple. However, as rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoacylated product, posed a difficult challenge. This type of non-regioselective reaction also produced a 31,42-bis-acylated by-product and as well, some unreacted rapamycin remained in the reaction mixture. The final result was a lower yield that required extensive purification to obtain pure 42-monoacylated product. [0007]
    • DESCRIPTION OF THE INVENTION
  • This invention provides a regioselective method for the preparation of a 42-ester or ether rapamycin having the structure [0008]
    Figure US20010039338A1-20011108-C00001
  • wherein R is an ester or ether, which comprises: [0009]
  • (a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether; [0010]
  • (b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether; [0011]
  • (c) treating the rapamycin 31-silyl ether with a suitable esterifying or etherifying reagent to form rapamycin 31-silyl ether 42-ester or ether; and [0012]
  • (d) selectively hydrolyzing the 31-silyl ether in mild acid to provide the desired rapamycin 42-ester or ether. [0013]
  • Preferred 42-esters and ethers of rapamycin which can be prepared by the method provided by this invention are disclosed in the following patents, which are all hereby incorporated by reference: alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S. Pat. No. 5,118,677); carbamate esters (U.S. Pat. No. 5,118,678); silyl ethers (U.S. Pat. No. 5,120,842); aminoesters (U.S. Pat. No. 5,130,307); acetals (U.S. Pat. No. 5,51,413); aminodiesters (U.S. Pat. No. 5,162,333); sulfonate and sulfate esters (U.S. Pat. No. 5,177,203); esters (U.S. Pat. No. 5,221,670); alkoxyesters (U.S. Pat. No. 5,233,036); O-aryl, -alkyl, -alkenyl, and -alkynyl ethers (U.S. Pat. No. 5,258,389); carbonate esters (U.S. Pat. No. 5,260,300); arylcarbonyl and alkoxycarbonyl carbamates (U.S. Pat. No. 5,262,423); carbamates (U.S. Pat. No. 5,302,584); hydroxyesters (U.S. Pat. No. 5,362,718); hindered esters (U.S. Pat. No. 5,385,908); heterocyclic esters (U.S. Pat. No. 5,385,909); gem-disubstituted esters (U.S. Pat. No. 5,385,910); amino alkanoic esters (U.S. Pat. No. 5,389,639); phosphorylcarbamate esters (U.S. Pat. No. 5,391,730); carbamate esters (U.S. Pat. No. 5,411,967); carbamate esters (U.S. Pat. No. 5,434,260); amidino carbamate esters (U.S. Pat. No. 5,463,048); carbamate esters (U.S. Pat. No. 5,480,988); carbamate esters (U.S. Pat. No. 5,480,989); carbamate esters (U.S. Pat. No. 5,489,680); hindered N-oxide esters (U.S. Pat. No. 5,491,231); biotin esters (U.S. Pat. No. 5,504,091); and O-alkyl ethers (U.S. Pat. No. 5,665,772). These patents also disclose methods for esterification or etherification utilized in step (c), above. [0014]
  • The following scheme illustrates the regioselective preparation of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid, as a representative 42-ester of rapamycin, which can be prepared according to the method provided in this invention. The original synthesis of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid is disclosed in U.S. Pat. No. 5,362,718. [0015]
    Figure US20010039338A1-20011108-C00002
  • While the chemical preparation of rapamycin esters and ethers appears to be simple, and the desired products are obtainable, the synthetic yield of the esters and ethers is often poor. As rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoester such as compound [B] poses a difficult challenge. For example, the synthesis of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid described in U.S. Pat. No. 5,362,718, example 10, was non-regioselective, the 31,42-bisester by-product was also generated. As a result, the crude product [B] after work-up contains the desired product [B], 31,42-bisester by-product and unreacted rapamycin. In an effort to consume the remaining starting rapamycin, the reaction was allowed to proceed for a longer period with negative consequences, the quantity of the 31,42-bisester increased significantly. The resulting crude product [B] is contaminated with unreacted rapamycin and 31,42-bisester, and subsequent column chromatography purification effort has proved to be difficult as the 42,31-bisester has a very close retention time with product [B]. Overall, the major obstacle in large-scale production of compound [B] appears to be the non-regiospecificity that is further complicated by purification difficulties. This invention overcomes these difficulties by providing a regioselective synthesis of 42-esters or ethers of rapamycin by selectively protecting the 31-hydroxyl group as a silyl ether (i.e., compound [D]), leaving the 42-position hydroxyl accessible for regioselective esterification or etherification to produce 31-O-silyl, 42-esters or ethers (i.e., compound [E]). The 31-hydroxyl group can then be deprotected under mild acidic conditions (i.e., compound [B]). [0016]
  • In accordance with this invention, it is preferred that the 31, and 42-hydroxyl groups are protected as trialkyl silyl ethers. The 42-silyl protected hydroxyl group of the 31,42-bis-silylated rapamycin can be selectively cleaved under mildly acidic conditions to provide 31-silyl rapamycin. The silylating agents used for this transformation are common, commercially available chloroalkylsilanes, such as chlorotrimethylsilane, chlorotriethylsilane or chlorotripropylsilane. However, the bulkier the trialkylsilane, the more time is needed to deprotect in acid media during the penultimate chemical step to regenerate the 31-hydroxyl group. Also, a longer reaction time in the acid media generates more degradation by-products. Although, chlorotrimethylsilane, chlorotriethylsilane or chlorotripropylsilane can be used for the preparation of rapamycin 31-O-trialkylsilyl ethers, chlorotrimethylsilane is the preferred silylating agent. The trimethylsilyl group is more acid labile and therefore easier to de-protect during the transformation and in effect, this minimizes the formation of degradation products. The preparation of 31-O-trimethylsilyl rapamycin [D] is described in Example 1. Rapamycin is treated with excess chlorotrimethylsilane in ethyl acetate at 0-5° C. in the presence of an organic base and the 42- and 31- hydroxyl groups of rapamycin are silylated to form rapamycin 31,42-bis-O-trimethylsilyl ether in quantitative yield. The common organic bases such as imidazole, 1-methylimidazole, triethylamine and N,N-diisopropylethylamine can be used for the general silylation reaction. However, imidazole is found to be the preferred base for the silylation of rapamycin as the reaction is completed within 30 minutes. [0017]
  • Selective de-protection of the 42-O-trimethylsilyl group of rapamycin 31,42-bis-O-trimethylsilyl ether to form rapamycin 31-O-trimethylsilyl ether, is effected in situ at 0-5° C. with ethanol, ethanol-water mixtures, water, diluted inorganic or organic acids. Sulfuric acid (0.5 N) is preferred since the reaction is clean and can be completed in 4-5 h. A number of organic solvents can be used for silylation and in particular, DMF is often mentioned in the literature. However, in this invention, ethyl acetate is the preferred solvent. [0018]
  • The esterification or etherification of the 31-protected rapamycin can be carried out under conditions described in the patents listed above. For example, in Scheme I, the acylation of rapamycin 31-trimethylsilyl ether was accomplished using 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid in the presence of 4-dimethylaminopyridine or a similar reagent. In addition, 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride was also found to be an effective acylation agent in this invention in the presence of 4-dimethylaminopyridine or a similar reagent. For the acylation conditions, methylene chloride is the preferred solvent rather than tetrahydrofuran which was described in the prior art. In addition, lower reaction temperature of less than 0° C., with −20 to −15° C. or lower being more preferred, provides better results than the room temperature acylation described in U.S. Pat. No. 5,362,718. In Scheme I, the acylation products, 31-O-TMS, 42-(protected-hydroxy) esters (compound [E]) can be further treated with diluted acid to convert them to 42-(protected-hydroxy) esters (compound [B]) or used directly to make final product 42-hydroxyesters (final product [C]). This methodology can be used to prepare other esters or ethers of rapamycin, by simply varying the esterfiying or etherifying agent used. [0019]
  • In Scheme I, conversion of compound [B] to rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid [C], can be accomplished under mildly acidic conditions. It is preferred that aqueous sulfuric acid is used, as it minimizes the formation of impurities generated when aqueous hydrochloric acid is used, as described in the U.S. Pat. No. 5,362,718. The tetraene impurity formed when using hydrochloric acid has been reported to be difficult to separate from the desired product by column chromatography (Caufield et al, Tetrahedron Lett., 1994, 37,6835). It is also preferrable to carry out the hydrolysis at 0-5° C. rather than room temperature as described in U.S. Pat. No. 5,362,718. [0020]
  • The synthetic route disclosed in this invention provides several distinct advantages over the synthetic methodology which has been published for the preparation of rapamycin esters or ethers; mainly in the yield and ease of purification of the desired 42-esters or ethers. As this is a regioselective synthesis, the overall yields of the desired 42-esters or ethers is dramatically improved. For example, the synthetic methodology taught in U.S. Pat. No. 5,362,718 provides compound [B] in a 35% yield, whereas, the synthesis of [B] is accomplished in 85% yield using the methodology disclosed herein. Additionally, the conversion to rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid from [B] is accomplished in approximately 75% yield using the process described herein, whereas only a 20% conversion is provided using the methodology of U.S. Pat. No. 5,362,718. [0021]
  • Using the same methodology, 42-ethers of rapamycin can be prepared in a regioselective manner. As an example, U.S. Pat. No. 5,665,772 discloses the preparation of 40-O-alkyl ethers of rapamycin in a non-regioselective manner. Owing to nomenclature differences, the 42-position of rapamycin (as named in this invention) is referred to as the 40-position in U.S. Pat. No. 5,665,772. These positons are identical. Using the methodology disclosed herein, rapamycin 31-O-trimethylsilyl ether can be treated with, for example, 2-(t-butyldimethylsilyl)oxyethyl triflate) to provide 31-O-trimethylsilyl, 42-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin. Removal of the silyl protecting groups from the 31-hydroxyl group of rapamycin and from the 42-hydroxyethyl moiety can be accomplished under mildly acidic conditions, such as dilute sulfuric acid to provide 42-O-(2-hydroxy)ethyl rapamycin. The non-regioselective formation of other 42-ethers of rapamaycin is disclosed in U.S. Pat. No. 5,665,772. These also can be prepared regioselectively via rapamycin 31-O trimethylsilyl ether. [0022]
  • This invention also covers 31-silyl ethers of rapamycin, which are useful in the preparation of the 42-esters and ethers of rapamycin, as disclosed herein. The silicon moiety as represented by —SiR′R″R′″, contains 3 groups which can be the same or different. Typical silyl ethers of this invention contain R′, R″, or R′″ moieties which are alkyl of 1-6 carbon atoms, phenyl, or benzyl groups. The alkyl groups can be branched or straight chain. It is preferred that R′, R″, and R′″ be alkyl groups, and more preferred that R′, R″, and R′″ are methyl or ethyl. It is still more preferred that the 31-silyl ether is rapamycin 31-O-trimethylsilyl ether. [0023]
  • The following examples illustrate the preparation of rapamycin 31-silyl ethers and a rapamycin 42-ester, which is representative of the compound which can be prepared by the process of this invention.[0024]
    • EXAMPLE 1 Rapamycin 31-O-trimethylsilyl ether
  • A solution of rapamycin (25.0 g, 92.4% strength; 25.28 mmol) in 750 mL ethyl acetate was cooled to 0-5° C.; 7.5 g (110.20 mmol) of imidazole was added and stirred to form a solution. To this cold solution 11.0 g (101.25 mmol) of chlorotrimethylsilane was added dropwise over 30 min and stirred for a further 30 min at 0-5° C. in order to complete the formation of rapamycin 31,42-bis-O-trimethylsilyl ether. A 50 mL quantity of 0.5 N sulfuric acid was added dropwise over a 10 min period and the mixture was stirred for 2.5 h at 0-5° C. The reaction mixture was transferred into a separatory funnel and the aqueous layer was separated and extracted with 125 mL ethyl acetate. The organic layers were combined and successively washed with brine (125 mL), saturated sodium bicarbonate solution (100 mL), water (125 mL×2) then brine to pH 6-7. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a beige color foam product, 28.5 g (theory 24.94 g). HPLC analysis showed it contained 86% (by area %) of rapamycin 31-O-trimethylsilyl ether and 7% of rapamycin. The product was used directly for the subsequent reaction. [0025]
  • LC/MS electrospray (+) mode (M−H)=985. [0026] 1H NMR (400 MHz, d-6 DMSO) δ 4.60 (m, 1H, (42C)OH), 4.10 (m, 1H, C(31) H), 3.09 (m, 1H, C(42) H), −0.027 (s, 9H, 31-O-TMS).
    • EXAMPLE 2 2,2,5-Trimethyl[1.3-dioxane]-5-carboxylic acid chloride
  • A solution of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid (17.42 g, 0.1 mol) in 200 mL of dry toluene was warmed to 40° C., and 26.0 mL of oxalyl chloride (37.83 g, 0.3 mol) added dropwise over a period of 30 min and then stirred at 40° C. for 2.5 h. The reaction mixture was evaporated under reduced pressure to remove solvent and excess oxalyl chloride. The residual product was evaporated twice with dry toluene (200 mL), then dried under high vacuum at 40° C. for 2 h to obtain 19.75 g of product as an orange colored liquid. [0027] 1H NMR (300 MHz, CDCl3) δ 4.28 (2H, d, J=10.5 Hz), 3.76 (2H, d, J=10.5 Hz), 1.46 (3H, s), 1.29 (3H, s). 13C NMR (75 MHz, CDCl3) δ 176.43, 98.76, 66.06, 52.07, 25.82, 21.20, 18.10.
    • EXAMPLE 3 Rapamycin 31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid
  • Method A: [0028]
  • To a solution of the 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid (9.77 g, 56.08 mmol) and N,N-diisopropylethylamine (12.00 g, 92.80 mmol) in 200 mL methylene chloride at room temperature under nitrogen, 2,4,6-trichlorobenzoyl chloride (13.35 g, 54.73 mmol) was added and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was cooled to −20 to −15° C. and a solution of rapamycin 31-O-trimethylsilyl ether (28.50 g, crude, made from 25.28 mmol of rapamycin) in 120 mL methylene chloride was added. A solution of 4-dimethylaminopyridine (11.68 g, 95.60 mmol) in 110 mL methylene chloride was added dropwise over a 2 h period. The reaction mixture was further stirred for 16 h at −15 to −16° C. The reaction mixture was quenched with 100 mL water and the organic layer was separated and washed with 0.5 N sulfuric acid (180 mL), followed by brine (100 mL), saturated sodium bicarbonate solution (100 mL), water (100 mL×2), brine (100 mL) to pH 6-7. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound (33.18 g) as a beige color foam. [0029]
  • LC/MS electrospray (+) mode (M+NH[0030] 4)=1160. 1H NMR (400 MHz, d-6 DMSO) δ 4.57 (m, 1H, C(42)H), 4.10 (m, 1H, C(31) H), 4.03 (d, 2H), 3.57 (d, 2H), 1.34 (s, 3H), 1.24 (s, 3H), 1.13 (s, 3H), −0.023 (s, 9H, 31-O-TMS)
  • Method B: [0031]
  • A solution of rapamycin 31-O-trimethylsilyl ether (11.00 g; from 10.0 g of rapamycin; 11.15 mmol) in 120 mL methylene chloride, containing 2 mL of N,N,-dimethylformamide, was stirred under nitrogen and cooled to −15 ° C., 4-dimethylaminopyridine (4.80 g, 39.29 mmol) was added and the mixture was stirred to form a solution. To this cold solution a 7.5% solution of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride (42.18 g; 16.42 mmol) in methylene chloride was added dropwise over a 2 h period. The solution was further stirred for 1 h at −15° C., and an additional 7.5% solution of acid chloride (14.06 g, 5.47 mmol) in methylene chloride was added over a 30 min period. The reaction mixture was further stirred for 16 h at −15 C. to −16° C. The reaction mixture was quenched with 100 mL brine and the organic layer was separated and washed with cold 0.5 N sulfuric acid (100 mL), brine (100 mL), saturated sodium bicarbonate solution (100 mL) water (100 mL), brine (100 mL) to pH 6-7. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford product (12.15 g) as a yellow foam. [0032]
    • EXAMPLE 4 Rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid
  • A solution of rapamycin 31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid (33.18 g; from example 3, method A) in 100 mL of acetone was stirred and cooled to 0-5° C. To this cold solution 17 mL of 0.5 N sulfuric acid was added dropwise over a 10 min period and the mixture was stirred for 2.5 h at 0-5° C. A solution of sodium bicarbonate (1.44 g) in 20 mL water was added over a period of 20 min followed by an additional 33 mL water over a period of 30 min; the product started to precipitated after about 1 h of stirring. The mixture was stirred overnight at 0-5° C. and after filtration the solid product was washed with 60 mL of acetone-water (1:1). The product was dried in a vacuum oven at 30° C. to obtain 28.85 g of product (83.9% strength, 89.3% overall yield from rapamycin). The [0033] 1H NMR of the product was identical to the product described in U.S. Pat. No. 5,362,718 example 10.
    • EXAMPLE 5 Ragamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid
  • Method A: [0034]
  • A solution of rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid (28.85 g; from example 4) in 276 mL of tetrahydrofuran was stirred and cooled to 0-5° C. To this cold solution 83 mL of cold 2 N sulfuric acid was added dropwise over a 30 min period and the mixture was stirred for 60 h at 0-5° C. The reaction mixture was diluted with 600 mL of ethyl acetate and washed with 120 mL brine. The aqueous layer was extracted once with 120 mL of ethyl acetate and the organic extracts were combined and washed with saturated sodium bicarbonate solution (120 mL), water (200 mL×2) and brine (120 mL) to pH 6-7. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure at room temperature to obtain product (28.42 g), as a beige color foam. The crude product was chromatographed on a silica gel column and eluted with 30% acetone in heptane to give 18.06 g of pure product, a white solid (69.4% overall from rapamycin). The [0035] 1H NMR of the product is identical to the product described in U.S. Pat. No. 5,362,718 example 11.
  • Method B: [0036]
  • A solution of rapamycin 31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid (23.25 g, prepared from 20.06 g of rapamycin, strength 92.7%, 20.34 mmol) in 230 mL of tetrahydrofuran was stirred and cooled to 0-5° C. To this cold solution 115 mL of cold 2 N sulfuric acid was added dropwise over a 45 min period and the mixture was stirred for 88 h at 0-5° C. The reaction mixture was diluted with 500 mL of ethyl acetate and washed with 100 mL brine. The aqueous layer was extracted once with 100 mL of ethyl acetate and the organic extracts were combined and washed with saturated sodium bicarbonate solution (80 mL), water (80 mL×2) and brine (100 mL) to pH 6-7. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure at room temperature to afford product (22.48 g), a beige color foam. The crude product was chromatographed on a silica gel column and eluted with 30% acetone in heptane to give 16.50 g of pure product as a white solid (78.4% overall from rapamycin). The [0037] 1H NMR of the product is identical to the product described in U.S. Pat. No. 5,362,718 example 11.
    • EXAMPLE 6 Rapamycin 31,42-bis-O-trimethylsilyl ether
  • A solution of rapamycin (10.0 g, 94.3% strength; 10.3 mmol) in 150 mL ethyl acetate was cooled to 0-5° C.; 3.0 g (44 mmol) of imidazole was added and stirred to form a solution. To this cold solution, 4.4 g (40.5 mmol) of chlorotrimethylsilane was added dropwise over a 20 min period and following this, the solution was stirred at 0-5° C. for a further 30 min. The reaction mixture was filtered to remove the imidazole HCl and the filtrate was evaporated under reduced pressure to obtain a yellow foam. Heptane (200 mL) was added and stirred at room temperature for 20 min and the mixture was filtered. The filtrate was washed with 40 mL of saturated sodium bicarbonate solution, then twice with water (80 mL), then brine (50 mL). [0038]
  • The organic layer was dried over anhydrous sodium sulfate and evaporated to obtain the product, a yellow foam of 11.42 g (98.6%). [0039]
  • LC/MS electrospray (−) mode (M−H)=1057. [0040] 1H NMR (400 MHz, d-6 DMSO) δ 4.10 (m, 1H, C(31) H), 3.31 (m, 1H, C(42) H), 0.057 (s, 9H, 42-O-TMS), −0.027 (s, 9H, 31-O-TMS).
    • EXAMPLE 7 Rapamycin 31-O-triethylsilyl ether
  • A solution of rapamycin (5.00 g, 92.7% strength; 5.07 mmol) in 75 mL ethyl acetate was cooled to 0-5° C.; 1.50 g (22.03 mmol) of imidazole was added and stirred to form a solution. To this cold solution, 3.05 g (20.23 mmol) of chlorotriethylsilane was added dropwise over a 10 minutes period. The mixture was stirred for 30 min at 0-5° C., then stirred at room temperature overnight to complete the formation of rapamycin 31,42-bis-O-triethylsilyl ether. Following filtration of the reaction mixture, the filtrate was evaporated under reduced pressure at room temperature to remove most of the solvent. The residual solution (ca. 10 mL) was dissolved in 60 mL acetone and 15 mL of 0.15 N sulfuric acid was added and the mixture stirred for 25 h at 0-5° C. The rapamycin 31,42-bis-O-triethylsilyl ether disappeared at this stage. The reaction mixture was diluted with 80 mL of ethyl acetate and successively washed with brine (60 mL×2), saturated sodium bicarbonate solution (40 mL), water (60 mL×2), brine (60 mL) to pH 6-7. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a product of light yellow gum, 6.92 g (theory 5.21 g). HPLC analysis showed it contained 95.2% (by area %) rapamycin 31-O-triethylsilyl ether and 0.9% rapamycin. [0041]
    • EXAMPLE 8 Rapamycin 31-O-tripropylsilyl ether
  • A solution of rapamycin (5.00 g, 92.7% strength; 5.07 mmol) in 75 mL ethyl acetate was cooled to 0-5° C.; 1.50 g (22.03 mmol) of imidazole was added and stirred to form a solution. To this cold solution, 3.91 g (20.3 mmol) of chlorotripropylsilane was added dropwise over 10 min period. The mixture was stirred for 30 min at 0-5° C., then at room temperature for 21 h to complete the formation of rapamycin 31,42-bis-O-tripropylsilyl ether. Following filtration of the reaction mixture, the filtrate was evaporated under reduced pressure at room temperature to remove most of the solvent and the residual solution was dissolved in 60 mL acetone. A 15 mL quantity of 0.25 N of sulfuric acid was added and the mixture was stirred for 45 h at 0-5° C.; the rapamycin 31,42-bis-O-tripropylsilyl ether disappeared at this stage. The reaction mixture was diluted with 100 mL of ethyl acetate, and successively washed with brine (40 mL×2), saturated sodium bicarbonate solution (40 mL), water (40 mL×2), and brine (50 mL) to pH 6-7. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a product of light yellow gum, 8.07 g (theory 5.43 g). HPLC analysis showed it contained 96.7% (by area %) of rapamycin 31-O-tripropylsilyl ether and 1% of rapamycin [0042]

Claims (20)

What is claimed is:
1. A process for preparing a 42-ester or ether of rapamycin having the structure
Figure US20010039338A1-20011108-C00003
wherein R is an ester or ether, which comprises:
(a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;
(b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;
(c) treating the rapamycin 31-silyl ether with a suitable esterifying or etherifying reagent to form rapamycin 31-silyl ether 42-ester or ether; and
(d) selectively hydrolyzing the 31-silyl ether in mild acid to provide the desired rapamycin 42-ester or ether.
2. The process according to
claim 1
, wherein the silylating agent in step (a) is a trialkylsilyl halide.
3. The process according to
claim 2
, wherein the silylating agent in step (a) is trimethylsilyl chloride.
4. The process according to
claim 3
, wherein the acid used to perform the hydrolysis in step (b) is dilute sulfuric acid.
5. A process for preparing rapamycin 31-trimethylsilyl ether, which comprises:
(a) treating rapamycin with chlorotrimethylsilane in an inert solvent in the presence of a suitable base to provide rapamycin 31,42-bis-trimethylsilyl ether; and
(b) treating the 31,42-bis-trimethylsilyl ether with dilute acid to provide rapamycin 31-trimethylsilyl ether.
6. The process according to
claim 5
, wherein the base in step (a) is imidazole, 1-methylimidazole, triethylamine, or N,N-diisopropylethylamine.
7. The process according to
claim 6
, wherein the acid in step (b) is sulfuric acid.
8. A process for preparing rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid, which comprises:
(a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;
(b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;
(c) acylating the rapamycin 31-silyl ether with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid chloride or the 2,4,6-trichlorobenzoyl mixed anhydride of 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid to give rapamycin-31-O-trimethylsilyl ether, 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid;
(d) selectively hydrolyzing the 31-silyl ether in mild dilute acid to provide rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid; and
(e) treatment of rapamycin 42-ester with 2,2,5-trimethyl[1.3-dioxane]-5-carboxylic acid with mild acid to provide 42-ester with 2,2-bis-(hydroxymethyl)propionic acid.
9. The process according to
claim 8
, wherein the silylating agent is a trialkylsilyl halide.
10. The process according to
claim 9
, wherein the silylating agent is chlorotrimethylsilane.
11. The process according to
claim 10
, wherein the acid used in steps (b) and (d) is sulfuric acid.
12. The process according to
claim 11
, wherein the acylation in step (c) is carried out at less than 0° C.
13. A process for preparing 42-O-(2-hydroxy)ethyl-rapamycin which comprises:
(a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;
(b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;
(c) treating the rapamycin 31-silyl ether with a an ethylene glycol equivalent containing an acid labile hydroxyl protecting group protecting on one terminus of the ethylene glycol equivalent and a leaving group suitable of alkylating a hydrxyl group as the other terminus of the ethylene glycol equivalent.
(d) hydrolying the protecting groups on the 31-postion and on the 42-hydroxyethyl position under mildly acidic conditions.
14. The process according to
claim 13
, wherein the silylating agent is is a trialkylsilyl halide.
15. The process according to
claim 14
, wherein the silylating agent is chlorotrimethylsilane.
16. The process according to
claim 15
, wherein the ethylene glycol equivalent is 2-(t-butyldimethylsilyl)oxyethyl triflate).
17. The process according to
claim 16
, wherein the acid used in steps (b) and (d) is sulfuric acid.
18. A compound which is a rapamycin 31-O-silyl ether.
19. The compound of
claim 18
, in which the 31-O-silyl ether is a trialkylsilyl ether.
20. The compound of
claim 19
, which is rapamycin 31-O-trimethylsilyl ether.
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GB0609962D0 (en) * 2006-05-19 2006-06-28 Biotica Tech Ltd Novel compounds
WO2008022256A2 (en) * 2006-08-16 2008-02-21 Blagosklonny Mikhail V Methods and compositions for preventing or treating age-related diseases
US20080051691A1 (en) * 2006-08-28 2008-02-28 Wyeth Implantable shunt or catheter enabling gradual delivery of therapeutic agents
TW200824713A (en) * 2006-10-18 2008-06-16 Wyeth Corp Processes for the synthesis of individual isomers of mono-PEG CCI-779
CA2669675A1 (en) * 2006-11-10 2008-05-15 Syndax Pharmaceuticals, Inc. Combination of er.alpha.+ ligands and histone deacetylase inhibitors for the treatment of cancer
TW200845960A (en) * 2007-04-05 2008-12-01 Wyeth Corp Wortmannin-rapalog conjugate and uses thereof
TW200901989A (en) * 2007-04-10 2009-01-16 Wyeth Corp Anti-tumor activity of CCI-779 in papillary renal cell cancer
US8022216B2 (en) 2007-10-17 2011-09-20 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
WO2009067453A1 (en) * 2007-11-19 2009-05-28 Syndax Pharmaceuticals, Inc. Combinations of hdac inhibitors and proteasome inhibitors
US20090253733A1 (en) * 2008-04-02 2009-10-08 Biointeractions, Ltd. Rapamycin carbonate esters
US20110098241A1 (en) * 2008-04-14 2011-04-28 Poniard Pharmaceuticals, Inc. Rapamycin analogs as anti-cancer agents
SI2310011T1 (en) 2008-06-17 2013-10-30 Wyeth Llc Antineoplastic combinations containing hki-272 and vinorelbine
CN101633669B (en) * 2008-07-23 2012-05-30 中国科学院上海药物研究所 Novel method for protecting 31-position or 42-position hydroxyl of rapamycin by selective silicon etherification
CN101676291B (en) * 2008-09-18 2012-05-09 上海海和药物研究开发有限公司 Rapamycin carbonate analog, pharmaceutical composition thereof, and preparation method and uses thereof
DE102008060549A1 (en) 2008-12-04 2010-06-10 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Drug-peptide construct for extracellular accumulation
TW201035104A (en) * 2009-03-27 2010-10-01 Chunghwa Chemical Synthesis & Biotech Co Ltd Improved synthesis method for Temsirolimus and its similar compounds
EP2480557A2 (en) 2009-09-25 2012-08-01 Cadila Healthcare Limited Process for the preparation of rapamycin derivatives
WO2011053938A1 (en) 2009-10-30 2011-05-05 Ariad Pharmaceuticals, Inc. Methods and compositions for treating cancer
EP2528906A2 (en) * 2010-01-28 2012-12-05 Fresenius Kabi Oncology Ltd Process for the preparation of temsirolimus and its intermediates
MX2013011412A (en) * 2011-04-01 2014-04-30 Sandoz Ag Regioselective acylation of rapamycin at the c-42 position.
CN102424829B (en) * 2011-10-26 2013-10-16 苏州汉酶生物技术有限公司 Method for synthesizing temsirolimus through enzyme catalysis
US9750728B2 (en) 2012-09-29 2017-09-05 Targeted Therapeutics, Llc Method and pharmaceutical composition for inhibiting PI3K/AKT/mTOR signaling pathway
CN103705925B (en) 2012-09-29 2018-03-30 段磊 Pharmaceutical composition for inhibiting PI3K/AKT/mTOR signaling pathway
EP2994758B1 (en) 2013-05-08 2017-12-20 Opthea Limited Biomarkers for age-related macular degeneration (amd)
CN103421023B (en) * 2013-07-30 2015-09-23 福建省微生物研究所 A kind of synthesis technique of CCI-779
CN107073066B (en) 2014-09-11 2021-09-17 加利福尼亚大学董事会 mTORC1 inhibitors
CN106153758B (en) * 2015-04-25 2020-03-31 山东新时代药业有限公司 Method for measuring content of everolimus intermediate
BR112020022201A2 (en) 2018-05-01 2021-02-02 Revolution Medicines, Inc. analogues of rapamycin bound to c40, c28, and c-32 as inhibitors of mtor
IL312291A (en) 2018-05-01 2024-06-01 Revolution Medicines Inc C26-linked rapamycin analogs as mtor inhibitors
CN113164557A (en) 2018-07-23 2021-07-23 因柯利尔疗法公司 Methods of treating neurological disorders
WO2020023417A1 (en) 2018-07-23 2020-01-30 Enclear Therapies, Inc. Methods of treating neurological disorders
EP3952947A4 (en) 2019-04-11 2024-07-03 Enclear Therapies, Inc. Methods of amelioration of cerebrospinal fluid and devices and systems therefor
AU2021355470A1 (en) 2020-09-29 2023-06-01 Enclear Therapies, Inc. Subarachnoid fluid management method and system
CN119604293A (en) 2022-05-25 2025-03-11 锐新医药公司 Methods of treating cancer with mTOR inhibitors

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4316885A (en) 1980-08-25 1982-02-23 Ayerst, Mckenna And Harrison, Inc. Acyl derivatives of rapamycin
US4650803A (en) 1985-12-06 1987-03-17 University Of Kansas Prodrugs of rapamycin
US5130307A (en) 1990-09-28 1992-07-14 American Home Products Corporation Aminoesters of rapamycin
US5221670A (en) 1990-09-19 1993-06-22 American Home Products Corporation Rapamycin esters
US5233036A (en) 1990-10-16 1993-08-03 American Home Products Corporation Rapamycin alkoxyesters
US5120842A (en) 1991-04-01 1992-06-09 American Home Products Corporation Silyl ethers of rapamycin
US5100883A (en) 1991-04-08 1992-03-31 American Home Products Corporation Fluorinated esters of rapamycin
US5118678A (en) 1991-04-17 1992-06-02 American Home Products Corporation Carbamates of rapamycin
US5118677A (en) 1991-05-20 1992-06-02 American Home Products Corporation Amide esters of rapamycin
US5162333A (en) 1991-09-11 1992-11-10 American Home Products Corporation Aminodiesters of rapamycin
US5151413A (en) 1991-11-06 1992-09-29 American Home Products Corporation Rapamycin acetals as immunosuppressant and antifungal agents
US5177203A (en) 1992-03-05 1993-01-05 American Home Products Corporation Rapamycin 42-sulfonates and 42-(N-carboalkoxy) sulfamates useful as immunosuppressive agents
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
US5434260A (en) 1992-10-13 1995-07-18 American Home Products Corporation Carbamates of rapamycin
US5411967A (en) 1992-10-13 1995-05-02 American Home Products Corporation Carbamates of rapamycin
US5480988A (en) 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
US5302584A (en) 1992-10-13 1994-04-12 American Home Products Corporation Carbamates of rapamycin
US5489680A (en) 1992-10-13 1996-02-06 American Home Products Corporation Carbamates of rapamycin
US5480989A (en) 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
US5262423A (en) 1992-10-29 1993-11-16 American Home Products Corporation Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents
US5258389A (en) 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5260300A (en) 1992-11-19 1993-11-09 American Home Products Corporation Rapamycin carbonate esters as immuno-suppressant agents
US5504091A (en) 1993-04-23 1996-04-02 American Home Products Corporation Biotin esters of rapamycin
US5387680A (en) 1993-08-10 1995-02-07 American Home Products Corporation C-22 ring stabilized rapamycin derivatives
US5391730A (en) 1993-10-08 1995-02-21 American Home Products Corporation Phosphorylcarbamates of rapamycin and oxime derivatives thereof
US5385909A (en) 1993-11-22 1995-01-31 American Home Products Corporation Heterocyclic esters of rapamycin
US5385910A (en) 1993-11-22 1995-01-31 American Home Products Corporation Gem-distributed esters of rapamycin
US5385908A (en) 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
US5389639A (en) 1993-12-29 1995-02-14 American Home Products Company Amino alkanoic esters of rapamycin
US5362718A (en) 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
US5463048A (en) 1994-06-14 1995-10-31 American Home Products Corporation Rapamycin amidino carbamates
US5491231A (en) 1994-11-28 1996-02-13 American Home Products Corporation Hindered N-oxide esters of rapamycin
US5563145A (en) 1994-12-07 1996-10-08 American Home Products Corporation Rapamycin 42-oximes and hydroxylamines
KR100400620B1 (en) 1995-06-09 2004-02-18 노파르티스 아게 Rapamycin Derivatives
US6015809A (en) 1998-08-17 2000-01-18 American Home Products Corporation Photocyclized rapamycin

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050234086A1 (en) * 2004-04-14 2005-10-20 Wyeth Proline CCI-779, production of and uses therefor, and two-step enzymatic synthesis of proline CCI-779 and CCI-779
WO2005100366A1 (en) * 2004-04-14 2005-10-27 Wyeth Proline cci-779 (proline-rapamycin 42-ester with 2,2-bis (hydroxymethyl) propionic acid) and two-step enzymatic synthesis of proline cci-779 and cci-779 using microbial lipase
US7202256B2 (en) 2004-04-14 2007-04-10 Wyeth Proline CCI-779, production of and uses therefor, and two-step enzymatic synthesis of proline CCI-779 and CCI-779
US20060199954A1 (en) * 2005-03-02 2006-09-07 Wyeth Purification of rapamycin
WO2006093745A1 (en) * 2005-03-02 2006-09-08 Wyeth Purification of rapamycin
US7288647B2 (en) 2005-03-02 2007-10-30 Wyeth Recovery of CCI-779 from mother liquors
US7384953B2 (en) 2005-03-02 2008-06-10 Wyeth Purification of rapamycin

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