MXPA96004694A - Hydroxysteres of rapamycin, process for supreparation and pharmaceutical compositions that loscontie - Google Patents

Abstract

The present invention relates to a compound of structure I wherein R1 and R2 are each, independently, hydrogen-CO (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl or -F; R5 and R6 are each independently, hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) fOR10, -CF3, -Fo-CO2R11, or R5 and R6 can be taken together to form X or a ring cycloalkyl which is optionally mono-, di-substituted with - (CR3R4) fOR10; R7 is hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) fOR10, -CF3, -F, or -CO2R11; R8 and R9 are each one independently, hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) fOR10, -CF3, -Fo-CO2R11, or R8 and R9 can be taken together to form X or a cycloalkyl ring which is optionally mono-, di-substituted or with - (CR3R4) fOR10; R10 is hydrogen, alkyl, alkenyl, alkynyl, tri- (alkyl) silyl, tri- (alkyl) silylethyl, triphenylmethyl , benzyl, alkoxymethyl, tri- (alkyl) silylethoxymethyl, chloroethyl or tetrahydropyranyl; R11 is hydrogen, alkyl, alkenyl or phenylalkyl; X is 5- (2,2-dialkyl) [1,3] dioxanyl, 5- (2-spiro) -cycloalkyl) - [1,3] dioxanyl, 4- (2,2-dialkyl) [1,3] dioxanyl, 4- (2-spiro-cycloalkyl) [1,3] dioxanyl, 4- (2,2- dialkyl) - [1,3] -dioxalanylo4- (2-spiro-cycloalkyl) [1,3] dioxalanyl; 4- (2,2-dialkyl) - [1,3] -dioxalanyl or 4- (2-spiro-cycloalkyl) [1,3] dioxalanil, b = O-6, b = O-6, d = O-6, and f = 0-6, with the proviso that R1 and R2 are not both hydrogen, and with the condition in addition to that R1 or R2 contains at least one cycloalkyl group substituted with - (CR3R4) fOR10, X, or- (CR3R4) fOR10, or a pharmaceutically acceptable salt thereof, which is useful as an immunosuppressant, anti-inflammatory, antifungal, antiproliferative and antitumor agent

Description

HYDROXYSTERES OF RAPAMICINA. PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM BACKGROUND OF THE INVENTION This invention relates to the hydroxyesters of rapamycin and to a method for use for the induction of immunosuppression, and in the treatment of transplant rejection, graft versus host disease, autoimmune diseases - inflammatory diseases, adult T-cell leukemia-lymphoid, solid tumors, fungal infections, and hyperproliferative vascular disorders. Rapamycin is a macrocyclic trienic antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, either in vitro and in vivo [C. Vezina et al .; J. Antibiot 28,721 (1975); S.N. "Sehgal et al J. Antibiot 28,727 (1975), HA Baker et al J. Antibiot 31,539 (1978), US Patent No. 3,929,992; and US Patent No. 3,993,749], Rapamycin alone (US Patent No. 4,885,171) or in combination with picibanil (US Patent No. 4,401,653) has been shown to have REF: 23271 antitumor activity, R. Martel et al. [Can J. Physiol Pharmacol 55.48 (1977)] reported that rapamycin is effective in the experimental model of allergic encephalomyelitis, a model for multiple sclerosis, in the model of adjuvant arthritis, a model for rheumatoid arthritis, and effectively inhibited the formation of IgE-like antibodies.The immunosuppressive effects of rapamycin have been described in FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, have also been shown to be effective as immunosuppressive agents, therefore useful in the prevention of 'rejection of the transplant [FASEB 3, 3411 (1989) FASEB 3, 5256 (1989); R. and Calne et al. Lancet 1183 (1978); and US Patent No. 5, 100,899]. Rapamycin has also been shown to be useful in the prevention or treatment of systemic lupus erythematosus [U.S. Patent No. 5,078,999], pulmonary inflammation [U.S. Patent No. 5, 080, 899], insulin-dependent diabetes mellitus [Fifth Int. Conf. Inflamm. Res. Assoc. 121 (abstract), (1990)], smooth muscle cell proliferation and intimal thickening after vascular damage [Morris, RJ Heart Lung Transplant 11 (pt.2): 197 (1992)], leukemia / Unino cell Adult T [European Patent Application No. 525,960 A1], and eye inflammation [European Patent Application No. 532,862 A1]. The mono- and diacylated derivatives of rapamycin (esterified at positions 28 and 43) have also been shown to be useful as antifungal agents (U.S. Patent No. 4,316,885) and used to prepare aminoacylated prodrugs of water-soluble rapamycin (U.S. Patent No. 4,650,803). Recently, the numbering convention for rapamycin has been changed; therefore, according to the CHEMICAL ABSTRACTS nomenclature, the steres described above could be in positions 31 and 42.

DESCRIPTION OF THE INVENTION This invention provides rapamycin derivatives which are useful as immunosuppressive, anti-inflammatory, antifungal, antiproliferative and antitumor agents having the structure 1 2 wherein R and R are each, independently, hydrogen or -C0 (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -CO ^ 11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R) ^ 0R, -CF ", -F, or -002RU; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F, or -CO-jR11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or trisubstituted with - (CR3R4) f0R10; R 'is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms »alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl) from 1 to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] -dioxanil, 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] dioxalanil, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxalanil, b = 0-6, d = 0-6, and f-0-6 with the proviso that R 1 and R2 are not both hydrogen, and with the additional proviso that either R or R contains at least one group - (CR R) f0R, X, or - (CR R) f0R substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts are those derived from inorganic cations such as sodium, potassium and the like; and organic bases such as: mono-, di- and tri-alkylamines of 1 to 6 carbon atoms, per alkyl group and mono-, di- and tri-hydroxyalkylamines of 1 to 6 carbon atoms per alkyl group, and Similar. The terms "alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, and alkynyl of 2 to 7 carbon atoms, include straight chain as well as branched chain carbon chains. Since the compounds of this invention may contain more than one group - (CR R) f 0 R, R, R, f and R may be the same or different. Similarly, when other descriptions of generic substituents are repeated in the same structure, they may be the same or different. For a compound in which R contains R 9 and R taken together to form X, where X is - (2, 2-di- (C 1-6 alkyl)) [1,3] -dioxanil, the alkyl group of X contains 1 carbon atom, and d = 0, R could have the following structure.

Similarly, for a compound in which R 1 contains R8 and R9 taken together to form X, where X is 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1.3 Idioxanil, the group X-alkyl-cycle contains 6 carbon atoms, and d = 0, could have the following structure.

For compounds containing X, preferred compounds include those in which the alkyl group of X, if present, is methyl and the cycloalkyl group of X, if present, is cyclohexyl. Where R is not hydrogen, alkyl, alkenyl, or alkynyl, it is intended that R is a group that can serve as an alcohol protecting group. In this way, these groups are intermediates of the free hydroxylated compounds, as well as being biologically active by themselves. R covers tri- (C 1 -C 6 alkyl) silyl, tri- (C 1 -C 6 alkyl) silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (1 to 6 alkyl) 6 carbon atoms) silylethoxymethyl, chloroethyl and tetrahydropyranyl. Other alcohol protecting groups are known to those skilled in the art, and are also considered part of this invention. Of the compounds of this invention the preferred members are those in which R is 2 hydrogen; b = 0, and d = 0; those in which R is hydrogen, b = 0, d = 0, and R 8 and R 9 are each, independently hydrogen, alkyl or - (CR R) f 0 R, or are taken together to form X. The compounds of this invention having the ester group -C0 (CR3R4) b (CR5R6) dCR7R8R9 at positions 42- or 31.42 can be prepared by acylation of rapamycin using the protected hydroxy- and polyhydroxy acids, the alkoxy- or polyalkoxy acids. carboxyelines that have been activated, followed by removal of the alcohol protective groups, if desired. Various methods for carboxylate activation are known in the art, but preferred methods use carbodiimides, mixed anhydrides or acid chlorides. For example, an appropriately substituted carboxylic acid can be activated as a mixed anhydride, with an acylating group such as 2-, 6-trichlorobenzoyl chloride. The treatment of rapamycin with the mixed anhydride under slightly alkaline conditions provides the desired compounds. Alternatively, the acylation reaction can be achieved with l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and dimethylaminopyridine. Mixtures of 42- and 31,42-esters can be separated by chromatography. Accordingly, the invention also provides a process for the preparation of the rapamycin compounds of this invention. In particular this invention provides a process for the preparation of rapamycin hydroxyesters, including those of the formula I as defined above, which comprises: a) the acylation of rapamycin or a functional derivative or analogue thereof, with an agent of acylation; b) the sequential acylation of rapamycin or a functional derivative or analogue thereof with two acylation agents; said acylating agents are selected from the acids of the formula H0-C0 (CR3R4) b (CR5R6) d CR7R8R9 (II) or a reactive derivative thereof wherein R 3 -R 9, b and d are as defined above, with the proviso that free hydroxyl groups are protected, if desired protecting the 42 position of rapamycin or the functional derivative with a group appropriate protector, and then the reaction that removes any protective groups present, as required. The reaction can be carried out in the presence of a coupling reagent, such as a coupling reagent suitably substituted with carbo-diimide. The above-mentioned compounds of this invention can also be prepared by acylation using reactive derivatives of the acid of the formula II such as an anhydride, a mixed anhydride, or an acid halide such as the chloride. The 31-ester-42-hydroxyl compounds of this invention can be prepared by protecting the 42-alcohol of rapamycin with a protecting group, such as with a tert-butyl-dimethylsilyl group, followed by esterification of the 31-position by the procedures described above. The preparation of the 42-silyl ethers of rapamycin is described in US Pat. No. Bl 5,120,842, which is incorporated by reference herein. Removal of the protecting group provides the 31-esterified compounds. In the case of the tert-butyl-dimethylsilyl protecting group, the deprotection can be achieved under mildly acidic conditions, such as acetic acid / water / tetrahydrofuran. The deprotection process is described in Example 15 of U.S. Patent No. 5,118,678, which is incorporated by reference herein. Having the position 31 esterified and the position 42 deprotected, the position 42 can be esterified using a different acylating agent that was reacted with the 31-alcohol, to give the compounds having different esters at the 31 and 42 positions. Alternatively, 42-esterified compounds, prepared as described above, can be reacted with a different acylating agent to provide compounds having different esters at positions 31 and 42. This invention also covers the analogous hydroxy esters of other rapamycins, such as , but not limited to 29-demethoxyrapamycin [U.S. Patent No. 4,375,464, 32-demethoxyrapamycin under the Chemical Abstracts nomenclature]; rapamycin derivatives in which double bonds at positions 1-, 3-, and / or 5 have been reduced [US Patent No. 5,023,262]; 29-demethylrrapamycin [U.S. Patent No. 5,093,339, 32-demethyl-rapamycin under the Chemical Abstracts nomenclature]; 7, 29-bisdesmethylrapamycin [U.S. Patent No. 5,093,338, 7, 32-desmethylrrapamycin under the Chemical Abstracts nomenclature]; and 15-hydroxyrapamicin [U.S. Patent No. 5,102,876]. The descriptions in the aforementioned US Patents are incorporated by reference herein. The immunosuppressive activity for the representative compounds of this invention was evaluated in a standard pharmacological test procedure, in vitro, to measure the inhibition of lymphocyte proliferation (LAF) and in two standard pharmacological test procedures, in vivo. The narrow skin graft test procedure measures the immunosuppressive activity of the tested compound, as well as the ability of the compound tested to inhibit or treat the rejection of the transplant. The standard adjuvant arthritis pharmacological test procedure, which measures the compound's ability to inhibit immune-mediated inflammation. The adjuvant arthritis test procedure is a standard pharmacological test procedure, for rheumatoid arthritis. The procedures for these standard pharmacological test procedures are provided below. The procedure of proliferation of thymocyte-induced comitogen (LAF) was used as an in vitro measure of the immunosuppressive effects of the representative compounds. Briefly, cells from the thymus of normal BALB / c mice were cultured for 72 hours with PHA and IL-1, and pulsed with tritiated thymidine for the last six hours. The cells were cultured with or without varying concentrations of rapamycin, cyclosporin A, or the test compound. The cells are harvested and the incorporated radioactivity is determined. Inhibition of lymphoproliferation is evaluated as the percentage change in counts per minute from controls not treated with the drug. For each compound evaluated, rapamycin was also evaluated for comparison purposes. An IC-j was obtained for each test compound, as well as for rapamycin. When evaluated as a comparator for the representative compounds of this invention, rapamycin had an IC, -n in the range of 0.6-1.5 nM. The results obtained are given as an IC_.Q and as the percentage inhibition of the proliferation of T cells at 0.1 μM. The results obtained for the representative compounds of this invention were also expressed as a ratio compared to rapamycin. A positive proportion indicates immunosuppressive activity. A ratio of more than 1 indicates that the test compound inhibited the proliferation of thymocytes to a greater degree than rapamycin. The calculation of the proportion is shown below.

IC- .. of Rapamycin IC -., - of the Test Compound The representative compounds of this invention were also evaluated in an in vivo test procedure designed to determine the survival time of the narrow skin graft from male BALB / c donors transplanted into male C "H (H-2K) vessels. The method is adapted from Billingham R. E. and Medawar P. B., J. Exp. Biol. 28: 385-402, (1951). Briefly, a narrow skin graft from the donor was grafted onto the back of the recipient as an allograft, and an isograft was used as a control in the same region. The containers were treated with varying concentrations of the test compounds either intraperitoneally or orally. Rapamycin was used as a test control. Untreated containers serve as rejection control. The graft was checked periodically on a daily basis and the observations were recorded until the graft became dry and a blackened scab formed. This was considered as the day of rejection. The mean survival time of the graft (number of days ± standard deviation) of the drug treatment group was compared with the control group. The following table shows the results that were obtained. The results are expressed as the average survival time in days. Untreated (control) narrowed or pinched skin grafts are usually rejected within 6 to 7 days. The compounds were tested using a dose of 4 mg / kg. The standard adjuvant arthritis pharmacological test procedure measures the ability of test compounds to prevent immunologically mediated inflammation, and to inhibit or treat rheumatoid arthritis. The following briefly describes the test procedure used. A group of rats (consanguineous male Wistar Lewis rats) are pretreated with the compound to be tested (1 hour before the antigen) and then injected with Freund's Complete Adjuvant (FCA) in the right hind paw to induce arthritis. The rats are then orally administered in a scheme of Monday, Wednesday, Friday from day 0-14 for a total of 7 doses. Both hind legs are measured on days 16, 23 and 30. The difference in paw volume (ml) from day 16 to day 0 is determined, and a percentage change is obtained from the control. Inflammation in the left hind paw (non-injected paw) is caused by inflammation mediated by T cells and is recorded in the previous table (percentage change from the control). Inflammation in the right hind paw, on the other hand, is caused by non-specific inflammation. The compounds were tested at a dose of 5 mg / kg. The results are expressed as the percentage change in the paw not injected on day 16 versus the control; The more negative the percentage change, the more powerful the compound. Rapamycin provided a change between -70% and -90% versus control, indicating that the rats treated with rapamycin had between 70-90% less immunologically induced inflammation, than the control rats. The results obtained in these standard pharmacological test procedures are provided following the procedure for the elaboration of the specific compounds that were tested. The results of these standard pharmacological test procedures demonstrate the immunosuppressive activity in vitro and in vivo for the compounds of this invention. The results obtained in the LAF test procedure indicate the suppression of T cell proliferation, thereby demonstrating the immunosuppressive activity of the compounds of this invention. Further demonstration of the utility of the compounds of this invention as suppressive agents was shown by the results obtained in the standard pharmacological test procedures of skin grafting and arthritis by adjuvant. In addition, the results obtained in the skin graft test procedure further demonstrate the ability of the compounds of this invention to treat or inhibit rejection to transplantation. The results obtained in the standard pharmacological test procedure for arthritis by adjuvant, further demonstrates the ability of the compounds of this invention to treat or inhibit rheumatoid arthritis. Based on the results of these standard pharmacological test procedures, the compounds are useful in the treatment or inhibition of transplant rejection such as allografts of kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea. , small intestine and skin, and heart valve xenografts; in the treatment or inhibition of autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and inflammation diseases such as psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease, lung inflammation (including asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis and the like), and ophthalmic uveitis. Due to the profile of activity obtained, the compounds of this invention are also considered as possessing antitumor and anti-fungal activities, and antiproliferative activities. The compounds of this invention are therefore also useful in the treatment of solid tumors, leukemia, adult T-cell lymphoma, fungal infections, and hyperproliferative vascular diseases such as restenosis and atherosclerosis. When used for restenosis, it is preferred that the compounds of this invention be used to treat restenosis that occurs after an angioplasty procedure. When used for this purpose, the compounds of this invention may be administered prior to the procedure, during the procedure, subsequent to the procedure or any combination of the foregoing. When administered for the treatment or inhibition of the above disease states, the compounds of this invention can be administered to a mammal orally, parenterally, intranasally, intrabronchially, transdermally, topically, intravaginally or rectally. It is contemplated that when the compounds of this invention are used as an immunosuppressant or anti-inflammatory agent, they may be administered in conjunction with one or more other immunoregulatory agents. Such immunoregulatory agents include, but are not limited to, azathioprine, corticosteroids, such as prednisone and methylprednisolone, cyclophosphamide, rapamycin, cyclosporin A, FK-506, 0KT-3, and ATG. By combining the compounds of this invention with other drugs or agents for the induction of immunosuppression or treatment of inflammatory conditions, smaller amounts of each of the agents are required to achieve the desired effect. The basis for such combination therapy was established by Stepkowski, whose results showed that the use of a combination of rapamycin and cyclosporin A at subtherapeutic doses significantly prolonged the survival time of the cardiac allograft. [Transplantation Proc. 23: 507 (1991)]. The compounds of this invention can be formulated pure or with a pharmaceutical carrier, to a mammal in need thereof. The pharmaceutical carrier can be solid or liquid. When formulated orally, it has been found that 0.01% Tween 80 in PHOSAL PG-50 (phospholipid concentrate with 1,2-propylene glycol, A. Nattermann &Cié. GmbH) provides an acceptable oral formulation. A solid carrier may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending, fillers, glidants, compression aids, binders or tablet disintegrating agents; this can also be a material of encapsulation. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in the proper proportions, and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins. . Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which partially contains additives such as the above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example , glycols) and their derivatives, and oils (for example fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.

The liquid carrier for the pressurized compositions may be halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions that are sterile solutions or suspensions may be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds can also be administered orally either in the form of a liquid or solid composition. The compounds of this invention can also be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, and is non-toxic to the skin, and allows the distribution of the agent for the Isthmic absorption into the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occluder devices. The creams and ointments can be liquid or semisolid and viscous emulsions, either oil-in-water or water-in-oil. Pastes comprised of absorbent powders dispersed in petroleum or hydrophilic petroleum, containing the active ingredient, may also be suitable. A variety of occluder devices can be used to release the active ingredient into the blood stream, such as a semi-permeable membrane that covers a reservoir containing the active ingredient with or without a carrier, a matrix containing the active ingredient. Other occluder devices are known in the literature. In addition, the compounds of this invention can be employed as a solution, cream, or lotion by formulation with pharmaceutically acceptable carriers containing 0.1-5%, preferably 2%, of the active compound, which can be administered to a mycotic affected area. The dosage requirements vary with the particular compositions employed, with the route of administration, the severity of the present symptoms and the particular subject to be treated. Based on the results obtained in the standard pharmacological test procedures, the projected daily doses of the test compound could be 0.1 μg / kg - 100 mg / kg, preferably between 0.001 - 25 mg / kg, and more preferably between 0.001 - 5 mg / kg. The treatment will generally be initiated with small doses smaller than the optimum dose of the compound. After this, the dose is increased until the optimum effect is reached under the circumstances; The precise doses for oral, parenteral, nasal or intrabronchial administration will be determined by the doctor who administers it, based on the experience with the individual subject treated. Preferably, the pharmaceutical composition is a unit dose form, for example, as tablets or capsules. In such form, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sacks containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or this may be the appropriate number of any such compositions in packaged form.

The following examples illustrate the preparation and biological activities of the representative compounds of this invention.

Example 1 42-rapamycin ester with (tetrahydropyran-2-yloxy) acetic acid 2, 4, 6-trichlorobenzoyl chloride was added (0.55 ml, 3.51 mmol) by means of a syringe to a THP ether solution of glycolic acid (0.562 g), 3.51 mmoi) and triethylamine (0.49 ml, 3.51 mmol) in 10 ml of tetrahydrofuran at 0 ° C under nitrogen atmosphere. The mixture was stirred for 4 hours at room temperature, and a white precipitate formed. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 10 ml of benzene, then rapamycin (2.92 g, 3.19 mmol) and DMAP (0.429 g, 3.51 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with cold 1N hydrochloric acid (aqueous), saturated sodium acid carbonate (aqueous) and brine, dried over magnesium sulfate, filtered and concentrated to an oily yellow solid. . Flash chromatography (2X with 65% ethyl acetate-hexane) gave the title compound (1114 g, 33%) as a white solid.

(-) FAB-MS m / z 1055.5 (M-), 590.3 (southern fragment), 463.2 (northern fragment). 1 H NMR (400 MHz, d-6 DMSO) delta 4.60 (m, 1 H, C (42) H), 4.66 (m, 1 H), 4.14 (s, 2 H), 3.73 (m, 1 H) 3.42 (m, 1 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 169.2, 97.4, 63.5, 61.2, 29.7, 24.8, 18.8.

Example 2 42-rapamycin ester with hydroxyacetic acid P-Toluenesulfonic acid (10 mg) was added to a solution of the product of Example 1 (306 mg, 0.29 mmol) in 10 ml of methanol at 0 ° C. The solution was stirred 2 hours at room temperature, then quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to a white solid. Purification by flash chromatography (2 times with ethyl acetate) gave the title compound (145 mg, 51%) as a white solid.

(-) FAB-MS m / z 971.3 (M ~), 590 (southern fragment), 379.1 (northern fragment). 1 K NMR (400 MHz, d-6 DMSO) delta 4.60 (m, 1 H, C (42) H, 3.98 (s, 2 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 172.1, 59.7. Results obtained in the standard pharmacological test procedures: LAF IC5Q: 1.80 nM LAF ratio: 0.83 Percentage caries in arthritis per adjuvant versus control: -88% Example 3 42-Rapamycin ester with 2, 2-dimethyl-3- (tetrahydropyran-2-yloxy) propionic acid To a THP ether solution of 2,2-dimethyl-3-hydroxypropionic acid (0.319 g, 1.58 mmol) and triethylamine (0.22 mL, 1.58 mmol) in 5 mL of anhydrous tetrahydrofuran at 0 ° C under nitrogen atmosphere was added dropwise 2-4,6-trichlorobenzoyl chloride (0.25 ml, 1.58 mmol) by syringe. The mixture was stirred 4.5 hours at room temperature. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 5 ml of benzene, then rapamycin (1.31 g, 1.43 mmol) and DMAP (0.193 g, 1.58 mmol) were added. The mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with 1 N hydrochloric acid (aqueous), saturated sodium hydrogen carbonate (aqueous), water and brine, dried over magnesium sulfate, filtered and concentrated to a yellow oily solid. Flash chromatography (IX with 60% ethyl acetate-hexane, IX with 55% ethyl acetate-hexane) gave the title compound (0.356 g, 23%) as a white solid.

(-) FAB-MS m / z 1097.7 (M ~), 590.4 (southern fragment), 505.3 (northern fragment). 1 H NMR (400 MHz, d-6 DMSO) delta 4.55 (m, 1 H, C (42) H), 4. 55 (m, 1 H), 3.69 (m, 1 H), 3.60 (m, 2 H), 3.42 (m, 1 H), 1.13 (s, 3 H), 1.11 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 175.0, 98.0, 73.8, 60. 7, 42.6, 30.0, 24.9, 22.0, 21.6, 18.7 Results obtained in the standard pharmacological test procedures: LAF IC Q: 7.10 nM LAF Ratio: 0.34 Example 4 42-Rapamycin ester with 3-hydroxy-2,2-dimethylpropionic acid It was added. p-toluenesulfonic acid (10 mg) to a solution of the product of Example 3 (250 mg, 0.23 mmol) in 10 ml of methanol at 0 ° C. The solution was stirred 2 hours at room temperature, then quenched with saturated sodium hydrogen carbonate solution. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to a white solid. Purification by flash chromatography (2X with 75% ethyl acetate-hexane) gave the title compound (103 mg, 45%) as a white solid.

(-) FAB-MS m / z 1013.3 (M "), 590.2 (southern fragment), 421.1 (northern fragment).

NMR XH (400 MHz, d-6 DMSO) delta 4.48 (m, 1 H, C (42) H), 3.39 (d, 2 H), 1.06 (s, 6 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 175.5, 68.0, 44.1, 21.7.

Results obtained in standard pharmacological test procedures: LAF IC: 0.80 nM LAF Ratio: 1.25 Skin graft survival time: 10.7 ± 0. 5 days .

Examples 5 and 6 42-rapamycin ester with 2,2-dimethyl [1,3] -dioxalan-4-carboxylic acid (Example 5) 31, 2-diester of rapamycin with 2,2-dimethyl [1, 3] -dioxalan-4 acid carboxylic acid (Example 6) 2, 4, 6-trichlorobenzoyl chloride was added (0.56 ml, 3.61 mmol) by means of a syringe to a solution of the isopropylidene ketal of 2,3-dihydroxypropionic acid (0.527 g, 3.61 mmol) and triethylamine (0.50 ml, 3.61 mmol) in 10 ml of tetrahydrofuran at 0 °. C under nitrogen atmosphere. The mixture was stirred 4 hours at room temperature. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 15 ml of benzene and rapamycin (3.00 g, 3.28 mmol) was added, then DMAP (0.441 g, 3.61 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with cold 1N hydrochloric acid (aqueous), saturated sodium acid carbonate (aqueous) and brine, dried over magnesium sulfate, filtered and concentrated to a yellow foam. Flash chromatography on silica gel (gradient elution: 50-60-75-100% ethyl acetate-hexane, 4X with 65% ethyl acetate-hexane) provided the title compounds. The less polar 31, 2-diester (0.415 g) eluted first, and the more polar 42-monoester (0.601 g, 16%) eluted in second place, and were then isolated as white solids.

Example 5 (-) FAB-MS m / z 1041.4 (M ~), 590.3 (southern fragment), 449. 2 (northern fragment). 1 H NMR (400 MHz, d-6 DMSO) delta 4.6 (m, 1 H, C (42) H), 4. 6 (m, 1 H), 4.20 (dd, 1 H), 3.96 (m, 1 H), 1.36 (s, 3 H), 1.30 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 170.5, 110.2, 73.4, 66.6, 25.7, 25.4.

E emplo 6 (-) FAB-MS m / z 1169.6 (M ~). 1 H NMR (400 MHz, d-6, DMSO) delta 5.3 (m, 1 H; C (31) H), 4.6 (m, 1 H, C (42) H), 4.6 (m, 2H), 4.19 (t, 1H), 4.13 (t, 1H), 3.9 (m, 2 H), 1.36 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.28 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 170.5, 169.2, 110.3, 110.2, 73.4, 66.6, 66.5, 25.8, 25.7, 25.4, 25.1, 25.1.

Results obtained in standard pharmacological test procedures: Example 5 LAF IC5Q: 1.20 nM LAF Ratio: 0.74 Example 6 LAF IC5Q: 1.30 nM LAF Ratio: 0.5 Example 7 42-Rapamycin ester with 2,3-dihydroxypropionic acid A solution of the product of Example 5 (351 mg, 0.34 mmol) in 10 ml of tetrahydrofuran and 10 ml of 1 N hydrochloric acid was stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to an oil. Flash chromatography (IX with ethyl acetate, IX 'with 10% methanol-methylene chloride, IX with 5% methanol-ethyl acetate) afforded the title compound (78 mg, 23%) as a white solid.

(-) FAB-MS m / z 1001.2 (M ~), 590.2 (southern fragment), 409.1 (northern fragment). NMR XH (400 MHz, d-6 DMSO) delta 4.5 (m, 1 H, C (42) H), 3.60 (m, 1 H), 3.45 (m, 2 H).

Results obtained in standard pharmacological test procedures: LAF IC5Q: 1.4 nM LAF Ratio: 0.40 Example 8 42-Rapamycin ester with 2, 2-dimethyl [1, 3] dioxan-5-carboxylic acid 2-, 4,6-Trichlorobenzoyl chloride (0.98 ml, 6.27 mmol) was added via syringe to a solution of 2- (hydroxy-methyl) -3-hydroxypropionic acid isopropylidene-ketal (1,000 g, 6.24 mmmol) and triethylamine (0.90 ml, 6.46 mmol) in 20 ml of tetrahydrofuran at 0 ° C under nitrogen atmosphere. The mixture was stirred for 4 hours at room temperature, and a white precipitate formed. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 20 ml of benzene, then rapamycin (5.70 g, 6.24 mmol) and DMAP (0.762 g, 6.24 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Flash chromatography (75% ethyl acetate-hexane) gave the title compound (4.17 g, 63%) as a white solid.

(-) FAB-MS m / z 1055.8 (M), 590.5 (southern fragment), 463.4 (northern fragment). 1 H-NMR (400 MHz, d-6 DMSO) delta 4.55 (m, 1 H, C (42) H), 3. 95 (m, 4 H), 1.30 (s, 6 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 170.1, 97.4, 59.5, 24. 8, 22.5.

Results obtained in standard pharmacological test procedures: LAF IC5Q: 0.76 nM LAF Ratio: 0.45 Example 9 42-Rapamycin ester with 3-hydroxy-2-hydroxymethyl-propionic acid A solution of the product of Example 8 (3.30 g, 3.12 mmol) in 50 ml of tetrahydrofuran and 25 ml of 1 N hydrochloric acid was stirred 2 hours at room temperature. The solution was diluted with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3X). The combined organic phases were washed with saturated sodium chloride (aqueous), dried over magnesium sulfate, filtered and concentrated to a yellow foam Purification by flash chromatography (IX with ethyl acetate; 2X with 5%. of ethanol / ethyl acetate) gave the title compound (1.68 g, 53%) as a white solid.

(-) FAB-MS m / z 1015.5 (M), 590.3 (southern fragment), 423.3 (northern fragment). NMR! H (400 MHz, d-6 DMSO) delta 4.6 (broad s, 2 H), 4.55 (m, 1 H, C (42) H), 3.55 (m, 4 H), 2.57-2.53 (m, 1 HOUR). 13 C NMR (100.6 MHz, d-6 DMSO) delta 172.2, 59.3, 51.5, Results obtained in the standard pharmacological test procedures: LAF IC5Q: 0.84 nM LAF Ratio: 0.57 Example 10 42-Rapamycin ester with 2, 2, 5-trimethyl- [1, 3] dioxan-5-carboxylic acid To a solution of the isopropylidene ketal of 2,2-bis (hydroxymethyl) propionic acid (1.041 g, 5.98 mmol) (prepared according to the procedure of Bruice, J. Am. Chem. Soc. 89: 3568 (1967)) and triethylamine (0.83 ml, 5.98 mmol) in 20 ml of anhydrous tetrahydrofuran at 0 ° C under nitrogen atmosphere, 2, 4,6-trichlorobenzoyl chloride (0.93 ml, 5.98 mmol) was added and the resulting white suspension was stirred 5 hours at room temperature. The precipitate was removed by vacuum filtration, rinsing the flask and the filter press cake with an additional 10 ml of anhydrous tetrahydrofuran. The filtrate was concentrated by rotary evaporation to a white solid. The residue was dissolved in 20 ml of anhydrous benzene, then rapamycin (5.47 g, 5.98 mmol) and DMAP (0.731 g, 5.98 mmol) were added. After stirring overnight at room temperature, the mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride (aqueous), dried over magnesium sulfate, filtered and evaporated to a yellow solid. Flash chromatography (5X with 60% ethyl acetate-hexane) gave the title compound (2.2 g, 34%) as a white solid.

(-) FAB-MS m / z 1069.5 (M), 590.3 (southern fragment), 477.2 (northern fragment). NMR 1E (400 MHz, d-6 DMSO) delta 4.57 (m, 1 H, C (42) H), 4.02 (d, 2 H), 3.60 (d, 2 H), 1.34 (s, 3 H), 1.24 (s, 3 H), 1.06 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 173.2, 99.0, 65.0, 22.2, 18.1.

Results obtained in standard pharmacological test procedures: LAF IC5Q: 4.90 nM LAF Ratio: 0.41 Skin graft survival time: 11.0 ± 1. 3 days .

Example 11 42-Rapamycin ester with 2,2-bis- (hydroxymethyl) propionic acid A solution of the product from Example 10 (2.8 g, 2.65 mmol) in 50 ml of tetrahydrofuran and 25 ml of 1 N hydrochloric acid was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogen carbonate solution, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to a yellow oily solid. Purification by flash chromatography (3X with ethyl acetate) provided the title compound (1.6 g, 59%).

(-) FAB-MS m / z 1029.6 (M ~), 590.4 (southern fragment), 437.3 (northern fragment). NMR XH (400 MHz, d-6 DMSO) delta 4.5 (m, 1 H, C (42) H), 3.45 (s, 4 H), 1.04 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 174.2, 63.7, 63.6, 49.9, 16.8.

Results obtained in the standard pharmacological test procedures: LAF IC5Q: 0.80 and 1.80 nM LAF ratio: 1.00 and 0.44 Skin graft survival time: 11.4 ± 1. 5 and 12.0 ± 1.1 days. Percentage change in arthritis by adjuvant versus control: -88% Example 12 42-Rapamycin ester with 2,2-dimethyl-5- (2-trimethylsilylethylethoxymethyl) [1,3] -dioxan-5-carboxylic acid 2, 4,6-Trichlorobenzoyl chloride (0.14 ml, 0.86 mmol) was added via syringe to a solution of the isopropylidene ketal of 2,2-bis (hydroxymethyl) -2- (2-trimethylsilylethoxy) propionic acid ( 0.250 g, 0.86 mmol) and triethylamine (0.12 ml, 0.86 mmol) in 2 ml of tetrahydrofuran at 0 ° C under nitrogen atmosphere. The mixture was stirred for 4 hours at room temperature, and a white precipitate formed. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 2 ml of benzene, then rapamycin (0.786 g, 0.8.6 mmol) and DMAP (0.105 g, 0.86 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Flash chromatography (gradient elution: 40-60-80-100% ethyl acetate-hexane) provided the title compound (0.559 g, 54%) as a white solid (-) FAB-MS m / z 1185.2 (M), 590.1 (southern fragment), 593 (northern fragment). NMR 1E (400 MHz, d-6 DMSO) delta 4.55 (m, 1 H, C (42) H), 3. 73 (m, 4 H), 3.57 (s, 2 H), 3.43 (t, 2 H), 1.29 (s, 6 H), 0.79 (t, 2 H), -0.04 (s, 9 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 171.1, 97.7, 70.2, 68. 1, 61.3, 46.0, 24.6, 22.1, 14.6, -1.3.

Results obtained in the standard pharmacological test procedures: LA5 IC5¿: 7.20 nM LAF Ratio: 0.05 Examples 13 and 14 42-rapamycin ester with 3-methyl-l, 5-dioxa-spiro [5, 5] undecan-3-carboxylic acid (Example 13) 31, 42-diester of rapamycin with 3-methyl-l, 5- acid dioxa-spiro [5, 5] undecan-3-carboxylic (Example 14) 2, 4, 6-trichlorobenzoyl chloride was added (0.16 ml, 1.0 mmol) by means of a syringe to a solution of the cyclohexylidene ketal of 2,3-dihydro-xipropionic acid (0.214 g, 1.0 mmol) and triethylamine (0.14 ml, 1.0 mmol) in 2.5 ml of tetrahydrofuran a 0 ° C under nitrogen atmosphere. The mixture was stirred 4 hours at room temperature. The white precipitate was removed by vacuum filtration and the filtrate was concentrated with a stream of nitrogen and a hot water bath. The residue was dissolved in 3 ml of benzene and rapamycin (0.457 g, 0.5 mmol) was added, then DMAP (0.061 g, 0.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with cold 1N hydrochloric acid (aqueous), saturated sodium carbonate (aqueous) and brine, dried over magnesium sulfate, filtered and concentrated to a yellow foam. . Flash chromatography on silica gel (45-50% ethyl acetate-hexane) provided the title compounds. The 31, 2-diester (0.168 g, 26%) eluted first, and the more polar 42-monoester (0.301 g, 52%) eluted in second place, and the products were isolated as white solids.

Example 13 (-) FAB-MS m / z 1109.5 (M ~), 590.3 (southern fragment), 517.3 (northern fragment). H-NMR (400 MHz, d-6 DMSO) delta 4.55 (m, 1 H, C (42) H), 3.61 (t, 4 H), 1.04 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 173.3, 97.2, 64.2 Example 14 (-) FAB-MS m / z 1305.6 (M ~). 1 H NMR (400 MHz, d-6 DMSO) delta 5.25 (m, 1 H, C (31) H), 4.55 (m, 1 H, C (42) H), 3.64-3.54 (m, 8 H) , 1.05 (s, 3 H), 0.97 (s, 3 H). 13 C NMR (100.6 MHz, d-6 DMSO) delta 173.2, 172.1, 97.3, 97.2, 64.3, 64.2, 63.9.

Results obtained in standard pharmacological test procedures: Example 13 LAF IC5Q: 0.6 nM LAF Ratio: 2.00 Example 14 LAF: inhibited the proliferation of T cells by 43% at 0.1 μM.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (25)

1. A composite of the structure characterize it p o r q u '. are each "not independently, hydrogen -C0 (CR3R4) (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoroethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, - (CR3 R4) f0R1O, CF3 > _F or -C02 R11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di-, or tri-substituted with - (CR3R4) fOR10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R ^ OR, -CF "," * »0 -C02RU; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F , or -COjR11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl of 1) to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] -dioxanil, 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] dioxalanyl, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) 1, 3] dioxalanil, b = 0-6, d = 0-6, and f = 0-6 with the proviso that R 1 and R 2 are not both hydrogen, and with the additional condition that either R or R contains at least one group ~ (CR R) f0R, X, or ~ (CR R) f0R substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 2 1, characterized in that R is hydrogen or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, characterized in that b »0 and d or 0 or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, characterized in that R 8 and R 9 are each, independently, independently hydrogen, alkyl or - (CR R) f 0 R ' 0 taken together form X or a pharmaceutically acceptable salt thereof.

5. The compound in accordance with the claim 1, characterized in that it is the 42-ester of rapamycin with the acid (tetrahydropyran-2-yloxy) acetic acid or a pharmaceutically acceptable salt thereof.

6. The compound in accordance with the claim 1, characterized in that it is the 42-ester of rapamycin with hydroxyacetic acid or a pharmaceutically acceptable salt thereof.

7. The compound in accordance with the claim 1, characterized in that it is the 42-ester of rapamycin with 2,2-dimethyl-3- (tetrahydropyran-2-yloxy) propionic acid or a pharmaceutically acceptable salt thereof.

8 ^ The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with the 3-hydroxy-2, 2-dimethylpropionic acid, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with 2,2-dimethyl [1, 3] dioxalan-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, characterized in that it is the 31, 2-diester of rapamycin with > 2,2-dimethyl [1,3] dioxalan-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin of 2,3-dihydroxypropionic acid, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with 2,2-dimethyl [1, 3] dioxan-5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with the 3-hydroxy-2-hydroxymethylpropionic acid or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with 2, 2, 5-tr imethyl [1, 3] dioxan-5-carboxylic acid Or a pharmaceutically acceptable salt thereof.

15. The compound in accordance with the claim 1, characterized in that it is the 42-ester of rapamycin with > 2, 2-bis- (hydroxymethyl) propionic acid or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, characterized in that it is the 42-ester of raparaicin with 2,2-dimethyl-lime-5- (2-trimethylsilylethylethoxymethyl) [1, 3] -dioxan-5-carboxylic acid or a salt pharmaceutically acceptable thereof.

17. The compound according to claim 1, characterized in that it is the 42-ester of rapamycin with 3-met il-1,5-dioxa-spiro [5.5] undecan-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

GO. The compound in accordance with the claim 1, characterized because it is 31, 42-diester of rapamycin with 3-methyl-l, 5-dioxa-spiro [5.5] undecan-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

19. A method for the treatment of transplant rejection or graft versus host disease in need thereof, characterized in that the method comprises administering to said mammal an effective anti-rejection amount of a compound of the structure wherein each is, independently, hydrogen 0 -C0 (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 alkenyl carbon atoms of 2 to 7 carbon atoms, alkinyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 alkynyl carbon atoms of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -C02RU, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 atoms carbon that is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R 7 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R) f0R, -CF ^, -F, or -C02RU; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F , or -CO ^ 11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R), 0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms »alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl) 1 to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X 'is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3 ] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] -dioxanil, 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1 , 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] dioxalanyl, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxalanil, b = 0-6, d = 0-6, and f-0-6 with the proviso that R and R are not both hydrogen, and with the additional proviso that either R or R contains at least one group - (CR R) f 0 R, X, or - (CR R) f 0 R substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

20. A method for treating a fungal infection in a mammal in need thereof, characterized in that the method comprises administering to said mammal an effective antimycotic amount of a compound of the structure wherein R 1 and R 2 are each, independently, hydrogen or -C0 (CR3 R4) b (CR5R6) dCR7R8 R9; R 3 and R 4 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 alkynyl carbon atoms of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -CO ^ 11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R) f0R, -CF3, -F, or -C02RU; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF, -, -F, or -CO ^ 11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, »alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- ( alkyl of 1 to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] -dioxanil, 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] dioxalanyl, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [ 1, 3] dioxalanil, b = 0-6, d = 0-6, and f-0-6 with the proviso that R 1 and R 2 are not both hydrogen, with the additional proviso that either R or Rz contains at least one group - "(CR 3 '" R4) fn0uRlO X, "(CR3R4) OR 10 substituted with cycloalkyl of 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

21. A method for treating rheumatoid arthritis in a mammal in need thereof, characterized in that the method comprises administering to said mammal an effective anti-arthritis amount with a compound of the structure wherein R 1 and R 2 are each, independently, hydrogen 0 -C0 (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 alkenyl carbon atoms of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoromethyl R and R are each, independently, hydrogen, to the uyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 atoms carbon alkynyl of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -CO ^ 11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 atoms of carbon that is optionally mono-di-, or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 7 carbon atoms, - (CR3R4), 0R10, -CF, -F, or. -C02RU; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F, or -CO ^ 11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or trisubstituted with - (CR3R) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl of 1) to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] -dioxanil, 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] dioxalanyl, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [ 1, 3] dioxalanil, b = 0-6, d = 0-6, and f-0-6 with the proviso that R 1 and R 2 are not both hydrogen, and with the additional proviso that either R or R contain at least one group - (CR R) f0R, X, 0 (CR .3nR4.) F0R, 10 substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

22. A method for treating restenosis in a mammal in need thereof, characterized in that it comprises administering to said mammal an effective antiproliferative amount of a compound of the structure 1 2 wherein R and R are each, independently, hydrogen 0 -C0 (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -CO ^ 11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) fOR10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF, -, ~ F »or eleven - . 11 -C02R; R 8 and R 9 are each, independently, hydrogen, alkylaryl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F, or -COjR11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl of 1) to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] -dioxanil, 4- (2-spiro (C3-C8-cycloalkyl)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms)) [1, 3] dioxalanil, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxalanil, b = 0-6, d = 0-6, and f = 0-6 with the proviso that R 1 and R 2 are not both hydrogen, and with the additional proviso that either R or R contain at least one group "(CR R) f0R, X, or ~ (CR R) .substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

23. A method for the treatment of pulmonary inflammation in a mammal in need thereof, characterized in that the method comprises administering to said mammal an effective anti-inflammatory amount of a compound of the structure 1 2 wherein R and R are each, independently, hydrogen or -CO (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently *, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F, or -C02Rp, O R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally, mono-, di- or tri-substituted with - (CR3R) f0R10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R) f0R, -CF ", -F, 0 -C02Rn; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3 > -F, or -COjR11, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl of 1 to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) [1,3] dioxanyl, 5- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] -dioxanil, 4- (2-spiro (C3-C8-cycloalkyl)) [1, 3] dioxanyl, 4- (2, 2-di- (C 1-6 alkyl)) [1,3] dioxalanyl, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms)) [ 1, 3] dioxalanil, b = 0-6, d = 0-6, and f = 0-6 with the proviso that R 1 and R 2 are not both hydrogen, and with the additional condition that either R or R contains at least one group - (CR R), 0R, X, or - (CR R) f0R substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition, characterized in that it comprises a compound of the structure wherein R 1 and R 2 are each, independently, hydrogen 0 -C0 (CR3R4) b (CR5R6) dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl of 1 to 6 carbon alkenyl atoms of 2 to 7 carbon atoms, alkinyl of 2 to 7 carbon atoms, trifluoromethyl or -F; R and R are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 alkynyl carbon atoms of 2 to 7 carbon atoms, - (CR3R4) f0R10, -CF3, -F, or -COjR11, or R5 and R6 can be taken together to form X or a cycloalkyl ring of 3 to 8 atoms of carbon which is optionally mono-, Hi-tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR R) f0R, -CF ", -F, or C02Rn; R 8 and R 9 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, - (CR3R4) fOR10, -CF3, -F, or -C02RU, or R8 and R can be taken together to form X or a cycloalkyl ring of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with - (CR3R4) f0R10; R is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 7 carbon atoms alkynyl of 2 to 7"carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyl, tri- (alkyl of 1 to 6 carbon atoms) silylmethyl, triphenylmethyl, benzyl, alkoxymethyl of 2 to 7 carbon atoms, tri- (alkyl of 1 to 6 carbon atoms) silyloxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl of 1 to 6 atoms of carbon, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms; X is 5- (2, 2-di- (alkyl of 1 to 6 carbon atoms) carbon) [1, 3] dioxanil, 5- (2-spiro (C3-C8-cycloalkyl)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl of 1 to 6 carbon atoms) carbon)) [1,3] -dioxanil, 4- (2-spiro (C3-C8-cycloalkyl)) [1, 3] dioxanyl, 4- (2, 2-di- (alkyl from 1 to 6 carbon atoms)) [1, 3] dioxalanil, or 4- (2-spiro (cycloalkyl of 3 to 8 carbon atoms) carbon)) [1, 3] dioxalanil; b = 0-6; d = 0-6; and f = 0-6 1 2 with the proviso that R and R are not both hydrogen, and with the additional proviso that either R or i? or R contains at least one group - (CR R) ^ 0R, X, 0 - (Cl? R) f0R substituted with cycloalkyl of 3 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof.

25. A process for the preparation of the rapamycin hydroxy esters, including those of the formula I as defined according to claim 1, characterized in that the process comprises: a) the acylation of rapamycin or a functional derivative or analog thereof same with an acylating agent; or b) sequentially acylating rapamycin or a functional derivative or analogue thereof with two acylation agents; the acylation agent (s) are selected from the acids of formula H0-C0 (CR3R4) b (CR5R6) dCR7R8R9 (ID or a reactive derivative thereof, wherein R 3 -R 9, b and d are as defined in accordance with claim 1, with the proviso that the free hydroxyl groups are protected, if desired protecting the 42 position of rapamycin or of the functional derivative with an appropriate protecting group, and thereafter the elimination reaction of any protective groups present, as required. SUMMARY OF THE INVENTION A compound of structure I is described where R 1 and R 2 are each, i ndepend i in tement e, h i erogenous or -CO (CR 3 R 4) b (CR 5 R 6) d CR 7 R 8 R 9; R3 and R4 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl or -F; R and R are each independently, hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) fOR10, -CF3, -F or -CO ^ 11, or R5 and R can be taken together to form X or a cycloalkyl ring which it is optionally mono-, di- or tri-substituted with - (CR R) f0R; R is hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) f0R10, -CF3, -F, or -C02RU; R8 and R9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4) fOR10, ~ CF3, -F or -COjR11, or R8 and R9 can be taken together to form X or a cycloalkyl ring which is optionally mono-, di- or tri-substituted with - (CR R) f0R; R is hydrogen, alkyl, alkenyl, alkynyl, tri- (alkyl) silyl, tri- (alkyl) silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tr i- (alkyl) silyletoxymethyl, chloroethyl or tetrahydropyranyl; R is hydrogen, alkyl, alkenyl, alkynyl or phenylalkyl; X is 5- (2,2-dialkyl) [1,3] dioxanyl, 5- (2-spiro-cycloalkyl) "[1,3] dioxanyl, 4- (2,2-dialkyl) [1,3] dioxanyl , 4- (2-spiro-cycloalkyl) [1, 3] .dioxanil, 4- (2,2-dialkyl) - [1,3] -dioxalanyl or 4- (2-spiro-cycloalkyl) [1,3] dioxalanil; b = 0-6; d = 0-6; and f = 0-6, with the proviso that R 1 and R 2 are not both hydrogen, and with the proviso further that R 1 or R 2 contains at least one cycloalkyl group substituted with - (CR R) f 0 R, X, or - (CR R) f0R, or a pharmaceutically acceptable salt thereof, which is useful as an immunosuppressant, anti-inflammatory, antifungal, antiproliferative and antitumor agent.