Regiospecific synthesis of rapamycin 42-ester derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.

EFFECT: increased output of the product under mild conditions.

13 cl, 12 ex

 

Rapamycin (drug Rapamune) is immunosupressants of natural origin, which has a new mechanism of action. CCI-779 (42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) is an ester of rapamycin, which demonstrates a significant inhibitory effect on tumor growth in models in vitro and in vivo.

Modification of rapamycin is mainly aimed at deriving its 42-hydroxyether. These derivatives 42-hydroxyether of rapamycin are used to stimulate immunosuppression and in the treatment of rejections after transplantation, autoimmune diseases, inflammation, Mature T-cell leukemia/lymphoma, solid tumors, fungal infections and other Substantial rapamycin 42 position performed directly by the reaction of rapamycin with allerease agents. However, since rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to distinguish between these two hydroxyl groups to meet regioselective synthesis of 42-manuallyand products represent a complex task.

He published a number of patents relating to the synthesis of 42-acylated derivatives, such as alkyl ether (U.S. patent No. 4316885), aminoalkyl esters (U.S. patent No. 4650803), fluorinated esters (U.S. patent No. 4650803), amide esters (U.S. patent No. 5118677), ethers of urea U.S. patent No. 5118678), alkoxyamine (U.S. patent No. 5233036), carbonic acid esters (U.S. patent No. 5260300), hydroxyamine (U.S. patent No. 5362718 and No. 6277983). However, none of the patents described methods of synthesis, which would be stereospecific. Moreover, the outputs 42-monoamino rapamycin obtained by these methods is generally low due to the lack of regioselectivity and instability of the molecule rapamycin in the basic or acidic conditions. To obtain the pure product typically requires separation by high performance liquid chromatography (HPLC). One option for improving regioselectively is used as intermediate 31-silylamines rapamycin. However, in this method included a few additional steps.

Thus, an effective method for the synthesis of ethers of rapamycin.

BRIEF description of the INVENTION

The invention provides catalyzed by lipase synthesis of derivatives 42-ester of rapamycin. Distinctive features of this simple process are regiospecificity and high yield under mild conditions.

Other aspects and advantages of this invention will be apparent to a person skilled in this field.

DETAILED description of the INVENTION

This invention provides a method of obtaining a 42-ester of rapamycin with the General formula (I) R is geospecific form using a lipase in the presence of rapamycin and acyl donor.

where R is a linear or cyclic, aliphatic or aromatic, saturated or unsaturated hydrocarbon, which choice contains hydroxyl, halogen and/or sulfur-containing substituent (sulfur-containing substituents). In one embodiment, the halogen is Cl, Br, I or F.

Rapamycin can be obtained in accordance with the previously described ways. See, for example, U.S. patent No. 3929992, issued December 30, 1975 alternatively, rapamycin can be purchased commercially (e.g Rapamune, Wyeth] or obtained using alternative methods. Methods of cooking, cleaning and/or obtain the source material rapamycin this invention is not limited to.

In one experiment the invention provides regiospecificity method of manufacturing ketal-protected 42-ester of rapamycin used in the production of 42-ester of rapamycin. In one experiment the invention provides for the production of isopropylidene-protected 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, the precursor of the CCI-779 (example 7). CCI-779 is an ester of rapamycin, which demonstrates a significant inhibitory effect on tumor growth in models in vitro and in vivo. The use of these and other hydroxyamino rapamycin are described in U.S. patent No. 362718 and No. 6277983 and patent publication U.S. No. US 2005-0033046 A1 (patent application U.S. No. 10/903062). Remove Catalinas protecting group can be carried out in moderately acidic conditions. In General, you can follow the methodology, published in U.S. patent No.. 6277983 and cited documents. In one experiment deprotection perform in a single-phase system of water acid/organic solvent, for example dissolved in tetrahydrofuran (THF) sulfuric acid, such as 2 N. H2SO4/THF at a temperature of from about 0 to 5C. However, to complete this reaction may take about three days or more, in addition, required by solvent extraction to separate the product from the aqueous medium after completion of the reaction. Other ways to remove Catalinas protecting group, such as described in international patent application, called Proline CCI-779, Production and Uses Therefor, and Two Step Enzymatic Synthesis of Proline CCI-779 and CCI-779 (Shu and others, (Chew et al.), grounded in the provisional applications U.S. patent No. 60/562069 (registered 14 April 2004) and No. 60/623594 (registered 29 October 2004)), must be known to specialists in this field.

Used herein, the terms "microbial lipases" includes enzymes that catalyze the hydrolysis and formation of ester bonds, which were originally isolated from neocaridina sources such as Aspergillus niger, Candida antarctica, Candida rugosa, Mucor miehei, Pseudomonas cepacia, Pseudomnas fluorescens, Rhizopus delemar, etc. However you want selected for use in the invention, the enzyme did not require the isolation and purification directly from the source, and can be prepared synthetically, recombinante, or using other appropriate techniques. A number of these enzymes are available from several commercial sources, moreover, these enzyme preparations can be used in a crude, partially purified, purified or immobilized form, they can be different microbial origin, under different trade names and from different vendors.

Found that the implementation of the present invention is particularly suitable lipase In type from Candida antarctica. From all studied lipase lipase of this type provides the highest conversion speed and highest output allocated product. Lipase C. antarctica is commercially available enzyme with the trade name, for example, NOVO SP435 or NOVOZYME 435 from Novo Nordisk, or CHIRAZYME L-2 from Roche Molecular Biochemicals and BioCatalytics.

Lipase PS from Pseudomonas cepacia, especially in its immobilized form of the lipase PS-C [e.g., available as lipase "Amano" II from Amano], can conduct the reaction with the same efficiency as the lipase NOVOZYM 435 from the point of view of synthesis, albeit with a lower reaction rate. In this invention microbial lipase (for example, C. antarctica (type)) together with the criterion solvent for the catalysis of the reaction between the acyl donor and rapamycin. The person skilled in the art can easily choose the suitable solvent of, for example, toluene, tert-butyl methyl ether (TBME), ethyl ether, THF, MeCN, CH2Cl2, CHCl3, hexane, dioxane or mixtures containing these solvents. In one experiment using TBME (tert-butyl methyl ether). Acyl donor used in the method of this invention, are selected from activated esters, such as vinyl esters, isopropanolamine esters and anhydrides.

In one experiment the vinyl esters are selected from ethers with the formula CH2=CH-O-COR1where R1is alkyl, alkenyl, aryl, benzyl, unsubstituted or substituted by hydroxyl, halogen (F, Cl, Br, I) and grey. To apply the vinyl esters include vinyl acetate, finalproject, vinylchloride, vinylketones, vinylbenzoate and benildeans. However, the person skilled in the art may choose to use other vinyl esters.

In one experiment isopropanolamine ester chosen from esters with the formula CH2=C(CH3)-OCOR2where R2is alkyl, alkenyl, aryl, benzyl, unsubstituted or substituted by hydroxyl, halogen (F, Cl, Br, I) and grey. In another experience acyl donor is isopropenylacetate.

Used herein, the term "alkyl", refers to both straight and branched chain substituted hydrocarbon is aliphatic groups, containing from one to ten carbon atoms, preferably from one to eight carbon atoms and even more preferably from one to six carbon atoms.

It is assumed that the term "alkenyl" includes alkyl groups of straight and branched chain, containing at least one double bond in the carbon-carbon and from two to eight carbon atoms, preferably from two to six carbon atoms.

Used herein, the term "aryl" refers to a carbocyclic aromatic system, which may consist of one ring or multiple aromatic rings fused or linked together in such a way that at least one part of a condensed ring or the United forms forms the conjugated aromatic system, for example, from 6-14 carbon atoms. Aryl groups include phenyl, naphthyl, biphenyl, antril, tetrahydronaphthyl, tenantry, indan and others, but not limited to.

Used herein, the term "benzyl" refers to a group with the formula C6H5CH2.

The corresponding anhydrides can easily choose among alkanovykh anhydrides (i.e. C1C2With3With4C5With6C7and C8anhydrides), which can be branched or straight chain, and substituted with halogen, hydroxyl.

2until then, until all the original materials will not be spent. The reaction can be controlled in various ways, such as thin layer chromatography (TLC) and HPLC. In addition, a person skilled in the art can be used other ways of monitoring the response.

In the reaction using vinyl ester or isopropanolamine ester as acyl donor, the enzyme (lipase) is filtered off and washed with the appropriate solvent May be used in the same solvent as in the reaction, or distinct from it. If solvents are different, can be selected any of the above solvents or other commonly used solvents such as acetone, ethyl acetate, methanol, ethanol, isopropanol, etc. Combined organic solvent can then be evaporated under appropriate conditions, for example under reduced pressure. The residue is then purified by appropriate methods, for example by chromatographic silikagelevye column, with elution of the appropriate dissolve the LEM or recrystallization from an appropriate solvent (for example, with hexane-acetone, hexane-ethyl acetate, ethyl ether and other solvents). In this area there are other methods of purification. Moreover, other appropriate solvent mixtures and their ratio can be easily determined by the expert in this field.

In another experience as acyl donors catalyzed by the enzyme deriving 42-ester using anhydrides. The outputs of the product is usually high and is about 95% (example 9-11). In this experience anhydride and an appropriate amount of enzyme are mixed in an appropriate solvent with rapamycin and stirred for 16-96 hours, more preferably within 24 to 48 hours in the presence of N2without access of light. Suitably the reaction is performed at a temperature ranging from room temperature up to about 50C. the mass Ratio of the enzyme by weight of rapamycin may vary depending on the form of the anhydride and the duration of the reaction, for example, from approximately equivalent quantities (weight ratios) of rapamycin and enzyme (in/in) until the excess amount of enzyme for the more rapid the reaction. If the reaction is not completed after a certain period of time, as indicated above, the choice of either adding additional enzyme or the mixture is stirred for an additional period of time on the completion of the reaction, measured by TLC or HPLC. After separation of the enzyme by filtration to separate solvent under reduced pressure. The residue is purified using appropriate methods, such as chromatographic silikagelevye column or recrystallization.

Regiospecificity 42-derivatives of rapamycin present invention used in the pharmaceutical compositions. Thus, can be prepared recipes with a 42-derivatives of rapamycin present invention by any appropriate method, described in the literature devoted to the rapamycin or its derivatives.

Formulations for oral administration containing an active compound of this invention can be carried out in any of the traditionally used forms for oral administration, including tablets, capsules, hominids forms, tablets, lozenges and liquids for oral, suspensions or solutions. Capsules may contain mixtures of active compounds (active compounds) with Energie fillers and/or strong solvents such as pharmaceutically acceptable starches (e.g. corn starch, potato starch or tapioca starch), sugars, artificial sweeteners, powdered cellulose such as crystalline and microcrystalline cellulose, powder, gelatin, thickeners, and so forth. Acceptable tablet recipe is s can be prepared by methods conventional jacking, wet or dry granulation using a pharmaceutically acceptable solvents, binding agents, lubricants, disintegrants, surface-modifying agents (including surfactants), including, without limitation, suspendresume or stabilizing agents, for example magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcixerollic, polyvinylpyrrolidone, gelatin, alginic acid, acacia thickener, xanthan thickener, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, decalcify phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch, powdered sugar. To preferred agents that modify the surface include nonionic and anionic substances. Examples of agents which modify the surface, are without limitation poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol (cetomacrogol) emulsion wax, sorbitane esters, silicon dioxide in the colloidal form, phosphates, sodium dodecylsulfate, magnesium-aluminum silicate, and triethanolamine. Formulations of the present invention for oral administration may utilize standard delay or gradual release to change is barbii active connections/connections. The formulation for oral administration can consist of solution was injected active ingredient in water or fruit juice, if needed, including appropriate soljubilizatory or emulsifiers.

In one experiment formulations for oral administration of a 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid described in the patent publication U.S. No. US 2004-0077677 A1 (also in patent publication U.S. No. 10/663506). Such formulations for oral administration include granulation using the technology of wet granulation.

In some cases it may be desirable introduction connections directly through the respiratory tract in the form of an aerosol.

The compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free base or pharmaceutically acceptable salts can be prepared in water, respectively, mixed with a surface-active substance, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, mixtures of the oils. These preparations contain a preservative to prevent the growth of microorganisms under normal conditions of storage and use

Pharmaceutical forms for injection include sterile aqueous solutions or dispersions, as well as strelnieki for extemporanea preparation of sterile solutions or dispersions for injection. In all cases the form must be sterile and must be fluid to the extent acceptable for injection through a syringe. It must be stable under the conditions of preparation and storage and resistant to the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, vysokodetalnye alcohols (e.g. glycerol, propylene glycol and liquid polyethylene glycol), and their respective mixtures and vegetable oil.

In one experiment injectable formulations for 42-ester of rapamycin with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid described in the patent publication U.S. No. US 2004-0167152 A1 (also in patent publication U.S. No. 10/626943).

Parenteral formulations used in this invention can be used to produce the dosage forms, which are appropriate for drug injection direct injection, or adding a drug to a sterile infusion fluids for intravenous administration.

Assume that transdermal introduction includes all methods of administration of the drug through the body surface and the inner lining pathways, including epithelial tissue and tissue of the mucous membranes. Such injection can be carried out using these compounds or their pharmaceutically receiving the salts utilized in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

Transdermal administration can be accomplished by using a transdermal patch containing the active compound and a carrier that is inert to the active component, is non-toxic to the skin and allows the delivery agent for somatic absorption into the bloodstream through the skin. The media can be, for example, in the form of creams and ointments, pastes, gels and occlusive devices. Creams and ointments can be viscous liquids or semisolid emulsions of the type oil-in-water" or "water in oil". Can also apply paste containing absorptive powders dispersed in petroleum or hydrophilic petroleumderived active ingredients. To release the active ingredient into the bloodstream can be used a variety of occlusive devices, such as a semi-permeable membrane covering a reservoir containing the active ingredient with the carrier or without it, or a matrix containing the active ingredient. Other known occlusive devices described in the literature.

Suppozitornoj recipes can be obtained from traditional substances, including cocoa butter, with or without the addition of waxes to change the melting point of suppositories, as well as glycerine. is also can be used water-soluble bases suppositories, such as polyethylene glycols of various molecular weights.

Moreover, this invention is a packaging & sets containing regiospecificity 42-derivatives of rapamycin, obtained in accordance with this invention and made according to the recipe for the introduction of the appropriate method. In one experiment regiospecificity 42-derivatives of rapamycin is provided for use in disposable dosage form. Various appropriate containers, including bottles, bubbles, transparent packaging or similar packaging known in this field. Such packaging and kits can contain other components, including, for example, instructions for use, syringes, instruments for introduction into the cavity remedies, etc.

The following examples illustrate how the methods of this invention regiospecifically production of derivative 42-ester of rapamycin. As shown in the following examples, lipase Candida antarctica is particularly well suited for its ability to catalyze the transesterification of rapamycin in his 42-ACI-derivatives using vinyl acetate as acyl donor. However, as stated above, the invention is not limited to only this type of lipase, therefore, can be used and other relevant lipase of microbial origin. For example, in the use of the implement lipase PS Pseudomonas cepacia and its immobilized form lipase PS-C "Amano" II, Lipase PS-D - reaction conditions can include a higher temperature with a large number of enzyme. For example, in one experiment using immobilized lipase PS-C, requires twice the amount of the lipase (i.e. to achieve conversion speed lipase Novozym 435 at room temperature is required to take 200% of the lipase by weight of rapamycin; alternatively, the temperature may be increased up to 45C, using a smaller amount of enzyme (100% by weight of rapamycin)).

EXAMPLES

The following examples illustrate the method of this invention using vinyl ether (examples 1-8), isopropanolamine ester (example 9) or anhydride (examples 10-12).

In one experiment, a mixture of rapamycin (20 mg, of 0.022 mmol), vinyl ether (50 ml) and lipase NOVOZYM 435 (20 mg) in TBME (0.5 ml) was stirred at room temperature (kg) or at 45C in the presence of N2until then, until all of the source materials were not spent, which was controlled by TLC. The enzyme was filtered and washed TBME. Mixed organic solvent evaporated under reduced pressure. The residue was purified using chromatographic silikagelevye column, elwira a mixture of hexane-acetone (volume ratio 2:1) and recrystallized from hexane-acetone. Additional examples are illustrated in nizhepredstavlennye hemah.

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

According to this invention derived 42-ester of rapamycin was obtained using anhydrides as acyl donor, as follows.

A mixture of rapamycin (20 mg, of 0.022 mmol), anhydride (30 mg) and lipase NOVOZYM 435 (20 mg) in TBME (0.5 ml) was stirred at room temperature for 48 h (in the presence of N2without access of light. [In the case of acetic anhydride or propionic anhydride after 48 h was added another portion of the lipase NOVOZYM 435 (20 mg) and TBME (0.1 ml)and the mixture was stirred an additional 48 h to complete the reaction]. The solvent was then removed by washing with gaseous nitrogen (N2). The residue was purified using chromatographic silikagelevye column, elwira a mixture of hexene-acetone (volume ratio 2:1) and recrystallized from hexane-acetone. The product was isolated as a white solid.

Example 10

Example 11

Primer

This invention is not limited to the framework described here is specific reactions. Undoubtedly, various modifications of the invention, in addition to the described herein will become apparent to the person skilled in the art from the above description, accompanied by drawings. It is implied that such modifications shall be performed in the framework of the attached claims.

In addition, it is clear that the values are approximate and are provided for description.

The patents, patent publications, articles, methods, and other similar documents cited in this document, the descriptions of which are presented here have links to their full version. Given that in this opening can be contradictions between the technical condition and are presented here document language style of this invention were subjected to the test.

1. The way regiospecifically obtain derivatives 42-ester of rapamycin with formula (I)

where R is isopropylidene, ketal protected 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched alkyl, C1-C10which may contain halogen, alkenyl
C2-C8or phenyl, with the specified method comprises the acylation 42-hydroxydopamine the acyl donor in the presence of lipase.

2. The method according to claim 1, characterized in that the lipase is a microbial lipase derived from of microorganisms such as Aspergillus niger, Candida antarctica, Candida rugosa, Mucor miehei, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar.

3. The method according to claim 2, in which the use of lipase type b, is obtained from Candida antarctica (lipase NOVOZYM 435) or Pseudomonas cepacia (lipase PS-C "Amano" II).

4. The method according to any one of claims 1 to 3, in which the acyl donor is a vinyl ether, isopropanolamine ester or anhydride.

5. The method according to claim 4, in which the vinyl ether has the formula CH2=CH-O-COR1where
R1selected from the group consisting of alkyl With1-C6alkenyl2-C6and phenyl.

6. The method according to claim 5, in which a vinyl ether selected from the group consisting of vinyl acetate, finalproject, vinylchloride, vinylketones, vinylbenzoate and viridicata.

7. The method according to claim 4, in which the vinyl ether is isopropylidene-protected vinyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropionate.

8. The method according to claim 4, in which isopropanolamine ether has the formula CH2=C(CH3)-OCOR2where R2selected from the group consisting of alkyl, C1-C6by choosing substituted with halogen, alkenyl2-C6or phenyl.

9. The method of claim 8, where isopropanolamine ether is isopropenylacetate.

10. The method according to claim 4, and in which the hydride is alkanoyl anhydride C 1-C8with a straight or branched chain.

11. The method according to any one of claims 1 to 10, in which the reaction is carried out in an organic solvent selected from the group of solvents consisting of toluene, tert-butyl methyl ether (TBME), ethyl ether, tetrahydrofuran (THF), MeCN, CH2Cl2, CHCl3, hexane, dioxane or mixtures thereof.

12. The method according to any one of claims 1 to 11, in which the reaction is carried out in the temperature range of 20-75C.

13. Regiospecifically preparation of 42-ester of rapamycin with isopropylidene ketal protected 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.



 

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