MXPA01001522A - Photocyclized rapamycins - Google Patents

Abstract

A compound of structure (I) or (II) or a 31- and/or 42- ester or ether thereof, which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

Description

PHOTOCYCLIZED RAPAMICINAS Field of the Invention This invention relates to photocyclic rapamycins and a method for using them to induce immunosuppression, and in the treatment of transplant rejection, graft-versus-host disease, autoimmune diseases, inflammation diseases, leukemia / lymphoid of adult cells, solid tumors. , fungal infections, and iterative hipe rprol vascular diseases.

Background of the Invention Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which has been found to have an activity against fungi, particularly against Candida albicans, both in vitro and in vivo [C. Vezma et al., J. Antibiot. 28, 721 (1995); S.N. Shegal et al., J. Antibiot, 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); Ref: 127152 * e VLf - * '-, rSÍ - ¿a ^^^ gS ^^^^^? U.S. Patent 3,929,992; and U.S. Patent 3, 993, 749].

Rapiamycin alone (U.S. Patent 4,885,171) or in combination with picibanila (U.S. Patent 4,401,653) has been shown to have an activity against tumors. R. Martel et al [Can. J. Physiol, Pharmacol. 55, 48 (1977)] describes that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model of rheumatoid arthritis; and to effectively inhibit the formation of IgE-like antibodies.

The immunosuppressive effects of rapamicma have been described in FASEB 3, 3411 (1989). Cyclosponna A and FK-506, other macrocyclic molecules, have also been shown to be effective as immunosuppressive agents, hence useful for preventing rejection of transplantation [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Caine et al., Lancet 1183 (1978); and U.S. Patent 5,100,899].

Rapamycin has also been shown to be useful in preventing or treating systemic lupus erythematosus [U.S. Pat. 5, 078, 99 ^ -3, pulmonary inflammation (US Patent 5,080,899), insulin-dependent diabetes mellitus [US Pat. No. 5,321,009], smooth muscle cell proliferation and vascular lesion followed by intimate widening [US Pat. No. 5,516,781], leukemia / T cell lymphoma in adult [European Patent Application 525,960 Al], and ocular inflammation [US Patent 5, 387, 589].

Description of the invention This invention provides photocilated photopaedic rapamycins having the structure or an ester or ether 31 and / or 42 thereof.

The compounds of this invention are useful as anti-inflammatory immunosuppressive agents, antifungal agents, anti-inflammatory agents, and anti-tumors.

This invention also provides a process for preparing a compound of formula I comprising cyclizing rapamycin in the solid under nitrogen using UV light. This invention also provides a process for providing a compound of formula II which comprises dissolving a compound of formula I in a mixture of aqueous / organic solvent and isolating a compound of formula II.

The β-lactam compound of formula I is prepared by subjecting rapimycin in the solid state to a photoreaction in a light cabinet solar for about 7 days under nitrogen. The β-lactam compound of formula II is prepared by dissolving the compound of formula I in a mixture of aqueous / organic solvent, such as acetate buffering solution. t et raet i lamonio / acetoni t r i lo 1: 1. Under the conditions described herein, the compounds of formulas I and II exist in equilibrium in the solution. In the tet rate ilamonium / acetonitrile buffer solution, equilibrium is forced towards the compound of formula II, which can be separated and isolated from the compound of formula I. The compounds of formulas I and II are also referred to as Compounds I and II, respectively. The esters and ethers of this invention can be prepared from the compounds of Formulas I and II. Methods for preparing rapamycin esters and ethers 31 and / or 42 are well documented in the patent literature. The following are preferred esters and ethers, together with the corresponding patent describing the preparation of analogous rapamycin esters and esters; the patents listed below are all incorporated herein by reference: alkyl esters (U.S. Patent 4,316,885); aminoalkyl esters (U.S. Patent 4,650,803); fluorinated esters (U.S. Patent 5,100,883); amide esters (U.S. Patent 5,118,677); 25 carbamate esters (U.S. Patent 5,118,678); esters of ^^^^ & ^^^^^^^^^^^^^^ e ^^^^^ ^ ^^^^^ ^^^^^ j ^^^ j ^^^ j ^^^^^^^ g & ^^^^^ silyl (US Patent 5,120,842); Aminoesters (U.S. Patent 5,130,307); acetals (U.S. Patent 5,51,413); aminodies teres (U.S. Patent 5,162,333); sulfonate and sulfate esters 5 (U.S. Patent 5,177,203); esters (U.S. Patent 5,221,670); alkoxyesters (U.S. Patent 5,233,036); esters of O-aryl, -alkyl, alkenyl, and -alkynyl (U.S. Patent 5,258,389); carbonate esters (U.S. Patent 5,260,300); 10 arylcarbonyl and alkoxycarbonyl carbamates (U.S. Patent 5,262,423); carbamates (U.S. Patent 5,302,584); hydroxy teres (U.S. Patent 5,362,718); hindered esters (U.S. Patent 5,385,908); heterocyclic esters (U.S. Patent 15 5,385,909); esters disubstituted by gem (U.S. Patent 5,385,910); amino-alkanoic esters (U.S. Patent 5,389,639); phosph orilcarbamate esters (U.S. Patent 5,391,730); carbamate esters (U.S. Patent 5,411,967), 20 carbamate esters (U.S. Patent 5,434,260); esters of amidino carbamate (U.S. Patent 5,463,048); carbamate esters (U.S. Patent 5,480,988); carbamate esters (U.S. Patent 5,480,989); carbamate esters (U.S. Patent No. 5,489,680); hindered N-oxide esters (U.S. Patent 5,491,231); biotin esters (U.S. Patent 5,504,091); and O-alkyl esters (U.S. Patent 5,665,772). When a compound of this invention is an ester or ether of compound I or II, it is preferred that it be a monoester or ether 42.

The antifungal activity of the compounds of this invention is stabilized by evaluating a Representative compound of this invention (compound I) against several strains of fungi. Briefly, the following procedure is used to evaluate such activity. A microtitre bottom tray in U 96 is filled (50 μl / well) with RPMI 1640. The compounds to be evaluated are placed in the appropriate wells and serially diluted in successive wells to provide 11 dilutions. The concentrations are in the range from 64 to 0.06 μg / ml. An inoculum fit of the fungus (50 μl) was add to each of the wells and the trays are incubated at 35 ° C for 24-48 hours. MIC is the lowest concentration of the compound that completely inhibits the growth of the organism in wells. The following table shows the results obtained in this test procedure pharmacological standard. Where the same fungus is listed more than once, this indicates that more than one strain was evaluated.

TABLE 1. ANTI-FUNGAL ACTIVITY (MIC in μg / ml) The results obtained in this standard pharmacological test procedure demonstrate that the compounds of this invention are useful as antifungal agents.

The antineoplastic activity for The compounds of this invention are stabilized by evaluating the antineoplastic activity of a representative compound of this invention. (compound 1) against six tumor cell lines In vitro. Briefly, the tumor cells of six cell lines are placed in wells of a microtitre 96-well tray. The following tumor cell lines were used: A2780S (ovary), A2780DDP (ovary - resistant to cisplatin), A431 (epidermoid originating in the ^ & ... ^^, e ^, ... ^^ -. a ^^. ^^^ ....- ^ --- ... - »,, ¿Aaái¡fe» É¡ ^^ vulva), SW620 (colon) SKBR3 (breast), MDA-MB-435 (breast). The tumor cells grow in the presence of a series of dilutions of the compound to be evaluated for 48 hours, and the cells that have grown are determined using a colorimetric procedure (sulforhodamine B). The inhibition of growth is calculated by comparing the number of cells at the time of the addition of the test compound. The results are expressed as an IC 50 (μg / ml). The following IC50's are obtained from compound 1: A2780S (IC5o = 8.756 μg / ml), A2780DDP (IC50 = 6.51 μg / ml), A431 (IC50 = 20.46 μg / ml), S 620 (IC50 = 24.84 μg / ml), SKBR3 (IC50 = 7.029 μg / ml), and MDA-MB-435 (IC50 = 27.28 μg / ml). The results of this standard pharmacological test procedure demonstrate that the compounds of this invention are useful as antineoplastic agents. In particular, the compounds of this invention are useful against solid tumors, including sarcomas and carcinomas; and more particularly against astrocytes, prostate cancer, breast cancer, colon cancer, small cell lung cancer, and ovarian cancer; and leukemia / 1 imforma of the T cell in adult.

• UßRÉLIDlB & amp; At? Í & iilM Based on the activity profile obtained, the compounds of this invention are also useful in the treatment or inhibition of rejection to transplantation such as liver, heart, kidney, lung. , marrow, pancreas (islet cells), cornea, small intestine, and skin allografts, and xenograft heart valves; in the treatment or inhibition of a graft against host disease; 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, bowel disease inflammatory, pulmonary inflammation, (including asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis, and the like), and uveitis of the eye; and vascular iterative hyperprol diseases such as restenosis and arteriesclerosis. 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 can «Gig ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ before the procedure, during the procedure, subsequent previous combinations.

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 immunosuppressive or anti-inflammatory agent, this may be administered in conjunction with one or more immunoregulatory agents. Such other immunoregulatory agents include, but are not limited to, azathioprine, corticosteroids, such as prednisone and metilprednisolone, cyclophosphamide, rapamycin, cyclosporin A, FK-506, OKT-3, and ATG. By combining the compounds of this invention with such other drugs or agents to induce immunosuppression or the treatment of inflammatory conditions, smaller amounts of each of the agents are required to effect the desired effect. The bases for such combination therapy are established by Stepkowski whose results show that the use of a combination of rapamycin and cyclosporin A, at 5 subtherapeutic doses that significantly prolongs the survival time of the allograft of the heart. [Transplantat ion Proc. 23: 507 (1991)].

The compounds of this invention can be formulated pure or with a pharmaceutical carrier for a mammal in need thereof. The pharmaceutical carrier can be solid or liquid.

A solid carrier may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binding agents or tablet disintegrants; these can also be in an encapsulated material. In the powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient. In tablets, the The active ingredient is mixed with a carrier that it has necessary compression properties in appropriate proportions and is compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. .

Liquid carriers are used to prepare 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, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffering solutions, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmotic regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, eg, glycols ) and its derivatives, leticines, and oils (for example, fractionated coconut oil and peanut 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 pressurized compositions can be halogenated hydrocarbon or another pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions or suspensions may be used by, for example, intramuscular, intotalpenal, or subcutaneous injection. Sterile solutions can also be administered intravenously The compounds can be administered orally either in the form of liquid or solid compositions.

The compounds of this invention can be administered rectally in the form of a conventional suppository. For administration by intranasal or intbronchial 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 patch Transdermal contacting the active compound and a carrier that is inert to the active compound, which is not toxic to the skin, and allowing the release of the agent for systemic absorption into the bloodstream by means of the skin. The carrier can be taken in any number of ways such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be semi-solid or viscous liquid emulsions of either type oil in water or water in oil. The pastas that - ^^^^ - - ** - * "- ^ * ^ - - • • * ^" ~ "& * i ~ ^^ comprise absorbent powders dispersed in petroleum or hydrophilic oil containing the active ingredient may also A variety of occlusive devices may be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix, containing the active ingredient. occlusive devices are known in the literature.

In addition, the compounds of this invention can be used as a solution, cream, or lotion in formulation with pharmaceutically acceptable carriers containing 0.1-5%, preferably 2%, of the active compound, which can be administered to an area affected by fungi. Dosage requirements vary with the particular composition used, the route of administration, the severity of the symptoms presented and the particular subject to be treated. 25 Based on the results obtained in the standard pharmacological test procedures, the projected daily doses of the active compound will be 0.1 μg / kg - 100 mg / kg, preferably between 0.001 - 25 mg / kg and more preferably 5 between 0.01 - 5 mg / kg. Treatment will generally start with small doses less than the optimal dose of the compound. Subsequently, the dose will increase to the optimum effect under the circumstances reached; precise doses for oral, parenteral, nasal or intbrbronquial administration will be determined by the administration of a physician based on experience with the individual subject treated. Preferably, the pharmaceutical composition is a unit dosage 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 dosage unit forms can be packaged in compositions, for example, packaged powders, small vials, ampoules, pre-filled syringes or pouches containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or it may be in a At =,. ftjie .e * appropriate number of any such compositions in packaged form.

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

Example 1 (SS, 2R, 3R, 6S, 8S, 9E, HE, 13E, 15S, 17R, 19R, 20R, 21E, 23R, 26S, 29S, 33R) - 1, 2, 30- 1 RI-hydroxy- 26 - [( lR) -2 - [(1S, 3R, 4R) -4-hydroxy-3-methoxy-cyclohexyl] -l-methyl-ethyl] -8, 19-dimethoxy-3, 9, 15, 17.21.23-hexamethyl -27, 36-dioxa-35- 15 azatetracíclo [27,4,2,1, [2,6], 0 [33,35]] hexatriacona-9, 11, 13,21-tetraene-18,24,28 , 34-tetrone (Compound I) Rapamycin (100 mg, 0.11 mmol every 20 ml) was sealed in 10 ml ampoules under nitrogen. The ampules were placed in a solar light cabinet for 7 days. HPLC analysis shows that 15% of Compound I was formed. The crude product was purified by preparative HPLC on a Prep 25 Nova-pak HR C18 column (300 x 19 mm) using a method M Mu mBfr? Vxs ***.? ^^^. ^^^^ ^. gradient that maintains 60% of A 'and 40% of B for the first 5 minutes and then changes from 60% of A and 40% of B to 55% of A and 45% of B in 30 minutes. Buffer A consists of 95% of 0.1 M TEAA, pH 3.9 and 5% acetonitrile. Buffer B consists of 5% TEAA 0.1 M pH 3.9 and 95% acetonitrile. The flow ratio was 25 ml / minute. The fraction at 28 minutes was collected and extracted with chloride of methylene (2 x 50 ml). The organic layer was dried with anhydrous sodium sulfate for 4 hours. The solvent was removed using a rotary evaporation system. The residue was dissolved in 20 mL of methylene chloride and precipitated by adding 100 mL of hexane. After filtering, the white solid was dried in a vacuum of speed overnight. The crude product was also purified by preparative normal phase HPLC on a Primesphere 10 silica column (250 x 50 mm) using a mobile phase consisting of 94% methylene chloride, 4% methanol and 2% isopropanol with the flow rate of 75 ml / minute. The fraction of the minute 7.6, was collected and the organic solvent was removed using an evaporation system rotary. Of the reaction mixture of 1.87 g, obtained 0.18 g of Compound I and recovered 1.42 g of rapamycin. The total conversion yield was 40%.

X H NMR (DMSO-d 6, 400 MHz), d 6.42 (dd, 1 H, J = 11.0, 14.7 Hz, H-4), 6.30 (dd, ΔH J = 10.3, 14.5 Hz, H-3), 6.20 (d , ÍH, J = 10 8 Hz, H-5), 6.10 (dd, 1H, J = 10.5, 15.2 Hz, H-2), 5.92 (s, ÍH, -OH to C-15), 5.45 (dd, ÍH, J = 9.9, 14.9 Hz, Hl), 5.32 (s, 1H, -OH to C-14), 5.20 (d, ÍH, J = 4.0 Hz, -OH to C-31), 5.10 (d, ÍH , J = 10.1 Hz, H-29), 5.04 (m, ÍH, H-25), 4.56 (s, ÍH), 4.21 (d, ÍH, J = 2.0 Hz), 4.05 (s, ÍH), 3.99 ( m, HH, H-9), 3.62 (m, 3H), 3.31 (s, 3H, -OCH3 to C-41), 3.19 (m, 1H), 3.17 (s, 3H, -OCH3 to C-32) , 3.12 (m, 3H), 3.03 (s, 3H, -OCH3 to C-7), 2.82 (m, 2H), 2.52 (d, ÍH, J = 21.3 Hz), 2.19-2.34 (m, 4H), 2.00 (m, ÍH, H-12), 1.91 (m, 2H), 1.76 (s, 3H, -CH3 to C-30), 1.70 (m, ÍH), 1.64 (m, 2H), 1.60 (s, 3H, -CH3 to C-ß), 1.53 (m, 1H), 1.38 (m, 3H), 0.97 (d, 3H, J = 6.6 Hz), 0.84 (d, 3H, J = 6.6 Hz) 0.80 (d , 3H, J = 6.6 Hz), 0.74 (d, 3H, J = 6.3 Hz), 0.61 (ddd, 1H, J = 11.9 Hz, H-40b); Data 113JC, NMR (DMSO-d6, 100 MHz, d 209.2 (C-33), 207.1 (C-27), 167.9 (C-23), 165.0 (C-16), 139.1, l ^^ já ^ s ^ ¡A ^ ¡^ ¿[& ^^^^^^ Ü ^^ 138.0, 136.2, 132.4, 130.6, 127.1, 126.9, 123.8, 97.8 (C-14), 91.8 (C-15), 84.5, 83.7, 82.0, 75.7, 73.1, 72.3, 65.1 , 64.8, 56.7, 56.5, 55.8, 44.3, 40.9, 35.9, 35.2, 34.7, 32.9, 32.1, 30.7, 27.2, 22.0, 21.5, 18.2 (-ch3 A C-14), 15.6, 14.9, 14.7, 13.9, 12.1 , 10.3.

ESI mass spectrometry showed a negative ion (MH) ~ m / z 911.7 and a positive ion (M + NH4) + m / z 931. The mass spectrometry Fab showed an m / z 913 (M), a m / z 936 (M + Na) + and m / z 952 (M + K) A HRMS (Fab) calculated for C? 5H79N013 (M + Na) + 936.5449, found 936.5480.

Example 2 (1S, 4S, 7R, 8E, 10R, 11R, 13R, 15S, 16E, 18E, 20E, 22S, 24S, 27R, 29S, 30R) -10, 24, 29-trihydroxy-4- [(IR) -2 - [(1S, 3R, 4R) -4-hydroxy-3-methoxycyclohexyl] -1-met yl) ethyl] -11, 22, -dime t oxy -7, 9, 13, 15, 21, 27-hexameth? l-3-oxa-34-azatricyclo [27, 4, 2, 30, 34] pentatriaconta-8, 16, 18, 20-tetraene-2, 6, 12, 28, 35-pentone (Compound II) ^ gfi e &? Yes A solution of Compound I was collected from preparative HPLC or prepared by dissolving Compound I in 50% of the 0.1 M TEAA buffer solution, pH 5.7 and 50% acetonitrile was kept at room temperature overnight. HPLC analysis showed 32% of Compound II which was eluted 1 minute before Compound I. The crude product was extracted with methylene chloride. The organic layer was collected and was concentrated using a rotary evaporator. The crude product was purified by preparative HPLC on a Prep Nova-pak HR C18 column (300 x 19 mm) using a gradient method that maintains 60% A and 40% B for the first 5 minutes and then changes from 60% A and 40 (5 B to 55% A and 45% B in 30 minutes.) Buffer A consists of 95% 0.1 M TEAA, pH 3.9 and 5% acetonitrile. Buffer B consists of 5% TEAA 0.1 M pH 3.9 and 95% acetonitrile. The 25 minute fraction was collected and extracted with methylene chloride (2 x 50 mL). The organic layer was dried with anhydrous sodium sulfate for 4 hours. The organic solvent was removed by rotary evaporation. He The residue was dissolved in 20 ml of methylene and precipitated by adding 100 ml of hexane. After filtering through a filter, Compound II was dried in a speed vacuum overnight.

X H NMR (DMSO-de, 600 MHz), d 7.19 (s, ÍH, -OH to C-15), 6.45 (dd, ÍH, J = ll.l, 14.2 Hz, H-4), 6.2 (m, 2H, H-2, H-3), 6.05 (d, ÍH, J = ll.l Hz, H-5), 5.50 (dd, ÍH, J = 9.2 14.3 Hz, Hl), 5.25 (d, ÍH, J = 4.3 Hz, -OH to C-31), 5.1 (m, 2H, H-29, H-25), 4.58 (d, 1H, J = 4.3 Hz, -OH to C-42), 4.30 (d , HH, J = 5.8 Hz, -OH to C-9), 3.90 (m, HH, H-22), 3.85 (m, HH, H- 31), 3.79 (d, HH, J = 7.6 H, H -32), 3.69 (dd, ÍH, J = 6.7, 7.0 Hz, H-7), 3.56 (m, 1H, H-28), 3.43 (dd, ÍH, J = 4.3, 11.3 Hz, H-18) , 3.30 (s, 3H, + OCH3 to C-41), 3.27 (m, 1H, H-42), 3.12 (s, 3H, -OCH3 to C- 32), 3.12 (m, ÍH, H-12) , 3.07 (s, 3H, -OCH3 to C- 7), 2.93 (dd, ÍH, J = 8.2, 17.4 Hz, H-26b), 2.81 (m, ÍH, H-41), 2.64 (m, 1H, H-34), 2.45 (dd, ÍH, J = 3.8, 17.4 Hz, H-26a), 2.26 (m, ÍH, H-36), 1.9 (m, 2H, H-37, H-40a), 1.72 (s, 3H, -CH3 to C-30), 1.77-1.67 (m, 4H, H-llb, H-20b, H-21b, H-43b), 1. 61 3H, -CH3 to C-6), 1.59-1.52 (m, 3H, H-8b, H-19a, H-44b), 1.4 (m, 5H, H-8a, H-lOb, H-20a, H-21a, H-35b), 1.27 (m, 1H, H-39), 1.18-1.15 (m, 3H, AHA*! Iaj »» «? | Fjf | faith?« Tf * < - SAa »- a» »t - && . * "-» * d H-lOa, H-43a, H-44a), 1.14-102 (m, 4H, H-lla, H-19a, H-35a, H-38a and H-38b), 1.00 (d, 3H, J = 6.7 Hz, -CH3 to C-36), 0.95 (d, 3H, J = 6.7 Hz, -CH3 to C-28), 0.93 (d, 3H, J = 6.4 Hz, -CH3 to C-34), 0.90 (d, 3H, J = 7.0 Hz, -CH3 to C-12), 0.82 (d, 3H, J = 6.7 Hz, -CH3 to C-37), 0.69 (ddd, ÍH, J = 11.9 Hz, H-40b); 13C NMR data (DMSO-d6, 100 MHz) d 213.0 (C-33), 211.4 (C-14), 208.2 (C-27), 168.2 (C-23), 163.2 (C-16), 139.3 (Cl), 138.3 (C-30), 137.0 (C-6), 132.6 (C-3), 130.4 (c-2), 127.7 (C-5), 126.7, ( C-4), 126.1 (C-29), 91.8 (C-28), 84.5 (C-32), 84.1 (C-7), 83.9 (C-41), 77.0 (C-31), 75.0 (C -25), 73.1 (C-42), 67.3 (C-9), 62.2 (C-18), 57.1 (-OCH3 to C-15 32), 56.7 (-OCH3 to C-41), 55.4 (-OCH3) to C-7), 54.3 (C-22), 46.0 (C-28), 41.4 (C-34), 41.1 (C-8), 39.1 (C-12), 38.8 (C-26), 38.5 ( C-38), 37.7 (C-35), 35.5 (C-40), 34.9 (C-36), 34.3 (C-10), 32.9 (C-43), 32.7 (C-39), 32.5 (C -37), 30.9 (C-44), 27.8 (C-11), 26.6 (C-21), 22.5 (C-19), 22.0 (-OCH3 to C-36), 19.3 (C-20), 15.3 (-CH3 to C-12), 15.1 ( -CH3 to C-28), 14.6 (-CH3 to C-37), 14.0 (-CH3 to C-34), 11.8 (-CH3 to C-30), 10.5 (-CH3 to C-6).

ESI mass spectrometry showed a negative ion (MH) "m / z 912.3 and a positive ion (M + NH4) + m / z 931. Fab mass spectrometry showed an m / z 913 (M), a m / z 936 (M + Na) + and one m / z 952 (M + K) A HRMS (Fab) calculated for C? 5H79N013 (M + Na) + 936.5449, found 936.5465.

It is noted that in relation to this date, the best method known to the applicant for The implementation of said invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (11)

Claims

1. A composite of the structure or an ester or ether 31 and / or 42 thereof.

2. The compound according to claim 1, characterized in that it is (IS, 2R, 3R, 6S, 8S, 9E, HE, 13E, 15S, 17R, 19R, 20R, 21E, 23R, 26S, 29S, 33R) -1, 2, 30- 1 r ihydroxy-26- [(IR) -2 - [(1S, 3R, 4R) -4-hydroxy-3-methoxy-cyclohexyl] -1-methylethyl] -8, 19-dimethy oxy- 3, 9, 15, 17, 21, 23-hexamethyl-27, 36-d-oxa-35-azatetracyclo [27, 4,2,1, [2,6], 0 [33,35]] hexatriaconta -9,11,13,21-tetraene-18,24,28,34-tetrone.

3. The compound according to claim 1, characterized in that it is (SS, 4S, 7R, 8E, 10R, 11R, 13R, 15S, 16E, 18E, 20E, 22S, 24S, 27R, 29S, 30R) -10, 24, 29- 1 r ihydroxy-4 - [(IR) -2 - [(lS, 3R, 4R) -4-hydroxy-3-methoxy-cyclohexyl] -1-methylethyl] -11, 22, -dime toxi-7, 9, 13, 15, 21, 27- hexamethyl-3-oxa-3-azatricyclo [27, 4, 2, 30, 34] pentatriaconta-8, 16, 18, 20-t and raeno-2, 6, 12 , 28, 35-pentona.

4. A method for the treatment of transplant rejection of a graft against a host disease in a mammal in need thereof, characterized in that comprises administering to the mammal an effective amount of anti-rejection compound of structure p ^ Í ^ A £ SÉ k. or an ester or ether 31 and / or 42 thereof

5. A method for the treatment of a fungal infection in a mammal in need thereof, characterized in that it comprises administering to the mammal an effective antihongo amount of a compound of the structure or an ester or ether 31 and / or 42 thereof

6. A method for the treatment of restenosis in a mammal in need thereof, characterized in that it comprises administering to the mammal an anti-proliferative effective amount of a compound of the structure or an ester or ether 31 and / or 42 thereof

7. A method for the treatment of solid tumors in a mammal in need thereof, characterized in that it comprises administering to the mammal an antitumor effective amount of a compound of the structure p raL * sJSSS & t a ^ aggw-j or an ester or ether 31 and / or 42 thereof

8. A pharmaceutical composition, characterized in that it comprises a compound of the structure p or an ester or ether 31 and / or 42 thereof and a pharmaceutical carrier.

9. A process for preparing a compound of formula I as defined in claim 1, characterized in that it comprises cyclizing rapimycin in the solid state under nitrogen using UV light.

10. A process for preparing a compound of formula II as defined in accordance with sÉjfatü. : Tt ... * «^ -ri rjgMflfcBa claim 1, comprising dissolving a compound of formula 1 in a solvent mixture aqueous / organic and isolating a compound of formula 11?. ^^^ ¿^^^^^ ¡¡¡¡