JP2002514165A - Materials and methods for treating or preventing pathogenic fungal infections - Google Patents

Abstract

  (57) [Summary] The present invention relates to derivatives of rapamycin and their use as antifungal agents. Materials and methods for the identification of non-immunosuppressive and antifungal rapamycin derivatives are also disclosed.

Description

DETAILED DESCRIPTION OF THE INVENTION               Materials and methods for treating or preventing pathogenic fungal infections Background of the Invention   Rapamycin is Streptomyces hygroscopicus is a macrolide antibiotic produced by S. scopeus. This is initially its anti-true Identified by bacterial activity, but more often studied as immunosuppressants Came.   A number of structurally modified compounds of rapamycin have been reported so far, Treatment of compounds typically occurring as separate fermentation products or as immunosuppressants It came out of synthetic research to improve the therapeutic index. For example, Lapamai Analogs, homologues, derivatives and other compounds structurally related to syn ["rapalog (r apalog) "], among others, the following modifications to rapamycin: Variants of rapamycin having one or more of: C7, C Demethylation, elimination or substitution of the methoxy group at 42 and / or C29; Elimination, derivatization or substitution of the hydroxy group of C43 and / or C28; , Elimination or derivatization of the ketone group of C24 and / or C30; Substitution of a 6-membered ring with a 5-membered prolyl ring; and another on the cyclohexyl ring Replacement with a substituent or substitution of a cyclohexyl ring by a substituted cyclopentyl ring. In almost all cases, the strong immunosuppressive activity associated with the antifungal activity of this rapalog Have been reported. For more historical information, see U.S. Patent Nos. 5,525,610, 5,310. , 903 and 5,362,718 in the background section.   U.S. Pat. No. 5,527,907 is an example of a patent document. This document has reduced side effects To disclose a series of compounds synthesized in a study to create an immunosuppressive Laparag I have. These compounds are disclosed in the form of seven Markush structures, Each Markush term lists possible substituents at various positions on the rapamycin ring. An explanation of two to five or more columns follows. This document contains more than 180 composites Includes examples. Many variants of the invention reported to be potent immunosuppressants Was done.   Rapamycin is Candida albicans, Candida albicans Adversely affect the growth of fungi, such as da) and gypsum-like microsporum (Microsporum gypseum) It is known that it has strong immunosuppressive activity. It is not excluded that this is a candidate for use as an antifungal agent. WO 94 / 02136 (SmithKline Beecham), WO 95/16691 (Sandoz), US 5,583,139 (Abbott) And even some of the more recent patent documents such as US 5,527,907 (Abbott) Despite showing structural modifications of a wide range of isin combinations, Sacrifice the antifungal properties of rapamycin, which would be desirable or necessary About reducing its immunosuppressive activity withoutpossibilityEven-to do so Some structural approach, of course, neglected to suggest anything. Actually Optimal response to any antifungal requires an active immune system in the treated patient. Predictions that may be necessary appear to prevent the use of rapalogs. Therefore For treating or preventing infection with pathogenic fungi in humans or other animals Surprisingly, there are no previous reports of clinical development of pamycin or rapalog Does not hit.   By the way, the clinical attack of pathogenic fungi is increasing, but existing antifungals are , Potency, toxicity, and pathogenic fungal strains resistant to currently available or developing drugs Have problems in terms of expression and / or discovery of Human smell as an example Fungal and pathogenic fungi include, among others: Candida albica C. albicans, C. tropicalis, C. albicans C. kefyr, C. krusei and C. gulbu Candida species including C. galbrata; Aspergillus fumigatus Asperum including A. fumigatus and Aspergillus flavus Aspergillus spp .; Cryptococc neoformans (Cryptococc) us neoformans); Blastomyces dermatitidis Blasttomyces spp. Containing Pneumocystis carini (Pneumo cystis carinii); Coccidioides immitis; Basidiobolus ranarum; Conidio bolus); Histplasma capsulatum; lyso P. oryzae (R. oryzae) and R. microsporus (R. microsporus) Rhizopus spp .; Cunninghamella spp .; Rhizomucor spp .; Paracoccidioides brasiliensis (P aracoccidioides brasiliensis); Pseudodalles cheria boydii); Rhinosporidium seeberi; Sporothrix schenckii [Kwon-Chung, K.J. And Bennett, J.E. (1992): Medical Mycology (Lea and Febiger, Pennsylvania State Malvern)].   Turner and Rodriguez, 1996,Current Pharmaceutical Design,Two, 209-224 States that: "The need for new antifungals is by no means greater over the past decade   People who are immunocompromised, including patients with cancer, organ transplants, and AIDS   As the number of people has increased, the emergence of life-threatening fungal infections has increased significantly.     … Also contributing to this danger is the increased use of broad spectrum antibiotics   , Increased use of invasive medical technology, and aging of the number of patients. "   Some pharmaceutical approach to exploit the antifungal activity of rapamycin or rapalog Little literature suggests the possibility of the method, but non- Epidemic-suppressing rapamycin derivatives are great for the treatment or prevention of pathogenic fungal infections. I would be interested.Summary of the Invention   Rapalog research, including results from some of the world's leading pharmaceutical research institutions Apart from the extensive literature on the invention, the present invention is, inter alia, a mammalian individual, In particular, human patients are infected with a pathogenic fungus and the individual is exposed to rapalogs-an inconvenient Methods and materials to treat or prevent by administration-without causing epidemic control Offer a fee. The method uses an antifungal effective amount of a non-immunosuppressive antifungal rapalog. Administering the composition to said individual.   From a pharmacological point of view, the present invention relates to a method for administering an immunosuppressive dose to an individual.  amount) of a composition containing rapalog, e.g., Rapa in an amount and in a manner that does not give an adverse immunosuppressive effect. Preventing or treating an individual's infection with a pathogenic fungus by administering a log Provide a way. Preferably, the rapalog is a non-immunosuppressive, antifungal rapalog. You.   Important applications of the invention include, inter alia, those listed above or mentioned below. Treatment or prevention of a patient's infection with such pathogenic fungi.   One aspect of the invention relates to one or more other antifungal agents, particularly rapamycin or Treat or predict the infection of patients with pathogenic fungi that are resistant to antifungal agents other than rapalog. It is to prevent. Examples of such other antifungal agents include amphotericin B. Or its analogs or derivatives [14 (s) -hydroxyamphotericin B methyl ester Steroid, hydrazide of amphotericin B with 1-amino-4-methylpiperazine And other derivatives] or, for example, nystatin, candicidin, Other polyene macrolide antibiotics including maricin and natamycin; full Echinocandins, including cytosine; griseofulvin; natural and semi-synthetic analogues Or aureobasidin; dihydrobenzo [a] naphthacenequinones; poly Nucleoside peptide antifungal agents including oxins and nikkomycins; Allylamines and other squalene epoxidase inhibitors such as futifin And, for example, clotrimazole, miconazole, ketoconazole, eco Nazole, butconazole, oxyconazole, terconazole, itraconazo Or azoles such as fluconazole, imidazoles and triazols And the like. Other conventional antifungal agents and new antifungal agents under development For example, see Turner and Rodriguez, 1996, Recent advances in medicinal chemistry of antifungals. Step,Current Pharmaceutical Design,Two209-224.   Another aspect of the invention is that the patient has an allele against one or more other antifungal agents. Gynecological, otherwise intolerant, or unresponsive, or patient If the use of other antifungals to the patient is contraindicated for other reasons, To treat or prevent an infection. Such other antifungal agents include This includes, for example, the antifungal agents disclosed above and elsewhere herein.   In the above treatment or prevention method, rapalog, preferably a non-immunosuppressive anti- The fungal rapalog is administered to the patient in an antifungal effective amount.   Another aspect of the invention is a rapalog, preferably a non-immunosuppressive antifungal rapalog With one or more other antifungal agents (e.g., the antifungal or antifungal agents described above). (Eg, amphotericin B, preferably Is a lipid or liposome formulation; for example, an azole such as fluconazole Or triazole; aureobasidin; dihydrobenzo [a] naphthacenequinone; Or in combination with echinocaldine treatment), and in combination with other rapalogs Administration to treat or prevent infection of the patient with the pathogenic fungus. And Rapalog may be administered before, after, or simultaneously with the administration of other antifungal agents. Can be done. In certain embodiments, the combination treatment results in one or both Use of the antifungal component of the above in a reduced amount compared to the amount used when used alone Will be possible.   Another aspect of the invention is a rapalog, preferably a non-immunosuppressive antifungal rapalog Is preferably used to alleviate neutropenia and / or other immune dysfunction. One or more immune response enhancers (eg, GM-CSF, M- (Including drugs such as CSF and IL-3) to patients. More to treat or prevent a patient from being infected by a pathogenic fungus. Rapalog's The administration can be performed before, after, or simultaneously with the administration of the immune response enhancer. . Further, the administration of rapalog and the immune response enhancer is one or more as described above. May be combined with the administration of other antifungal agents.   Still other applications of the invention include, for example, genetic disorders, diabetes or HIV or Chemotherapy or radiation treatment for other infectious diseases, cancer or other diseases, or tissue or Is immunization with drugs or other triggers related to organ transplantation or treatment of autoimmune disorders Pathogenic if the patient is immunosuppressed or immunocompromised as a result of suppression Including administering rapalog to the patient to treat or prevent a fungal infection. No. The patient is treated with an immunosuppressant, for example, in connection with a tissue or organ transplant. Treatment or prevention of pathogenic fungal infections, if any Can be co-administered with immunosuppressants. Of the patient Non-immunosuppressive antifungal to avoid unduly suppressing remaining immune function It may be preferable to use a rapalog.   Another aspect of the present invention relates to the pathogenesis of a patient infected or suspected of being infected with HIV. Infection with a fungal, a rapalog, preferably a non-immunosuppressive antifungal rapalog, One or more anti-HIV therapeutic agents (eg, HIV protease inhibitors, reverse transcription (Enzyme inhibitors or antiviral agents). Or to prevent. Rapalog may be administered before or after administration of the anti-HIV agent, Can be done at the same time.   Another aspect of the invention is a rapalog, preferably a non-immunosuppressive antifungal rapalog With one or more, preferably in an amount and schedule effective to treat or prevent a bacterial infection. Combination and administration of two or more other antibiotic compounds, especially one or more antimicrobial agents To treat or prevent infection of a patient with a pathogenic fungus. is there. Again, administration of rapalog may be prior to, after, or concurrent with the administration of other drugs. Can be done.   As a pathogenic fungal infection that can be treated or prevented by the method of the present invention Is, inter alia, aspergillosis, including invasive pulmonary aspergillosis; Or blasttomyces including rapidly progressive infections and central nervous system blastmycosis Disease; for example, kidney stones, urinary tract obstruction, kidney transplantation or poorly managed diabetes mellitus tus) in patients with retrograde candidiasis in the urinary tract; other chemotherapy Coccidioidomycosis, including chronic disease that does not respond adequately to law; Cryptococcus Histoplasmosis; for example, craniofacial mucormycosis and pulmonary mucormycosis Mucormycosis, including sickness; Paracoccidioidomycosis; and Sporothrix Disease. Administration of a composition comprising an antifungal effective amount of one or more rapalogs Whether the infectious fungus is resistant to one or more other antifungal treatments, or Or one or more other antifungal treatments are contraindicated, eg, as described above, It will be particularly useful for treating or preventing a pathogenic fungal infection in a mammalian individual.   At least one antifungal, preferably a non-immunosuppressive antifungal rapalog Antifungal drug compositions containing rapalogs are also useful in practicing the methods of the present invention. Provided for The pharmaceutical composition is used, inter alia, for its antifungal use Can be packaged with appropriate in-package insert containing description and information You. Pharmaceutical compositions comprising one or more rapalogs together with a second antifungal agent Is also provided.   In addition, new types of rapalogs for various applications are also proposed here. Immunosuppression Novel rapalogs that are sexually active include rapamycin, cyclosporin A, FK506 Etc. or in combination with them.Detailed description Rapalog   As used herein, the term "rapalog" refers to various analogs of rapamycin. Compounds, homologs and derivatives and other compounds structurally related to rapamycin. It refers to certain types of compounds that are included. “Rapalog” is a basic structure represented by Formula I Rapamycin (or 1,2,3,4 or 5, Modified only at the point of saturation of one or more carbon-carbon double bonds at the 6 position Rapamycin derivatives), and possesses an arbitrary number of various substituents. And, unless otherwise specified herein, optionally one or more carbon-carbon The bond may be unsaturated.  Rapalogs include, among others, one or two of the following modifications to rapamycin: Variants of rapamycin having the above: C7, C42 and / or Or demethylation, elimination or substitution of the methoxy group of C29; C13, C43 and / or Or elimination, derivatization or substitution of the hydroxy group of C28; C14, C24 and / or Or reduction, elimination or derivatization of a C30 ketone group; Substitution with a 5-membered prolyl ring; and one or more substitutions of a cyclohexyl ring Elimination, derivatization or substitution of substituents or substitution or non-substitution of Substitution with a substituted cyclopentyl ring. Rapalog as a term used herein is: It does not contain rapamycin itself and preferably has an oxygen bridge between C1 and C30. Not included. Examples of rapalogs are disclosed in the patent documents listed in Table I. Examples of rapalogs modified with C7 are shown in Table II.   The relative antifungal activity of a rapalog against rapamycin can be determined by any scientific On a molar basis, using antifungal assays that are highly effective and pathogenic fungal strains of interest Can be quantified. For such antifungal assays, in vitro and in vitro  A variety of methods, both in vivo, are known in the art. One example is a certain disease The rapalog has an EC50 of 6 nM for the protozoal fungal strain and the rapalog for the fungal strain If the EC50 of Syn is 2 nM, the relative antifungal activity ("AF") of the rapalog is 0.33. is there. Relative exemption of rapalog for rapamycin as discussed elsewhere herein As with all such comparisons, including determination of epidemic control activity, In order for data to be scientifically valid, it must be compared in parallel under identical conditions. Must be obtained, and must be repeated to obtain statistical significance Absent.   Similarly, the relative immunosuppressive activity of certain rapalogs against rapamycin indicates that Use any scientifically relevant test for immunosuppression of And can be quantified on a molar basis. Immunosuppression, any detection of immune function Possible reduction, eg, reduction of T or B cell numbers or mitogen stimulation Decreased T cell responsiveness can be identified clinically. "Inconvenience As used herein, the term "immunosuppressive" means that it is appropriate for the purpose of immunosuppression. Levels that occur characteristically when rapamycin is administered to human patients at different doses or It means a degree of immunosuppression. That is, undesired immunosuppression results in circulatory T and / or Or B cell concentration, total leukocyte count, T cell responsiveness to mitogen stimulation, delay One of the patient's immune functions, or their secondary symptoms, including a type-sensitivity response, etc. Or a substantial reduction in two or more aspects. One of immunosuppression in human patients A suitable in vitro surrogate test is inhibition of human T cell in vitro proliferation. This is Various human T cells including PBL and Jurkat cells or It is a conventional assay technique that can be performed in many well-known examples using cell lines. Like this Assay rapalog for human immunosuppressive activity and compare it to rapamycin be able to. Immunosuppression against rapamycin as determined by a suitable in vitro assay. Decreased anti-activity predicts reduced immunosuppressive activity in humans relative to rapamycin It will be. Using such in vitro assays, the relative Immunosuppressive activity ("IS") can be assessed. For example, a human T cell proliferation assay If the EC50 of rapalog at 400 nM and that of rapamycin at 1 nM, Has an IS value of 0.0025.   In the above example, the relative antifungal activity / relative immunosuppressive activity of rapalog ("AF / IS") Was 132 (ie, 0.33 / 0.0025).   The term "non-immunosuppressive antifungal rapalog" refers to rapalogs with low AF / IS values. For at least one pathogenic fungal strain, at least 25, preferably at least 100, more preferably Or more than 500, even more preferably more than 1000 Used here. A particularly preferred non-non-immunosuppressive antifungal rapalog is AF / IS value is 5000 or more. On the chemical structure of non-immunosuppressive antifungal rapalog A more detailed description will be given later.   The term “inadequate immunosuppression” in rapalogs refers to the Means a dose that is insufficient to cause immunosuppression.   Non-immunosuppressive antifungal rapalogs include antifungal effective doses and dosing regimens And rapalogs that do not confer an adverse immunosuppressive effect when administered. However However, rapalogs need not be completely devoid of immunosuppressive effects. Rather, Human immunosuppression measured clinically or preferably performed on tissue from the lymphatic system Immunosuppressive effect as measured by in vitro or in vivo surrogate studies 0.1 times or less of the immunosuppressive effect observed or expected with rapamycin, It is preferably 0.01 times or less, and even more preferably 0.005 times or less.   Preferably, the selected non-immunosuppressive antifungal rapalog has its intended antifungal effect. When administered in a manner and in an amount that can produce Does not confer any other toxicity. Other untoward toxicities, as referred to here, are those associated with antifungal therapy. Is the toxicity that prevents the use of rapalogs.Rapalog   The present invention relates to a novel substance as a non-immunosuppressive compound other than the compounds shown in Table II. Anti-fungal rapalogs. A particularly interesting sub-set of such compounds Buset) is represented by the general formula II^C7aIs a compound other than -OMe is there. Based on the findings of the present invention, the rapa shown in Table II known at the time of the present invention We believe that some of the logs constitute non-immunosuppressive antifungal rapalogs. believe. The compounds shown in Table II, as well as all other compounds already reported, The compounds themselves do not form part of the present invention. But still a book The pharmacological methods and related drug materials that are an important part of the invention are described in some aspects. Indicates the use of all non-immunosuppressive antifungal rapalogs, including those listed in Table II. Is included.   Rapalogs of particular interest for implementing various aspects of the present invention are represented by the following general formula II: Compounds that include:Where: And   R^C7aAnd R^C7bIs H and the other is -H, halogen, -OR¹, -S R¹, -OC (O) R¹Or -OC (O) NHR¹, -NHR¹, -NR¹R^Two, -N HC (O) R¹, -NH-SO_Two-R¹Or -R^TwoWhere R^TwoIs aliphatic, Teloaliphatic, aryl, heteroaryl, or alkylaryl (eg, benzyl Or substituted benzyl)   R^C30Is halogen, -OR^ThreeOr (= O),   R^C24Is = O, = NR^Four, = NOR^FourOr = NNHR^Four, -NHOR^FourIf Is -NHNHR^Four, -OR^Four, -OC (O) R^FourOr -OC (O) NR^Four,halogen Or -H;   R^C13Is H, halogen, -OR^Five, -OC (O) R^Five, -OC (O) NHR^Five, -SR^Five , -SC (O) R^Five, -SC (O) NHR^Five, -NR^FiveR^Five', Or -N (R^Five) (CO) R^Five'And   R^C14Is = O, -OR⁶, -NR⁶, -H, -NC (O) R⁶, -OC (O) R⁶Also Is -OC (O) NR⁶And   R^ThreeIs H, -R⁷, -C (O) R⁷Or -C (O) NHR⁷Or C28 and C30 A cyclic moiety (eg, carbonate)   R^C28Is halogen or -OR^ThreeAnd   R^C29Is H, OH or OMe;   Here, each ring substituent is present in either stereochemical direction unless otherwise specified. May be present and R¹, R^Four, R^Five, R⁶, R⁷, R⁹, R^TenAnd R¹¹Haso Each independently from H, aliphatic, heteroaliphatic, aryl or heteroaryl Chosen; and   R⁸Is H, halogen, -CN, = 0, -OH, -NR⁹R^Ten, -OSO_TwoCF_Three, -OSO_TwoF, -OSO_TwoR^Four', -OCOR^Four', -OCONR^Four'R^Five'Or -O CON (OR^Four') R^Five'Where the compound is not rapamycin.   In the case of rapamycin, R^C7aIs -OMe; R^C7bIs H; R^C14, R^C24And And R^C30Are each (= O); R^C13And R^C28Is -OH R^C29Is OMe and R^ThreeAnd R^FourIs H, and the stereoisomer is As shown on page 1. Rapalogs of general formula II useful for practicing the present invention include: Each substituent may be contained in any of the possible stereoisomeric orientations, and Consisting of one stereoisomer substantially free of isomers (> 90% on a molar basis, Preferably> 95% free of other stereoisomers) or It may consist of a mixture of isomers.   Pharmaceutically acceptable derivatives of the aforementioned compounds are also included. Here, "Pharmaceutical The term "acceptable derivative" refers to any pharmaceutically acceptable derivative of such a compound. A salt, an ester or a salt of the ester, or any other addition product or derivative A conductor that, when administered to a patient, is a rapalog as described herein, or Metabolites or residues, preferably those that are antifungal compounds, even more preferably Preferably a compound that is a non-immunosuppressive antifungal agent (direct or indirect Means) thing. That is, pharmaceutically acceptable derivatives are, inter alia, rapalog Prodrugs. Prodrugs are usually pharmacologically active compounds Is significantly reduced, and contains additional moieties that are susceptible to in vivo removal. And a derivative thereby producing a parent compound which is a pharmacologically active species. Prodora One example of a tag is an ester that yields a compound of interest upon cleavage in vivo. La Various prodrugs of pamycin and other compounds, as well as derivatives of the parent compound Materials and methods for making prodrugs are known in the art. Can be applied.   The term "aliphatic" as used herein refers to both saturated and unsaturated linear (i.e., non- Branch), branched, cyclic, or polycyclic aliphatic hydrocarbons, including 1 or 2 The above functional groups may be optionally substituted. Unless otherwise specified, this arch , Other aliphatic groups, alkoxy and acyl groups are preferably 1-8, Contains a total of 1-6 continuous aliphatic carbon atoms. Therefore, typical aliphatic groups include For example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -C H_Two-Cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl , Cyclobutyl, -CH_Two-Cyclobutyl, n-pentyl, sec-pentyl, isope Methyl, tert-pentyl, cyclopentyl, -CH_Two-Cyclopentyl, n-hexyl , Sec-hexyl, cyclohexyl, -CH_Two-A cyclohexyl moiety and the like; They may also have one or more substituents.   Examples of substituents include: -OH, -OR^{2 '}, -SH, -SR^{2 '} , -CHO, ＯO, -COOH (or its ester, carbamate, urea) Oxime or carbonate), -NH_Two(Or its substituted amine, amide , Urea, carbamate or guanidino derivative), halogen, trihaloal Kill, cyano, -SO_Two-CF_Three, -OSO_TwoF, -OS (O)_TwoR¹¹, -SO_TwoNH R¹¹, -NHSO_Two-R¹¹, Sulfate, sulfonate, aryl and hete Loaryl moieties. Aryl and heteroaryl substituents can themselves be substituted or substituted. May be unsubstituted (eg, mono-, di- and tri-alkoxyphenyl; methylene Dioxyphenyl or ethylenedioxyphenyl; halophenyl; or- Phenyl-C (Me)_Two-CH_Two-O-CO- [C_Three~ C₆] Alkyl or alkyla Mino).   The term "aliphatic" thus refers to alkyl, alkenyl, alkynyl, cyclo Loalkyl, cycloalkenyl, and cycloalkynyl moieties is there.   As used herein, the term "alkyl" refers to all linear, branched and cyclic alky! Including a kill group. Similar provisions apply to other general terms such as "alkenyl", "alkynyl" This is also true. Further, the “alkyl”, “alkenyl”, “al “Quinyl” and the like includes both substituted and unsubstituted groups.   The term "alkyl" refers to groups having usually 1 to 8, preferably 1 to 6, carbon atoms. To taste. For example, “alkyl” refers to methyl, ethyl, n-propyl, isopropyl , Cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl Tyl, pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, It can mean isohexyl, cyclohexyl and the like. Suitable substituted alkyl Include, but are not limited to, fluoromethyl, difluoromethyl, Fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2- Hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl and the like. It is.   The term "alkenyl" refers to groups having usually 2 to 8, preferably 2 to 6 carbon atoms. means. For example, "alkenyl" refers to 2-propenyl, 2-butenyl, 3-butenyl , 2-methyl-2-propenyl, 2-hexenyl, 5-hexenyl, 2,3-dimethyl-2-butene Nil and the like. The term "alkynyl" also refers to compounds having usually 2 carbon atoms. To 8, preferably 2 to 6, for example, but not limited to, Pinyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-methyl-4-pentynyl, 2- Hexinyl, 5-hexynyl and the like.   The term “cycloalkyl” as used herein specifically has 3 to 7 carbon atoms. More preferably, it means 3 to 10 groups. Suitable cycloalkyls include, but are not limited to, But not cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl and the like, which are other aliphatic or heteroaliphatic or As with heterocyclic moieties, it may be optionally substituted.   As used herein, the term "heteroaliphatic" refers to a substitution for a carbon atom, for example, oxygen An aliphatic moiety containing one or more sulfur, nitrogen, phosphorus or silicon atoms. To taste. The heteroaliphatic moiety may be branched, unbranched or cyclic and may include morpholino, pyro Heterocyclic groups such as lysinyl are also included.   As used herein, the term "heterocycle" is preferably a ring having a total of 3 to 10 ring atoms. Means a heteroaliphatic radical of the formula, but is not limited to, oxetane, tetrahydro Furanyl, tetrahydropyranyl, aziridine, azetidine, pyrrolidine, pipet Lysine, morpholine, piperazine and the like can be mentioned.   The terms “aryl” and “heteroaryl” as used herein may be substituted A stable monocyclic or polycyclic, heterocyclic ring having 3 to 14 carbon atoms, which may be substituted or unsubstituted; It refers to the unsaturated moiety of telocycles, polycycles, and polyheterocycles. The substituents are as described above. And all of the substituents mentioned. Non-limiting examples of useful aryl ring groups include , Phenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, tri Alkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl , Anthryl, phenanthro and the like. Examples of typical heteroaryl ring groups As thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothia 5-membered monocyclic groups such as zolyl, furazanyl, isoxazolyl, and thiazolyl; pyridi , Pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and other 6-membered monocyclic groups Benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, iso Benzofuranyl, chromenil, xanthenyl, phenoxathienyl, indolizy Nil, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, Quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, Benzothiazole, benzimidazole, tetrahydroquinolinecinnolinyl, Teridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridi Nil, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, And polycyclic heterocyclic groups such as enothiazinyl and phenoxazinyl (eg, Ka tritzky, see Handbook of Heterocyclic Chemistry). Aryl or hete The loaryl moiety is hydroxy, C₁~ C₈Alkoxy, C₁~ C₈Branched or straight chain Alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halo 1 selected from the group consisting of gen, trihalomethyl, cyano, and carboxyl It may be substituted with up to 5 substituents. Thus, an aryl moiety is, for example, Phenyl; and having one or more substituents selected from the group including Including substituted phenyl: halogen such as chloro or fluoro, hydroxy Si, C₁~ C₆Alkyl, acyl, acyloxy, C₁~ C₆Alkoxy (methoxy if Or ethoxy, especially 2,3-, 2,4-, 2,5-, 3,4- or 3,5-dimethoxy Di- or diethoxyphenyl, or methylenedioxyphenyl, or 3- A dialkoxyphenyl moiety such as methoxy-5-ethoxyphenyl; or examples Trialkoxy such as 3,4,5-trimethoxy or triethoxyphenyl Phenyl moiety), 3,5-dimethoxy-4-chlorophenyl and the like. Enyl), amino, -SO_TwoNH_Two, -SO_TwoNH (aliphatic), -SO_TwoN (aliphatic)_Two , -O-aliphatic-COOH, and -O-aliphatic-NH_Two(This is one or two N-aliphatic or N-acyl substituents may be included).   A "halogen" substituent according to the present invention is a fluoro, chloro, bromo, or iodo May be a substituent. Fluoro is often the preferred halogen.   Compounds of general formula II excluding all compounds shown in Table II are of particular interest And constitute an important class of novel compounds. Compounds of this kind are 1, 2, 3 4, 4, 6 or 7 substituent moieties may differ from rapamycin. is there. This class includes, inter alia, C7 and C13; C7 and C14; C7 and C43; C7 and C24; C7 and C28; C7 and C30; C7, C13 and a; C7, C13 and C43; C7, C13 and C24; C7, C13 and C28; C7, C13 and C30; C7, C14 and a; C7, C14 and C24; C7, C14 and C28; C7, C14 and C28; And C30; C7, a and C24; C7, a and C28; C7, a and C30; C7, C24, C30 and C13; C7, C24, C30 and C13; C24, C30 and C14; C24, C30 and C13; C24, C30 and a; C24, C 30 and C14; and C24, C30, C13 and a, Rapalogs that have been updated (all of the forms listed in Table II or previously reported to the public) (Excluding compounds). Antifungal rapalogs, especially non-immunosuppressive antifungal lapalogs Of particular interest are such compounds, including palogs.   A sub-group of rapalogs of general formula II of particular interest for carrying out the method of the invention One of the subsets of concepts is R^C7aIs a moiety other than OMe (or Or a pharmaceutically acceptable derivative thereof). This subset ("C7 Rapalog Kinds)) include R^C7aAnd R^C7bIs H and the other is substituted or unsubstituted Substituted alkenyl, aryl, heteroaryl or -Z-aliphatic, -Z-aryl , -Z-heteroaryl, or -Z-acyl (where Z and Z 'are Each is independently O, S or NH, and acyl is -CHO,-(C = O) -fat Group,-(C = O) -aryl,-(C = O) -heteroaryl,-(C = O) -Z'- Aliphatic, including-(C = O) -Z'-aryl,-(C = O) -Z'-heteroaryl A) a compound selected from the group consisting of: In some aspect of this subset Is R^C7aAnd R^C7bAre each independently selected from the group consisting of: H; Or unsubstituted straight-chain, branched-chain or cyclic alkenyl having 2 to 8 carbon atoms, Sil or alkyl mercapto; and substituted or unsubstituted aryl, Teloaryl, aryloxy or heteroaryloxy, arylmerca Or heteroaryl mercapto. Compounds in this subset include Rikari, R^C7aIs H; (R^C7bTogether with) = O; alkoxy; alkyl mercapto Amino (1 °, 2 ° or 3 °); amide; carbamate; aryl or Is substituted aryl; phenyl or substituted phenyl; substituted or unsubstituted thiof Substituted or unsubstituted heteroaryl such as phenyl, furyl, indolyl; Compounds that are benzyloxy or substituted benzyloxy are included. Of the present invention Examples of other C7 rapalogs and types of C7 rapalogs that may be used to implement the method Is R^C7aAnd R^C7bIs H and the other is -OEt, -O-propyl,- O-butyl, -OCH_TwoCH_Two-OH, -O-benzyl, -O-substituted benzyl (eg, , 3-nitro-, 4-chloro-, 3-iodo-4-diazo-, 3,4-dimethoxy -, And 2-methoxy-), -S-Me, -S-phenyl, -O (CO) Me, -allyl, -CH_TwoC (Me) = CH_Two, -OCH_Two-CCH, -OCH_Two-C C-Me, -OCH_Two-CC-Et, -OCH_Two-CC-CH_Two-OH, or -2 , 4-Dimethoxyphenyl, 2,4,6-trimethoxyphenyl, furanyl, thiophene A group selected from niel, methylthiophenyl, pyrrolyl and indolyl Compounds. In a rapalog of the type described above, the hydroxy substituent of C43 is It may be present in any stereochemical orientation and may be described elsewhere herein. It may be modified as described. C7 rapalogs are also 1, 2, 3, 4 May differ from rapamycin at five or more other positions. (1 Or an embodiment that does not differ from rapamycin at more than one other position is the O7 at C7a Differs from rapamycin in the removal or replacement of the Me moiety. This Of particular interest are the non-immunosuppressive antifungal rapalogs of Buset. As shown in Table II Other C7 rapalogs are novel and are included in the present invention as compounds per se. You.   The rapalogs of general formula II are of interest in the practice of the various methods of the invention. Are a subset of C30, C24 rapalogs, ie, R^C30And R^C24Are both ( = O). Of particular interest is R^C7aIs the part other than OMe Minutes are C30 and C24 rapalogs. In one aspect of this subset, R^C7aAnd And R^C7bAre each independently -H, -OR¹, -SR¹, -OC (O) R¹Or- OC (O) NHR¹, -NHR¹, -NHC (O) R¹, -NH-SO_Two-R¹And- R^TwoWhere R^TwoIs a substituted aryl or allyl or alkylaryl (eg Benzyl or substituted benzyl), provided that R^C7aAnd R^C7bOne of them is H. In one aspect of this subset, R^C30And R^C24Are both -OH (Eg, "S" arrangement). In another aspect, R^C30And R^C24Are independent Or OR^ThreeSelected from. This subset includes, inter alia, R^C30And R^C24 Is OH, and the MeO substituent at C7 of rapamycin is added to the compounds in Table II. All rapalogs substituted with any of the substituents at that position Is mentioned. This subset includes, inter alia, R^C30, R^C24And R^C7aWhen R^C7bRapamycin in which only one or both are different from rapamycin. This subset also differs from rapamycin with respect to part a Embrace. For example, this subset includes compounds of the formula: Where R^C7aAnd R^C7bIs a group other than -OMe. R^C7aYou And / or R^C7bOther substituents of are those disclosed elsewhere herein. is there. Of particular interest is R^C7aAnd R^C7bIs optionally substituted Compounds that are good cycloaliphatic, aryl, heterocyclic, or heteroaryl You. Other compounds included in this subset include 1, 2, 3, 4 or 5 Hydroxyl group is epimerized, fluorinated, alkylated, acylated or other Subject to other modifications by the formation of steles, carbamates, carbonates or ureas Are included. For example, an exemplary compound is the hydrochloride of C43 in general formula III. The xyl group is epimerized and the C28 and C30 hydroxyl groups are alkylated, Compounds linked by silation or carbonate formation.   Another subset of rapalogs of general formula II of particular interest is R^C13And R^C28One One or both are F. In various aspects of this subset, One, two, three, four or five other substituents of general formula II may be substituted for rapamycin. Different from the group. For example, this subset is a C13 file represented by the following structural formula. Luororapalog, C28 fluororapalog and C13, C28-difluororapalog Where R^C7aAnd R^C7bIs as described above:   In particular the immunity of 13-fluororapamycin and analogs and rapamycin itself Derivatives containing various substituents known to not abolish the inhibitory activity Included 13-fluororapalogs are of interest as immunosuppressants. Various other substitutions 13-Fluororapalogs and other fluoro- and difluoro-rapalogs And especially R^C7aIs other than OMe (eg, aryl or heteroaryl or (The others exemplified herein) are of interest as antifungal agents.   Compounds of interest that cross some of the various subsets of compounds described above R in Formula II^C24And R^C30Are other than (= O), and R^C13And R^C28One or A set of rapalogs, both F, or a pharmaceutically acceptable derivative thereof (Set). This set is, inter alia, 24,30-tetrahydro-13-F Rapalogs, 24,30-tetrahydro-28-F rapalogs, and 24,30-tetrahi Includes Dro-13,28-di-F rapalogs, and C7 variants of any of these And where R^C7aIs other than OMe. Part of this set is represented by the following structure: Where R^C7aAnd R^C7bIs as described above:   These compounds are, for example, based on the C14 and C43 substituents of rapamycin itself. R^C14And R^C43Further derivatization by changing one or both of Is also good.   Another subset of compounds of general formula II of particular interest is^C14Is O, OH or Rapalogs other than H, for example, R^C14Is -OR⁶, -NR⁶, -NC (O) R⁶, -OC (O) R⁶Or -OC (O) NR⁶And 1 or 2 for rapamycin Compounds with or without the above other changes.   Another subset of compounds of general formula II of interest is R^C13Is C₁~ C_FourAlkyl moiety And 1 or 2 at other positions relative to rapamycin Compounds with or without the above other changes. For example, this subset (A) Instead of OH of C13,₁~ C_FourR other than alkoxy^C13A substituent, or (b) Instead of MeO of C7, R^C7aAnd R^C7bHaving a substituent, And rapalogs having a different structure from rapamycin.   Another subset of interest is R^C24Is other than (= O) Compound with or without one or more other changes in other positions to the component Things.   Another subset of compounds of general formula II that are of interest in the practice of the method of the present invention Is R^C7aIs -OMe, and R^C30Is not (= O) but R^C24Is (= O) But R^C13Is not -OH, R^C14Is not (= O) and / or R^Three And / or R^FourWherein R is not H, which shares the stereoisomers of rapamycin Is mentioned.   Other compounds of interest include R^C14Include compounds of the general formula II It is.   Further, the present invention provides a method for treating one or more of the 1,2,3,4 or 5,6 positions of rapamycin. Rapalogs whose carbon-carbon double bonds are saturated are replaced by other positions in the molecule. (Eg, one or more of C7, C13, C43, C24, C28 and / or C30) , Regardless of whether they are combined. In this specification In any of the disclosed compounds, C3, C3 4 The double bond may be epoxidized;_TwoOH or -CH_Two OMe may be substituted; C43 hydroxy may be F, Cl or H or other substituents Or that the C42 methoxy moiety may be demethylated Will be appreciated. Also, part a may be replaced with any of the following:   The non-immunosuppressive antifungal rapalogs of all subsets of the compounds described above are particularly It is considered a significant compound.   The compounds disclosed herein may contain one or more pharmaceutically acceptable excipients, Prescription together with agents, carriers, etc. to prevent or treat pathogenic fungal infections. Human or other mammalian recipients by any of the pharmaceutically approved routes of A pharmaceutical or veterinary composition for administration to a subject can be prepared.   Rapalogs of the type disclosed herein (including various subsets and subclasses) Are needed as a way to treat or prevent infection with pathogenic fungi. Can be administered to an individual. One or more non-immunosuppressive antifungal rapa In some embodiments of the invention involving the administration of a log, the administration of rapalog Preferably, the recipient does not cause adverse immunosuppression. Compound administration is Typically, one or more pharmaceutically acceptable carriers, diluents, or other A medicament containing the compound, together with excipients, in an amount effective to prevent or inhibit fungal growth. It takes the form of a drug or veterinary composition.Synthetic guidance   The production of rapamycin by fermentation and complete synthesis is known. As fermented products It is also known to produce large numbers of rapalogs. As such a rapalog Especially to the characteristic cyclohexyl or pipecolate ring of rapamycin A rapalog having another portion, as well as C7-desmethylrapamycin, C29-de Smethylrapamycin and C29-desmethoxyrapamycin.   Performs various chemical transformations of rapamycin and structurally related macrolides. Methods and materials are well known in the art and can be used to ferment rapamycin and The same applies to the method of obtaining the seed rapalog. Rapamycin and various rapalogs Many such chemical transformations are disclosed in the patent documents listed in Table 1 above. Which are applicable in the practice of the present invention, as well as chemical synthesis and product recovery; It is illustrative of the skill and level of knowledge in the field of purification and formulation. Desired The following are representative conversions and / or references that can be taken to produce the rapalogs of An example is shown below.   The synthetic procedure for various fluoro and difluororapalogs is shown in the following scheme: Note: In place of the triethylsilyl protecting moiety, TES, replace the triisopropyl homolog, TIP.     May be used. DAST reaction to double protected rapamycin optionally at 0 ° C     May be performed.   The synthetic procedures for various 24,30-tetrahydrorapalogs are shown below:  As a further example, 13-fluororapamycin may be substituted for rapamycin. Emit to give the corresponding 13-fluoro-24,30-tetrahydroC7 rapalog.   One example of another method for synthesizing a C13 derivative is shown below.  Further, the rapalog used in the present invention and an intermediate for producing such rapalog are: For example, as described in Katz et al, WO 93/13663 and Cane et al, WO 97/02358. It is also conceivable to produce by directed biosynthesis such as   The non-immunosuppressive antifungal rapalogs of the present invention and other novel rapalogs are described herein. Utilizing methods and materials known in the art as described by the disclosure provided in It can be manufactured by those skilled in the art. For example, the methods and materials above Can be applied from known methods described or referenced in the documents cited in The entire contents of the document are incorporated herein by reference. Additional explanations and illustrations may be given to the practitioner. Some examples and further explanations are provided herein. Normal in this technical field Chemists with knowledge of can easily modify the above description (eg, during synthesis After the appropriate protecting groups have been added to sensitive areas, they can be protected if necessary or undesirable. Protecting groups can be removed) and other synthetic methods can be easily determined. Let's do it.Assay for human FKBP and FRAP binding   Rapamycin binds to the human protein FKBP12 and binds hFKBP12 and FRAP (yeast Human counterpart of proteins TOR1 and TOR2) and three-partite complex (tripartite complex) It is known to generate Rapalog has an ability to bind to human FKBP12. Force and / or human FKBP12 and human FRAP (or Fusion protein or fragment) and the ability to form a three-component aggregate Characterization and comparison with rapamycin. See WO 96/41865, the entire contents of which are incorporated herein by reference. The application states that certain compounds Ability to bind to FKBP12 or the FRB domain of human FKBP12 and human FRAP, respectively Form a ternary aggregate with the protein containing the protein (ie, "heterodimerization"). Disclose various materials and methods that can be used to qualify I have. Such assays include measuring binding with a fluorescence polarization assay. It is. In another assay, the ability of a compound to form a ternary aggregate is determined. Reporter gene produced by mammalian cells genetically engineered in the presence of a compound Cell-based transcription assays that measure indirectly by correlation to the observed level of product is there. Similar cell-based assays can be performed on genetically engineered yeast cells. You. See, for example, WO 95/33052 (Berlin et al.).Human immunosuppression assay   Several assays for immunosuppressive activity are known. As an example that is not intended to be limiting Thus, in mitogenesis using human T cells, immunosuppressive activity (binding activity) Gender). Such a human T cell proliferation assay B. The appropriate in vitro assay used to determine the AF / IS value of the rapalog of interest. This is one example of (a).   In one embodiment, a male BALB / c donor is transplanted into a male C3H (H-2K) recipient. In vivo assay designed to measure the survival of a pinch skin graft Representative compounds can be evaluated in the test method. This method is described by Billingham et al. . (1951) J.I. Exp. Biol. 28: 385-402. Briefly explain And a pinch skin graft from the donor as an allograft Implant on the back and use a (allogeneic) syngeneic graft in the same area as a control. Recipe En Can be administered intraperitoneally, intravenously, or with any of the varying concentrations of the test rapalog compound. Oral treatment. Rapamycin can be used as a test control. Unprocessed The recipient is the rejection control. Monitor the graft daily and make sure the graft is dry Observation records are made until black scabs are formed. Consider this a rejection date I can. Compare average graft survival (days ± standard deviation) of drug-treated group to control group . Animals required to produce mean graft survival extended to the same time as control grafts The ED50 value can be calculated as the average ratio of rapalog weight to weight. Departure The immunosuppressive activity of Ming rapalog compounds, such as the immunosuppressive ED50 value, is It can be determined by an elementary test and a delayed type hypersensitivity test. An example of a hemolysin test is D.H Campbell et al., “Methods in Immunology,” W.A. Benjamin, Ne w York 1963, pp. 172-175, humoral, ie, antibody immunity This is a method of measuring the response. In the delayed type hypersensitivity test, the test mice mount a cellular immune response to ycobacterium tuberculosis) H37Ra (mou nt) Determine the effect of the test rapalog compound on performance. Mouse to the base of the tail Sensitizes antigen by subcutaneous administration. Delayed type at any time starting on day 6 after sensitization The onset of a hypersensitivity response can be measured, but is usually performed on day 9 as follows. : Inject rapalog in the right hind leg and saline in the left hind leg (control). Both legs 24 hours later, a significant increase in the volume of the right hind limb is indicated for effective delayed type hypersensitivity. Measure the answer. All compounds are administered by the subcutaneous route. ED50 (mg / kg) Administered subcutaneously as needed to reduce antibody activity by 50% when compared to controls Expressed as the ratio of rapalog's weight (in milligrams) to body weight (in kilograms) You. In this case, the lower the ED50 value for rapalog, the stronger the immunosuppressive effect You.   Rapalog's immunosuppressive activity can also be demonstrated by graft-versus-host reaction (GVHR). Wear. In one exemplary embodiment, to induce GVHR, C57 B1 / 6XA / J (F6AF1) Male mice are injected intravenously with parental (C57 B1 / 6J) spleen and lymph node cells. So Test compound (rapalog) is orally administered for 10 days from the day before cell transfer . One day after the last treatment, the test animals are sacrificed and their spleens are excised and weighed. Host The spleen hugeness is the result of GVHR. To some extent, the spleen infiltrates and enlarges. Is the host's own cells, but the cells do the graft that reacts against the host It is because of the presence of the cells. The amount of spleen swelling (splenomegaly) is determined by the weight of GVHR. A measure of severity. When performing GVHR, the animals in the experimental group have parental cells, ie, Inject cells of the same type but different genotypes. These cells increase the weight of the spleen cause. In the control group, the syngeneic cells, that is, the spleen Inject cells with the same genotype. Compounds administered to mice in the experimental group Efficacy (ED50) was determined by spleen weight of untreated and syngeneic control cells treated GVH animals Measured by comparing with Rapalog has an ED50 value of immunosuppressive activity et al. (1955) Acta. Microbiol. Acad. Sci. Hung., 3: 105 or Cottney et al. (1980) Can be measured according to the method of Agents and Actions, 10:43 .   Rapalog's immunosuppressive activity can also be demonstrated in spleen atrophy tests, such as drug administration to BDF1 mice. It can also be shown by a decrease in spleen weight after oral administration for the next 7 days. Day 8 Let the mice be lethal. The percentage reduction in spleen weight is determined for each dose level.Assay for fungal FKBP and FRAP binding   The ability of the compounds of general formula II to bind their FKBP fungal counterparts and / or Is capable of forming a ternary complex with its FKBP counterpart and the fungal FRAP or TOR counterpart In terms of power, the assay materials referred to above ("Human Immunosuppression Assay") and By analogy with the method, characterization using the corresponding peptide sequence of the fungus instead of the human And rapamycin. The sequence for Candida FRAP is PCT / US95 / 06722 (Miotix, Inc.). Candida FKBP counterparts are also known. You. Ferrara et al. (1992) Gene 113, 125-127 (rapamycin binding protein , "RBP"). The cryptocox-corresponding FRB sequence is provided below.Assay for activity against pathogenic fungi   Compared to rapamycin for use in determining the AF / IS value of rapalog, The relative activity of rapalogs against pathogenic fungi can be determined, for example, by Diagn Micro and Infe ct Diseases 21: 129-133 (1995) It is measured directly on fungal organisms by microtiter plate application. Antifungal activity Can also be determined in a complete animal model of fungal infection. For example, lung mucor Mouse model of steroid treatment [Goldani, L.Z. and Sugar, A.M. (1994) Antimicrob. Chemother. 33: 369-372]. As an example, heel In some studies, large numbers of animals are used, starting before, concurrently with, or after fungal infection. , Each without rapalog, various doses of rapalog (and / or 1 or Administration in combination with two or more other antifungal agents) or a positive control (eg, Amphoteri) Administer Syn B). Animals are dosed with a defined dose of rapalog, positive control, or vehicle. Once every 24 hours. Continue treatment for a specified number of days (eg, within 10 days) You. Animals are observed for some time after the treatment period (eg, for a total of 3 weeks) and mortality is assessed daily. Value. The model was designed to mimic human subjects susceptible to infection, It can include lung, vagina and other models of infection, and may include other treatments (eg, May or may not be used in combination.   To further illustrate, in vivo therapeutic efficacy (ED50, eg, rapalog mg / test animal k One method for determining (expressed as g) is the rodent model system. For example, A fungal pathogen to the mouse, about 10 times the 50% lethal dose of the pathogen (10⁶C. albicans fine (Vesicles / mouse) by intravenous injection or the like. Immediately after this fungal infection, The log compound is administered to mice at a predetermined dose. ED50 was recorded 20 days after infection Van der Waerden (Arch. Exp. Pathol. Pharmakol. 195, 389-412, 1940). Generally, untreated control animals die 7-13 days after infection Die.   In another example embodiment, 28 Sabouraud dextrose agar (SDA) slopes C. grown at 48 ° C. for 48 days. albicans (Candida albicans) Wisconsin (C43) And C. suspend tropicalis (Candida tropicalis) (C112) in saline Adjust the density so that the transmittance at 550 nm is 46% with a photometer. This inoculum is Further adjust with a hemacytometer and measure about 1 by plate count. Or 5 × 10⁷Confirm that it is CFU / ml. CF-1 mouse (white, male, about 20 g Harlan Sprague Dawley, Inc. Tail, Indianapolis, Indiana) 1 or 5 × 10 to vein⁶Infected by injection of CFU. Ethanol antifungal: Intravenous or subcutaneous injection in water (10:90), 4 hours after infection and afterwards Administer once a day for another 3 or 4 days. Survival is monitored daily. ED50 It can be defined as the dose that allows 50% survival of the mouse.Fungal FKBP and FRB domains to facilitate discovery and development of antifungal rapalogs Cloning of homologs   The discovery and optimization of specific antifungal rapalogs has led to the discovery of FKBP and FR from fungal pathogens. Cloning of the AP homolog or a portion thereof may be facilitated. That To obtain commonly available nucleotide sequences encoding FRAP from various species, Used to anneal to a conserved region adjacent to the FRB domain. Immers can be designed. This technique is based on the pathogenic fungus Cryptococcus n Clonin, a FRB counterpart from eoformans (Cryptocox neoformans) Example. CDNA or genomic DNA from the target fungus can be The product can be amplified and cloned and sequenced. Can be. Alternatively, known sequences can be used as probes (or Can be used to design shorter synthetic oligonucleotide probes) These probes may be labeled and prepared from pathogenic fungi using standard methods. Can be used to screen isolated cDNA or genomic libraries. this These procedures can be used to isolate fungal FKBP homologs as well. FK The sequence of the BP homolog, and / or the FRB domain from the FRAP homolog, Align with human and other known sequences to determine where amino acid differences have occurred Can be specified.   The nucleotide sequences encoding FKBP and FRB homologs from fungal pathogens are: It can be used in a variety of ways for the discovery and improvement of antifungal rapalogs. For example, Two chimeric transcription factors whose reporter gene transcription is rapamycin or rapalog (Including at least one FKBP domain and at least one FRB domain Also includes a screen that is dependent on the ability to heterodimerize Good. Such assays may be performed using the methods described in WO 96/41865 for mammalian cells. And materials, and for yeast cells, the methods and materials described in WO 95/33052. And in each case at least one, and preferably Or both fungal nucleotide sequences in place of the corresponding human nucleotide sequences Used. Immunosuppressive activity of rapamycin in mammals and cell proliferation in fungi The ability to inhibit reproduction depends on heterodimerization of endogenous FKBP and FRAP proteins The activity of rapalog in the transcription assay is dependent on the fusion FKBP and FRB domains. This is one method for evaluating the activity of rapalog on cells derived from the source organism. Therefore, using a chimeric transcription factor containing a fungal FKBP and / or FRB domain, Indirectly assess the effect of various rapalogs on fungal growth using a modified assay be able to. If only one of these fungal sequences is available, the other Is a known sequence from a related organism, such as FKB or TOR from Candida albicans, May be substituted, but this is less preferred. These assays, for example, For example, rapalog may be used as part of an inference program to optimize antifungal activity. Lapalog for magnitude of propensity to interact with fungal FKBP and FRB proteins May be useful for linking. However, this assay is not AF or IS Since it is not a direct measure of activity, it can be used to calculate AF / IS ratios for AF or IS It is important not to use it to determine the value.   Example 9 below shows the FRB domain homolog from the pathogenic fungus Cryptococcus neoformans. It is the first to describe the cloning and nucleotide sequence of a log. Departure Light is the nucleotide sequence; the same peptide sequence or at least 90% of it Other nucleotides encoding a peptide sequence, preferably at least 95% identical Sequence; preferably 15 or more, more preferably about 25 or more, even more preferably about 50 A nucleotide sequence encoding a fragment thereof comprising the above amino acid residues; The disclosed C.I. Neoformans FRB peptide sequence, part or all, to different species Nucleotides encoding the fusion protein, including together with the derived peptide sequence A sequence; any one of the nucleotide sequences described above, Vector containing heterologous DNA containing conventional genetic elements such as sir, selectable markers, etc. -(This applies to cloning, transfection and bacterial, yeast, insect Or heterologous expression in mammalian host cells); and such vectors -Transfected cells. The nucleotide sequence can be ligated therein. Suitable vectors as described are well known in the art. Many types of city It is sold and the materials and methods for using it are well known and widely It is used. Thus, the nucleotide encoding the Cryptococcus neoformans FRB Otide sequence replaces the nucleotide sequence encoding the FRB domain of human FRAP In addition, it can be used in a transcription assay as described in the previous section.   Another use of the fungal FKBP and FRB domain nucleotide sequences is in pathogen-specific Very little heterodimerizes with rapalogs, i.e. human FKBP and FRAP (Less immunosuppressive) but heterologous to fungal FKBP and FRAP proteins The use of rapalogs, which can be dimerized, in speculative design. this is Ternary complex between human, FKBP12, rapamycin, and the FRB domain of human FRAP It utilizes the availability of the X-ray crystal structure of the body (three-component association). Fungus FK Using the predicted protein sequence of the BP and / or FRB domains, Utilizing known techniques and computer programs in the field, Using the coordinates of the robot, a homology model of those three-dimensional structures can be constructed. Wear. Examining them to find significantly different proteins in the predicted ternary complex A region near the interface with rapamycin was identified, and then fungal proteins were selectively or Would be specifically matched, but of human and / or mammalian origin Otherwise, determine the position and design of the substituents on the rapamycin molecule.   The use of sequence and modeling data to derive antifungal rapalogs FRAP domain of FRAP, S. cerevisiae TOR1 and TO R2, Candida albicans TOR FRB domain (WO95 / 33052) and Cryptococcus n This can be exemplified by comparing the sequences of the eoformans TOR FRB domain (Example 9). Wear.  Residue 2098 (human number) is a threonine in the human sequence; cerevisiae And asparagine in the Candida albicans sequence; gluta in neoformans Min. This residue is the rapamycin C7-medium in the crystal structure of the human ternary complex. It is in direct contact with the toxic part. Only human proteins have β-branched amino acids at this position. Since it has a non-acid side chain, when it forms a complex with FKBP, the C7-substituted rapalog Structural differences between proteins that may be specifically or selectively recognized Maybe. This knowledge should be used as a basis for modeling as described above. Can be.   A third use of the fungal FKBP and FRB homolog sequences is in repetitive and inferential drug design. Provides direct structural information about rapalog joins for instrumentation and optimization Is Rukoto. Encodes a fungal polypeptide by methods well known in the art. The nucleotide sequence can be cloned into bacterial, insect and / or mammalian expression vectors. To express and purify large amounts of protein. Nuclear magnetic resonance (NMR) and / or X-ray crystallography techniques to identify the protein German or rapalog and / or homologous or heterologous partner protein (FR Determine the three-dimensional structure of the complex with FKBP for B and FRB for FKBP) Can be The solution of these structures is the locus of the human ternary complex as a starting model. This can be significantly facilitated by using a molecular replacement technique using a target. Confirm the structure determination of the fungal FKBP and FRB domains by confirming the modeling results (see above). And specific additional fungal proteins compared to those of mammalian origin It can be used for identifying feature points. In addition, candidate antifungal rapalogs and fungi The structure of the complex with the protein is used to confirm the prediction of their binding mode. And to further enhance their affinity and / or selectivity. It can also be used to induce further denaturation.Pharmaceutical composition   The invention relates to at least one rapalog, preferably a non-immunosuppressive as described above. Anti-fungal rapalog and a pharmaceutically acceptable carrier that forms the rapalog drug composition. It also relates to a pharmaceutical composition comprising the body. Rapalog should be invested in patients who need it. When given, it is present in an amount effective to prevent or treat pathogenic fungal infections. this Pharmaceutical compositions also adversely affect the ability of rapalog to achieve its intended antifungal function And other additives that do not have an effect, many examples of which can be found in the art. Is known.   Rapamycin and various rapalogs may be in free form or as appropriate or desired. If present, it may be present in the form of pharmaceutically acceptable derivatives including esters, salts, etc. You. Pharmaceutically acceptable salts and their preparation are well known to those skilled in the art. This kind of Pharmaceutically acceptable salts of the compounds include, for example, inorganic or organic acids or bases. Conventional non-toxic salts or quaternary ammonium salts of this compound are formed You. The compounds of the present invention may form hydrates or solvates. Charged compound Forms hydrated species when freeze-dried with water and is in solution with an appropriate organic solvent It is known to those skilled in the art that concentrating at will form solvate species.   The amount of rapalog that is effective in treating or preventing infection with a particular fungal pathogen Determined in part by standard clinical techniques, depending in part on the fungal nature and extent of infection can do. In addition, to help determine optimal dosage ranges, In vivo assays may optionally be employed. Effective amounts can be determined by in vitro assays or Preferably, it may be extrapolated from dose-response curves obtained from animal model tests. Strict Close dose levels should be determined by the attending physician or other health care provider , Route of administration, and age, weight, sex and general health of the individual (patient) The nature, severity, and clinical stage of the infection; Will vary depending on known factors.   Effective amounts of rapalog / kg of mammal per day, typically from about 0.01 to About 50 mg / kg, preferably in the range of about 0.1 to about 10 mg / kg, one or more times Will be administered separately. In general, the compounds of the invention will be useful in patients in need of such treatment. May be administered within a daily dose range of about 1 to about 2000 mg per person. How much is rapalog In embodiments where such residual immunosuppressive effects may occur, the dosage may be It is preferable to make the amount smaller than that required for production.   The term "pharmaceutically acceptable carrier" means that rapalog exerts its intended antifungal function. A carrier or excipient that allows the patient to administer the rapalog to accomplish It means to include. Carriers include, for example, saline of pharmaceutically acceptable quality , Buffered saline, dextrose, water, glycerol, ethanol, and These mixtures are mentioned and will be explained in more detail later. The composition may also be May contain small amounts of wetting or emulsifying agents, or pH buffering agents.   Pharmaceutical compositions include liquid solutions, suspensions, emulsions, tablets, pills, capsules, It can take the form of an active formulation or powder. The composition is a conventional triglyceride Can be formulated as a suppository using the binder and carrier of the above. Oral prescription Quality mannitol, lactose, starch, magnesium stearate, sacchar It may contain standard carriers such as sodium, cellulose, magnesium carbonate and the like.   The formulation depends on the desired formulation, mixing of components, granulation (granulation) and compression, or Includes operations such as dissolution as appropriate. The pharmaceutical carrier used is, for example, a solid Any of liquids may be used. Examples of solid carriers include lactose, clay, sucrose, talc , Gelatin, agar, pectin, acacia, magnesium stearate, steari Acid and the like. Solid carriers include flavors, lubricants, solubilizers, suspending agents, fillers, Can also act as a glidant, compression aid, binder, or disintegrant It may contain one or more substances and is an encapsulating material, Is also good. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. You. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and the dose may be adjusted Compress to desired shape and dimensions. The content of the active ingredient in powders and tablets is preferably Is up to 99%. Suitable solid carriers include, for example, calcium phosphate, Magnesium alate, talc, sugars, lactose, dextrin, starch, gelatin , Cellulose, methylcellulose, sodium carboxymethylcellulose, Polyvinyl pyrrolidone, low melting waxes and ion exchange resins. liquid Examples of body carriers include syrup, peanut oil, olive oil, water and the like. . Liquid carriers include solutions, suspensions, emulsions, syrups, elixirs and pressurized Used in the preparation of compositions. Drugs such as water, organic solvents, and mixtures of both Dissolved or suspended in a physiologically acceptable liquid carrier or pharmaceutically acceptable oil or fat Can be made. Liquid carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, Flavors, suspending agents, thickeners, coloring agents, viscosity modifiers, stabilizers, osmotic pressure regulators, etc. Other suitable pharmaceutical excipients. Liquid carrier for oral and parenteral administration A suitable example is water (partially containing the above-mentioned additives, for example, cellulose derivatives). Having, preferably sodium carboxymethyl cellulose solution), alcohol (Including monohydric and polyhydric alcohols, such as glycols) and their derivatives There are conductors, as well as oils (eg, fractionated coconut oil and arachis oil). Non-tradition For buccal administration, carriers include ethyl oleate and isopropyl myristate. Such an oily ester may be used. Sterile liquid carrier is a sterile liquid form for parenteral administration Useful for aqueous compositions. Liquid carriers for pressurized compositions include halogenated hydrocarbons and others. Pharmaceutically acceptable propellants. Liquid drug compositions that are sterile solutions or suspensions Objects can be utilized, for example, by intramuscular, intraperitoneal, or subcutaneous injection. The sterile solution can also be administered intravenously. Compounds can also be liquids or solids. Orally administered in any of the composition forms. Carrier or excipient is monos Glyceryl theate or glyceryl distearate alone or together with Box, ethyl cellulose, hydroxypropyl methyl cellulose, methyl meta Contains slow-release materials well known in the art, such as combinations with acrylates and the like. It may be. When formulated for oral administration, PHOSAL PG-50 (1,2-propylene glyco Concentrate with phospholipids, A. Nattermann & Cie. GmbH) 0.01% Tween 80 solution Has been found to provide an acceptable oral formulation for rapamycin. this The solution can also be applied to formulations for various rapalogs. Various dosage forms can be adopted . When a solid carrier is used, the preparation is compressed into tablets or hardened in powder or pellet form. Or into troches or rosins. can do. The amount of solid carrier can vary widely but preferably is about 25 mg. It will be about 1 g. If a liquid carrier is used, the preparation may be syrup, emulsion Solutions, sterile injectable solutions in soft gelatin capsules, ampules or vials Or a suspension or non-aqueous liquid suspension. Obtain a stable water-soluble dosage form Pharmaceutically acceptable salt of rapalog with 0.3M succinic or citric acid It may be dissolved in an aqueous solution of an organic acid or an inorganic acid such as a liquid. Or acid The conductor can be dissolved in a suitable basic solution. Uses soluble salt forms If this is not possible, the compound is dissolved in a suitable co-solvent or a mixture of two or more co-solvents. Allow to dissolve. Examples of such suitable co-solvents include, but are not limited to, Alcohol, propylene glycol, polyethylene glycol 300, polysorbet Glycerin, polyoxyethylated fatty acids, fatty alcohols or glycerol Hydroxy fatty acid esters, etc., and a concentration within the range of 0 to 60% of the total volume. Used in.   Various delivery systems are known, including rapalog, or various formulations thereof (tablets). , Capsules, injections, liposome encapsulations, microparticles, microcapsules, etc. ) Can be administered. The introduction method is limited to this But not skin, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, lung, epidural, Ocular and oral routes, which are usually preferred.   Compounds may be administered by any convenient or otherwise advantageous route, e.g., by infusion or Is given by bolus injection to the epithelial or mucosal skin lining (eg, oral mucosa, rectum and intestine). May be administered by absorption through the mucosa of the tract, and may be combined with other biologically active agents. They may be administered together. Administration can be systemic or local. Nostrils, bronchial or pulmonary For the treatment or prevention of infection, the preferred route of administration is oral, nasal, or bronchial Aerosol or nebulizer. In certain embodiments, the compound requires treatment It may be desirable to administer locally to the site where it is to be. This is, for example, (Not always) Local infusion during surgery, local application, injection, use of catheter Or as a suppository or as a skin patch or graft (this graft is Porous, non-porous, or containing membranes or fibers, such as <sialastic> membranes Gelatinous materials). In certain embodiments In pharmaceutical compositions used for intravenous administration to humans Prescription according to the appropriate technique. Typically, compositions for intravenous administration are sterile isotonic aqueous solutions The solution in the impingement. If necessary, the composition may further comprise a solubilizing agent and an injection site. It may contain a local anesthetic to relieve pain. Generally, each component is separate Or mixed together to form a unit dose (single dose). Place the lyophilized powder in a sealed container, such as an ampoule or sachet, indicating the amount of active ingredient. Or as an anhydrous concentrate. If the composition is to be administered by infusion, It can be dispensed with an infusion bottle containing sterile medicinal water or saline. composition If the substance is administered by injection, the components can be mixed before administration. An ampoule of sterile water for injection or saline can be provided. Combination of effective amount Is administered to an individual by directly administering the compound to the affected area of the individual's skin. It can also be performed locally. To do this, use gels, ointments, lotions, or creams. The compound is administered in a composition that includes a pharmaceutically acceptable topical carrier, such as a cream. Or applied. Carriers include water, glycerol, alcohol, propylene glycol With recalls, fatty alcohols, triglycerides, fatty acid esters, or mineral oils Such carriers include, but are not limited to. Other topical carriers , Liquid paraffin, isopropyl palmitate, polyethylene glycol, eta Nol (95%), aqueous solution of polyoxyethylene monolaurate (5%), or lau Aqueous sodium sulphate solution (5%). Antioxidant, humectant, viscosity stable Other materials, such as additives such as agents, may be added as needed. In Azone Such a transdermal penetration enhancer can also be included. Further, in certain embodiments, The compound may be placed inside equipment placed on, in, or under the skin Is also expected. Such devices include compounds with passive or active release mechanisms. Patches, implants, and injections that release liposomes into the skin. Make various prescriptions Materials and methods are well known in the art and have applications in the practice of the present invention. can do. For example, US Pat. Nos. 5,182,293 and 4,837,311 (Tablet , Capsules and other oral and intravenous formulations) and European patents Published Application No. 0 649 659 (published April 26, 1995; rapamycin treatment for intravenous administration) 0648494 (published April 19, 1995; rapamycin treatment for oral administration) ). See also U.S. Patent No. 5,362,735.   In a preferred embodiment, rapalog is for oral administration, for example, solid tablets, pills, Capsules, caplets, etc. (hereinafter collectively referred to as "tablets") or aqueous solutions or suspensions It is prescribed in the form of In a preferred embodiment of the rapalog in tablet form, 20 tablets are taken at one time. Amount of rapalog (or multiple rapalogs) supplied in 20 tablets as taken Is at least 50% effective (ED50), e.g., at least 50% To give a rapalog dose of a dose that has shown a numerical effect of inhibiting bacterial cell growth It is preferred to formulate tablets. More preferably supplied in 10, 5, 2 or 1 tablet The total amount of rapalogs (or multiple rapalogs) Tablets are given to give at least the ED50 amount to the mammal. In another aspect , Rapalog (or 20 or 5 or 2 tablets taken in 24 hours) The amount of the multiple rapalogs should be at least as high as the EC50 concentration (eg, inhibition of fungal cell growth). Or 50% of the maximum effect on the statistical reduction of fungal infection levels) The dosing regimen gives the plasma rapalog concentration on average. The ED50 amount for humans is 10 Based on a weight of ~ 250 pounds (4.5-113 kg), but more preferably a weight of 100-25 For an adult weighing 0 pounds (45-113 kg). In a preferred embodiment, a single dose tablet The agent (1-20 tablets) supplies about 0.25-1250 mg of rapalog.   In addition, rapalog can be used for parenteral administration, for example, for subcutaneous, intramuscular or intravenous injection. It can also be formulated for administration. For example, rapalog may be added to a sterile solution or suspension (hereinafter (Collectively referred to as “injection solution” below). Injection solution, 200cc large injection The amount of rapalog (or rapalogs) supplied in the at least 50% effective amount It is preferred to formulate to give a rapalog amount. More preferably, 100, 50 Rapalog (or multiple rapalogs) delivered in 25, 10, 5, 5, 2.5 or 1 cc injections Prescribe the injection so that the total volume of the log) gives the patient an ED50 volume. In another aspect , Supplied in a total of 100 cc injection, injected at least twice in 24 hours If the amount of palog (or rapalogs) is at least the EC50 concentration of the average plasma laparo The dosage regimen gives the average concentration of the drug. In a preferred embodiment, a single injection is given. Provides about 0.25 to 1250 mg rapalog. For continuous intravenous injection (eg, infusion, push) Rapalog in the form of a sterile dilute solution or suspension (hereinafter referred to as "intravenous solution") Can be supplied at This intravenous solution is supplied in 1L of rapalog (or Multiple rapalogs) at least 50% if administered intravenously for 15 minutes or less It is preferred to formulate to provide an effective amount of rapalog. More preferably, Rapalog supplied in 1 L fluid administered intravenously for 60, 90, 120 or 240 minutes ( Or multiple rapalogs) to give the patient an ED50 dose to the patient I do. In a preferred embodiment, one intravenous "bag" contains about 0.25 to 5000 per liter of intravenous fluid. mg, more preferably 0.25 to 2500 mg, even more preferably 0.25 to 1250 mg of rapalog Supply. As mentioned above, preferred rapalog pharmaceutical formulations are injection or infusion Immunosuppression of the host, whether administered orally (or other route of administration) A dose less than the ED50, more preferably a dose at least an order of magnitude less, Even more preferably, at least 2, 3 or 4 orders of magnitude less rapalog is provided Try. That is, the dose of rapalog is defined as an immunosuppressive deficient amount. In a preferred embodiment, the injection solution Or the amount of rapalog supplied in tablets is less than the EC50 for rapalog Let's give the serum rapalog concentration.   At least one rapalog as described above, and FK506, rapamycin, cyclo Immunosuppressants such as sporin A; amphotericin B, its analogs also derivatives or other Antifungal agents such as polyene macrolide antibiotics; Flucytosine; Griseofulubi For example, clotrimazole, miconazole, ketoconazole, econazole , Butconazole, oxyconazole, terconazole, itraconazole if Or imidazole or triazole antifungal agents such as fluconazole or One or more other antifungal agents as described; one or more antibacterial Agent; infected with one or more antiviral agents or HIV as described above Other agents for treating the patient; or one or more immune response enhancers, Is also formulated as described above, or in the formulation Based on the prescription materials and methods used for the other drug it can. If combined with one or more other antifungal agents, consider combination To reduce the amount of one or more active ingredients (the amount used in a single formulation). Compared to). Alternatively, rapalog and the compounded drug may be separately prescribed.Wrapped rapalog   The present invention also provides a packaged rapalog, preferably a packaged non-immunosuppressive antifungal. Also related to sex rapalogs. The term refers to at least one rapalog as described above. As an antifungal agent without causing adverse immunosuppressive effects on human patients It is meant to include those packaged with instructions for administering the rapalog. Part of In embodiments, the non-immunosuppressive antifungal rapalog is a sub-class of the preferred compounds described above. Be a member of any of the sets. In some aspects, the non-immunosuppressive antifungal rapa The logs can be found in WO94 / 02136, WO95 / 16691, U.S. Pat.No. 5,583,139 or 5,527,907 (The contents of each of these documents are incorporated herein). Rapa The log may be packaged alone with the instructions, or other rapalog, rapamai Syn or other components or additives (eg, one or more of the pharmaceutical compositions of the present invention or (Two or more components). The packaging comprises the pharmaceutical composition of the invention. And one or more containers containing one or more of the following ingredients. Or Such containers may contain governmental authorities that supervise the manufacture, use, or sale of pharmaceutical or biological products. A notice in the form specified by the institution may be optionally attached, and the notice Reflects the regulatory approval of manufacturing, use, or sale for administration to a subject.How to treat fungal infections   The invention also relates to a method for treating or preventing a pathogenic fungal infection. like this Infections include, for example, aspergillosis, including invasive pulmonary aspergillosis; Brass including deep or fast-growing infections and central nervous system blast mycosis Stomosis; for example, kidney stones, urinary tract obstruction, kidney transplantation or poorly managed diabetes mellitus Candidiasis, including retrograde candidiasis in the urinary tract, found in patients with Tas; other chemotherapy Coccidioidomycosis, including chronic diseases that do not respond adequately to Histoplasmosis; for example, craniofacial mucormycosis and pulmonary mucormycosis Mucormycosis, including mycosis; paracoccidioidomycosis; and sporotrich Disease. The method of the present invention may comprise at least one rapalog as described above. A non-immunosuppressive antifungal rapalog, preferably in a human patient, Administered to treat or prevent fungal infections without eliciting beneficial immunosuppressive effects Including. In some aspects, the non-immunosuppressive antifungal rapalog is as defined above. A member of any of the preferred subsets of compounds. In some embodiments, non-immune Inhibitory antifungal rapalogs are described in WO94 / 02136, WO95 / 16691, U.S. Pat. Or US Patent No. 5,527,907. In some embodiments, Rapalog may be replaced with amphotericin B, or imidazole or In combination with one or more non-rapalog antifungal agents, such as lyazoles Administer.   Pathogenic fungal infections include, for example, Candida spp., Trichophyton spp. Fungi), Microsporum (microspores) or Epidermophyton (E. epidermidis) Topical as caused by any microbial species, or e.g. Candida albi Mucosal, as cans cause (eg, thrush and vaginal candidiasis) There is. This infection can be, for example, Candida albicans, Cryptocox. Neoformans, Aspergillus fumigatus, Coccidioides, Paraco Caused by species of Xidioides, Histoplasmas or Blastomyces Just as it can be systemic. Fungal infections are also fungal mycomas, chromob Last mycosis, cryptococcal meningitis, or mucormycosis (phycomico Cis).   In one embodiment, the method for treating or preventing a pathogenic fungal infection comprises one or two The above rapalogs, preferably non-immunosuppressive antifungal rapalogs, are immunocompromised Administration to a patient in a morbid state. Administration of drugs to immunocompromised patients is inconvenient. Preferably, no further immunosuppressive action is induced. Examples of such patients HIV-infected patients, including AIDS patients; organs or tissues, including bone marrow transplants Have you received or are currently receiving immunosuppressant treatment in preparation for a transplant? Immunosuppressed patients; autoimmune disorders or diseases such as diabetes, MS ( Multiple sclerosis), myasthenia gravis, systemic lupus erythematosus or rheumatoid arthritis Patients with a gusset; and as a result of cancer chemotherapy or radiation therapy Cancer patients whose epidemics have been suppressed. Taking into account the patient's remaining immune function And administer rapalog in an amount or regimen that is insufficient for immunosuppression. It will often be preferred. When administering rapalog, in such cases In some, it is preferred that the rapalog is a non-immunosuppressive antifungal rapalog Will. Rapalog is reduced in the dosage of one or more active ingredients by Administered in combination with one or more other antifungal agents to provide fungal therapy And other combinations disclosed herein.   In another aspect, the invention relates to Candida albicans, Candida tropicalis Includes Candida Kefir, Candida Krusay and Candida Galbrata Candida species; Aspergillus fumigatus and Aspergillus flav Aspergillus spp .; Cryptocox neoformans; Brass Blastomyces spp. Including T. dermatitidis; Pneumocystis mosquitoes Lini; Coccidioides Imitis; Basidiobolus Ranarum; Conidi Obolus spp .; Histoplasma capsatum; Rhizopus oryzae and Rhizopus Pseudosporus spp., Including Pseudosporus microsporis; Kninghamella spp .; Mucor spp .; Paracoccidioides brasiliensis; Pseudoaleche Leah Boijii; Rhinosporium zeberi; and Sporotrix Shen Provide a method for treating or preventing infection with a pathogenic fungus selected from the group consisting of key I do. Again, this method treats fungal infections without eliciting adverse immunosuppressive effects Or as a preventive, non-immunosuppressive antifungal Rapallo in patients in need thereof Administering the drug.   In yet another aspect, the invention relates to amphotericin B, flucytosine, One of dazole or triazoles (eg, fluconazole, ketoconazo (Including, but not limited to, itraconazole and the remaining examples already mentioned) Including pathogenic fungal infections resistant to one or more antifungal agents mentioned elsewhere Offers methods to treat or prevent pathogenic fungal infections that are resistant to other antifungal therapies Offer. This method cures fungal infections in the patient that are resistant to another antifungal therapy. One or more rapalogs in an amount and dosing regimen to treat or prevent; Preferably, the method comprises administering to the patient a non-immunosuppressive antifungal rapalog.   In yet another aspect, the invention is directed to allergic to another antifungal therapy. Or is intolerant or unresponsive, or the use of another antifungal Treat or prevent pathogenic fungal infections in patients who are contraindicated for any other reason Provide a way to Other antifungal agents include amphotericin B, flucytosine, One of imidazole or triazoles (eg, fluconazole, ketoco (Including Nazol, Itraconazole and the remaining examples already listed) It includes one or more other antifungal agents mentioned elsewhere in the specification. This one The method comprises treating one or two or more of such patients in an amount to treat or prevent a fungal infection. Administering more than one rapalog, preferably a non-immunosuppressive antifungal rapalog including.   In any of the various methods described above, the non-immunosuppressive antifungal rapalog is It can be a member of any of the subsets of preferred compounds described above, and some In embodiments, the non-immunosuppressive antifungal rapalog is WO94 / 02136, WO95 / 16691, US Pat. No. 5,583,139 or U.S. Pat. No. 5,527,907.   Certain subsets of the novel compounds disclosed herein, e.g., 13-fluorola Palogs, 28-fluoro-rapalogs, 13,28-difluoro-rapalogs, 43- A subset of fluoro-rapalogs and 24,30-tetrahydrorapalogs is A non-immunosuppressive antifungal rapa that retains immunosuppressive activity and is defined herein. Excluded from log types. These compounds are an alternative to rapamycin itself. And can be used as an immunosuppressant. Therefore, the present invention relates to the present invention Administer one or more novel immunosuppressive rapalogs to patients in an immunosuppressive effective amount A method of inducing immunosuppression in a patient is also provided. Furthermore, the present invention Is an antifungal in an amount effective to treat or prevent infection by a pathogenic fungal microorganism. Immunocompromising comprising administering an active rapalog to an immunocompromised patient Also provided is a method of treating or preventing a pathogenic fungal infection in a patient in a ready state. (However, , 13-fluoro-rapalogs containing a C7a substituent other than OMe, 28-fluoro -Rapalogs, 13,28-difluoro-rapalogs, 43-fluoro-rapalogs and And a subset of 24,30-tetrahydrorapalogs are antifungal and dimerizing I'm especially interested in )   According to another aspect of the invention, the rapalog obtained is non-immune as defined above. A portion present in rapamycin or having the characteristics of an inhibitory antifungal rapalog Non-immunosuppressive anti-tumor by denaturation (by covalent bond) Methods for producing fungal rapalogs are included. The invention also relates to non-immunosuppressive antifungal A method of formulating a sex rapalog drug composition is also included. This method is non-immunosuppressive The antifungal rapalog is mixed with a pharmaceutically acceptable carrier to produce adverse immunosuppression. Non-immunosuppressive antifungals for treating or preventing pathogenic fungal infections without cheating Forming a sex rapalog drug composition.   The present invention will be more specifically described by the following examples. Example is never more Should not be interpreted as a restriction. All references and pendants cited throughout this application The contents of the patent application and published patent application therein are incorporated herein by reference. Example Evidence of efficacy in Say is not predictive of efficacy in humans Will be understood.Example 1. Synthesis of typical C-24 modified rapalog Example 1.1 Rapamycin purification: Rapamycin was obtained by fermentation. Rapamycin A live microorganism, Streptomyces hygroscopicus (ATCC # 29253) was cultured in a complex medium in a batch fermentation fed 15 L or 30 L. After 9 to 14 days, the biomass was collected by centrifugation. The supernatant is absorbed with nonionic polymer. Contact was made with the adhesive resin XAD-16 (Rohm and Haas). The adsorbent is recovered by centrifugation , Combined with biomass and extracted repeatedly with methylene chloride. The solvent was removed under reduced pressure to give The obtained residue was extracted with acetonitrile, and the extract was concentrated similarly. Silage Flash chromatography (40% acetone / hexane) followed by C-18 Reversed phase HPLC (70% CH_ThreeCN / H_TwoO) by chromatographic purification of crude rapamycin Was done. The resulting rapamycin was subjected to the same HPLC as the authentic sample of rapamycin. Spectroscopic and biological properties.Example 1.2 Rapamycin (E and Z) -24- (O-methyloxime)(Five,6) (General person Law )   A solution of rapamycin (60 mg, 65.6 mmol) in MeOH (2 mL) was first added to NaOAc (22 mg, 262 mM). mol, 4.0 eq), then treated with methoxylamine hydrochloride (22 mg, 262 mmol, 4.0 eq) Stirred at room temperature for 48 hours. Thereafter, the reaction mixture was quenched with water (10 mL) and EtOAc ( 3 × 10 mL). Wash the combined organic extracts with saturated NaCl solution (2 × 10 mL) and add N a_TwoSO_Four, And the filtrate was concentrated under reduced pressure. The residue obtained is filtered on silica gel. Rash chromatography (10% methanol / dichloromethane), isomer A mixture was obtained. This isomer mixture was subjected to HPLC (35% AE 25% H_TwoO / MeCN to Kromasil C-18, passing through a 250 × 20 mm column, 12 mL / min), eluting first with the Z isomer 13m g (21%) and 7.6 mg (12%) of the other E isomer. Z isomer: high resolution mass Spectrum (FAB) m / z 965.5749 [(M + Na) +, C₅₂H₈₂N_TwoO₁₃Calculated value of Na 965.5710]. E Isomer: high resolution mass spectrum (FAB) m / z 965.5701 [(M + Na) +, C₅₂H₈₂N_TwoO₁₃Na's 965.5710].Example 1.3 Rapamycin (E and Z) -24- (O-ethyloxime)(7,8)   Prepared analogously to rapamycin (E and Z) -24- (O-methyloxime). Profit The isomer mixture obtained was purified by HPLC (30% H_TwoO / MeCN to Kromasil C-18 250 × 20mm column 7.7 mg (25%) of the Z-isomer eluting first and the other E 0.5 mg (2%) of the isomer was obtained. Z isomer: high resolution mass spectrum (FAB) m / z 975. 5902 [(M + Na) +, C₅₃H₈₄N_TwoO₁₃Calculated value of Na 979.5871].Example 1.4 Rapamycin (E and Z) -24- (O-isobutyloxime)(9,Ten)   Prepared analogously to rapamycin (E and Z) -24- (O-methyloxime). Get The separated isomer mixture was purified by HPLC (15% H_TwoPass O / MeCN through Kromasil C-18 250 × 20mm column (12 mL / min), 28 mg (65%) of the Z-isomer eluted first, and the other E-isomer. 3.0 mg (7%) of the active substance was obtained. Z isomer: high resolution mass spectrum (FAB) m / z 1007.6 146 [(M + Na) +, C₅₅H₈₈N_TwoO₁₃Na calculated 1007.6184]. E isomer: high resolution mass Vector (FAB) m / z 1007.6157 [(M + Na) +, C₅₅H₈₈N_TwoO₁₃Na calculated 1007.6184].Example 1.5 Rapamycin (E and Z) -24- (O-benzyloxime)(11,12)   Prepared analogously to rapamycin (E and Z) -24- (O-methyloxime). Get The separated isomer mixture was purified by HPLC (15% H_TwoPass O / MeCN through Kromasil C-18 250 × 20mm column And 19.6 mg (44%) of the Z-isomer eluted first and the other E 6.1 mg (14%) of the isomer were obtained. Z isomer: high resolution mass spectrum (FAB) m / z 1041 .6033 [(M + Na) +, C₅₈H₈₆N_TwoO₁₃Calculated value of Na 1041.6028]. E isomer: high resolution mass Spectrum (FAB) m / z 1041.5988 [(M + Na) +, C₅₈H₈₆N_TwoO₁₃Calculated value of Na 1041.6028] .Example 1.6 Rapamycin (E and Z) -24- (O-carboxymethyl oxime)(13 ,14)   Prepared analogously to rapamycin (E and Z) -24- (O-methyloxime). Get The isolated isomer mixture was purified by HPLC (45% H_TwoPass O / MeCN through Kromasil C-18 250 × 20mm column (12 mL / min), 4.6 mg (11%) of the Z-isomer eluted first, and the other E-isomer. 1.0 mg (2%) of the isomer was obtained. Z isomer: high resolution mass spectrum (FAB) m / z 1009.5 664 [(M + Na) +, C₅₃H₈₂N_TwoO_FifteenCalculated value of Na 1009.5613]. E isomer: high resolution mass Spectrum (FAB) m / z 1009.5604 [(M + Na) +, C₅₃H₈₂N_TwoO_FifteenCalculated value of Na 1009.5613].Example 1.7 Rapamycin (E and Z) -24- (O-carboxamidomethyloxy ) (Fifteen,16)   Prepared analogously to rapamycin (E and Z) -24- (O-methyloxime). Get The isomer mixture obtained was purified by HPLC (35% H_TwoPass O / MeCN through Kromasil C-18 250 × 20mm column (12 mL / min), 6.2 mg (10%) of the Z-isomer eluted first, and the other E-isomer. 1.4 mg (2%) of the sexual form was obtained. Z isomer: high resolution mass spectrum (FAB) m / z 1008.5 790 [(M + Na) +, C₅₃H₈₃N_ThreeO₁₄Na calculated 1008.5768]. E isomer: high resolution mass Vector (FAB) m / z 1008.5753 [(M + Na) +, C₅₃H₈₃N_ThreeO₁₄Na calculated 1008.5768].2. Binding assay of rapamycin C24 derivative to FKBP   Competition based on fluorescence polarization (FP) for affinity of rapamycin C24 analog to FKBP Measured using the assay. Synthesize fluorescein-labeled FK506 probe (AP1491) And increase the polarization of the fluorescence by an amount that fluctuates as a competitor with less than saturated FKBP. Direct binding probe rates in equilibrium binding experiments involving rapamycin analogs. Was used as the measured value.FK506 Synthesis of probe (AP1491) Example 2.1 FK506 24,32-bis (tert-butyldimethylsilyl) ether   tert-butyldimethylsilyl trifluoromethanesulfonate (108 μL, 470 μmol) with FK506 (103 mg, 128 μmol) and 2,6-lutidine (89.5 μL, 768 μmol). A drop wise solution of the stirred solution at 0 ° C. in dichloromethane (3 mL) was added. The resulting solution is kept at 0 ° C for 2 hours. After stirring for an hour, it was treated with MeOH (0.5 mL) and ether (15 mL). This mixture 10% NaHCO_ThreeWashed with aqueous solution (3 mL) and brine (3 mL). Decantes the organic layer And anhydrous Na_TwoSO_Four, Filtered and concentrated to give a yellow oil. Column chromatography The title compound was obtained as a colorless oil by chromatography (silica gel, hexane-EtOAc 3: 1). Obtained as a solid (104 mg).Example 2.2 Intermediate 1   24,32-bis (tert-butyldimethylsilyl) ether of FK506 (100 mg, 97 μm l) in THF (2.5 mL), morpholine N-oxide (68 mg, 580 μmol) and then water (6 0 μL) and a 4% osmium tetroxide aqueous solution (123 μL, 20 μmol). The resulting mixture The material was stirred at room temperature for 4.5 hours. The mixture was then combined with 50% aqueous MeOH (1.5 mL) and And treated with sodium periodate (207 mg, 97 μmol) and the suspension was stirred for an additional hour. did. The mixture was diluted with ether (10 mL) and saturated NaHCO_ThreeWash with aqueous solution (2 × 4mL) Was cleaned. Decant the organic layer and add anhydrous sodium sulfate containing a small amount of sodium sulfite. Dried over thorium, filtered and concentrated. Dissolve the residue in anhydrous THF (2.8 mL) and add nitrogen The mixture was cooled to −78 ° C. under Treatment with a 0.5 M solution of minium hydride in THF (282 μL). The resulting solution at -78 ° C. After stirring for 1.75 hours, ether (6 mL) and a saturated ammonium chloride solution (250 μL) were added. The reaction was stopped by addition. The mixture is warmed to room temperature and dried over anhydrous sodium sulfate. Processed. Filtration and concentration under reduced pressure gave a pale yellow oil (97 mg), which was Purification by column chromatography (silica gel, hexane-EtOAc 3: 1) 1 was obtained as a colorless oil.Example 2.3 Intermediate 2   Acetonitrile (10 mL) solution of the above alcohol (300 mg, 290 μmol) was added to 2,6-lutidine (338 μL, 2.9 mmol) and N, N′-disuccinimidyl carbonate (371 mg, 1.4 5 mmol). The resulting suspension was stirred at room temperature for 14.5 hours, then Concentrated. The residue was chromatographed (silica gel, hexane-EtOAc 2: 1 to 100% EtOAc gradient) to give mixed carbonate 2 as a pale yellow oil (127 mg) .Example 2.4 Intermediate 3   A mixture of the above carbonate (30 mg, 26 μmol) and triethylamine (36 μL, 260 μmol) Setonitrile (1 mL) solution was mixed with 4 ′-(aminomethyl) fluorescein (13.5 mg, 34 μm). mol). The resulting light orange suspension was stirred at room temperature for 1 hour and then concentrated under reduced pressure. did. The residue was chromatographed (silica gel, hexane-EtOAc 1: 1 -100% EtOAc to EtOAc-MeOH 1: 1 gradient) to give 3 (20.5 mg) as a light yellow solid.Example 2.5 Compound 4   A solution of bis-silyl ether 3 (35 mg, 25 μmol) in acetonitrile (2 mL) was added to 48% (w / w) Treatment with an aqueous HF solution (250 μL). The resulting mixture was stirred at room temperature for 5.5 hours. Then it was diluted with dichloromethane (10 mL) and washed with water (2 × 2 mL). Organic layer It was decanted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue After chromatography (silica gel, 100% EtOAc), 4 (13 mg) as a light yellow solid I gotExample 2.6 FP Of Binding Affinity (IC50) of Rapalogs Using HPLC   Apply 10-fold serial dilutions of each rapamycin analog (rapalog) in 100% ethanol. Prepared in Rusbin and stored on ice. All other operations were performed at room temperature. Recombinant pure FKBP (purified by standard methods, see, eg, Wiederrecht, G. et al. 1992, J. Am. Biol. Chem. 267, 21753-21760) in 50 mM potassium phosphate, pH 7.8. / 150mM NaCl / 100μg / ml bovine gamma globulin (“FP buffer”: Panvera low fluorescent (Prepared using only photoreagent) to about 3 nM, and add 98 μL each to Dynatech micro- Fluor black was transferred to each well of a 96-well fluorescent plate. Then, A 2.0 μL sample of the analog was transferred to each well with mixing. last First, prepare a probe solution containing 10 nM AP1491 in 0.1% ethanol / FP buffer, 100 μL was added to each well while mixing. Two control wells, Lapamai Ethanol (for 100% probe binding) instead of syn analog, or Or ethanol instead of rapamycin analog, and FP buffer instead of FKBP (For 0% binding).   After equilibrating by storing the plate in the dark for about 30 minutes with it covered, The fluorescence polarization of the sample in each well was measured using a Jolley FPM-2 FP plate reader (Jolley C onsulting and Research, Inc., Glades Lake, Illinois) Read according to Average polarization (in mP) for each competitor concentration, usually a control Converted to% of total binding to the value, the log Lot (y). Fit the curve using nonlinear least squares analysis and Used to derive an IC50.     y = M1 + (M4-M1) / (1 + exp (M2^*(M3-x)))   Here, M3 is the IC50. For incomplete curves, the IC50 was determined by interpolation. In each case rapamycin and C14-desoxo-rapamycin were included as controls. (C14-desoxo-rapamycin is described in Luengo, J.I. et al. 1994, Tet. Lett. . 35, 6469-6472).Example 2.7 Results of binding analysis of rapamycin C24 oxime   The affinity is determined by the IC50 and the fold loss of the affinity (= IC50 / Rapamisi) (IC50 ratio). (C24 rapalog to human FKBP12 vs rapamycin Comparative binding data for and Desoxo-rapamycin are plotted in PCT / US86 / 09848. Have been. ) 3. Synthesis of C7 rapalog and binding assay of C7 rapalog-FKBP complex to FRAP   Branched and unbranched alkoxy, arylalkyloxy, -NHCO-O Kill, -NHSO_TwoAlkyl and substituted aryl and heteroaryl moieties A series of C7 rapalogs containing various C7 substituents selected from Syntheses were generally performed using chemical techniques described in the literature (eg, Luengo et al. 1995. See Chemistry and Biology 2, 471-481 and above for background. (See references cited in II). See also the table below.Example 3.1 Compound 27, 28-(R^C7= Et) is Luengo et al.Chemistry and Biology  July 1995,Two: 471-481.Example 3.2 Compound 29-(R^C7= IPr)   A solution of rapamycin (60 mg, 0.066 mmol) in 2-propanol (3 mL) at room temperature was prepared. The mixture was treated with paratoluenesulfonic acid (75 mg, 0.394 mmol) and stirred for 4 hours. afterwards The resulting reaction solution was washed with saturated NaHCO_ThreeA two-phase solution of aqueous solution (20 mL) and EtOAc (30 mL) I put it in. Separate the organic layer with another saturated NaHCO_ThreeAqueous solution (2 × 20 mL), then saturated aqueous NaCl solution (2 × 1 0 mL), and then washed with Na_TwoSO_Four, Filtered and evaporated. The obtained residue is Kromasil C-18 column (20 × 250 mm) at 55 ° C. using eluent of% acetonitrile / water Purification by HPLC on) provided AP1700 (25 mg). MS (FAB): (M + Na)⁺Calculated value: 964 .5762, found: 964.5753.Example 3.3 Compound 30-(R^C7= Benzyl) isChemistry and Biology July 1995 ,Two: 471-481.Example 3.4 Compounds 31, 32-(R^C7= -NH-CO-OMe)Chemistry and Biology 1995 July,Two: 471-481.Example 3.5 Compound 33-(R^C7= -NH-SO_Two-Me)   Rapamycin (75 mg, 0.082 mmol) and methanesulfo in dichloromethane (3 mL) Amide solution (312 mg, 3.282 mmol) at −40 ° C. was added to trifluoroacetic acid (126 μL, 1.636 mmol) and stirred for 3 hours. Then, the reaction solution was washed with saturated NaHCO_ThreeAqueous solution ( 20 mL) and EtOAc (10 mL). The organic layer was washed with a saturated aqueous NaCl solution (2 × 10 mL) and then washed with Na_TwoSO_Four, Filtered, evaporated and flashed over silica gel Chromatography (dichloromethane: hexane: EtOAc: MeO H, 200: 50: 42.5: 7.5). The resulting semi-purified product is eluted with 65% acetonitrile / water as eluent. Purified by HPLC on a Kromasil C-18 column (20 × 250 mm) at 55 ° C. 4 mg). MS (FAB): (M + Na)⁺Calculated value: 999.5246, found: 999.5246.Example 3.6 Compound 34, 35-(R^C7= Furanyl)   These compoundsChemistry and Biology July 1995,Two: 471-481 Can be synthesized.Example 3.7 Compounds 36 and 37-(R^C7= Methylthiophene)   These compounds are described in Org. Chem.1994, 59, 6512-6513. Can be achieved.Example 3.8 Compound 39, 38-(R^C7= Ethylthiophene)   Rapamycin (50 mg, 0.055 mmol) and 2-ethyl in dichloromethane (1.5 mL) A solution of thiophene (248 μL, 2.188 mmol) at −40 ° C. was added to trifluoroacetic acid (84 μL, 1.0 μL). (94 mmol) and stirred for 3 hours. Thereafter, the obtained reaction solution was washed with saturated NaHCO._Three Poured into a biphasic solution of an aqueous solution (15 mL) and EtOAc (10 mL). Organic layer is saturated aqueous NaCl Solution (2 x 10 mL), then Na_TwoSO_Four, Filtered, evaporated and dried over silica gel Flash chromatography (MeOH: dichloromethane, 2:98 followed by 5:95). The resulting semi-purified product was purified by Kromasil at 55 ° C using 80% acetonitrile / water as eluent.  Purified by HPLC on a C-18 column (20 × 250 mm), AP1858 (6 mg) and AP1859 (28 mg). MS (ESf): (M + NH_Four)⁺1016; MS (ES-): (M-H)^-992.Example 3.9 Compounds 40 and 41-(R^C7= Tert-butylthiophene)   Rapamycin (50 mg, 0.055 mmol) and 2-tert- A solution of butylthiophene (276 mg, 2.188 mmol) at −40 ° C. was treated with trifluoroacetic acid (84 μL). , 1.094 mmol) and stirred for 3 hours. Then, the reaction solution was washed with saturated NaHCO_Three Poured into a biphasic solution of an aqueous solution (15 mL) and EtOAc (10 mL). Organic layer is saturated aqueous NaCl Solution (2 x 10 mL), then Na_TwoSO_Four, Filtered, evaporated and dried over silica gel Flash chromatography (MeOH: dichloromethane, 2:98, then 5:95) . Kromasil at 55 ° C using 80% acetonitrile / water as eluent  Purified by HPLC on a C-18 column (20 × 250 mm), AP1856 (4 mg) and AP1857 (14 mg). MS (ES +): (M + Na)⁺1045; MS (ES-): (M-H)^-1021. Example 3.10 Compound 43, 42-(R^C7= O, p-dimethoxyphenyl)   These compoundsChemistry and Biology July 1995,Two: See 471-481 Can be.Example 3.11 Compound 44, 45-(R^C7= Indrill)   Rapamycin (50 mg, 0.055 mmol) and indole (64 mg, 0.547 mmol) at −40 ° C. with trifluoroacetic acid (84 μL, 1.094 mmol). The mixture was treated and stirred for 3 hours. Thereafter, the reaction solution was washed with saturated NaHCO_ThreeAqueous solution (15mL) Poured into a two-phase solution with EtOAc (10 mL). Wash the organic layer with saturated aqueous NaCl (2 × 10 mL) After cleaning, Na_TwoSO_Four, Filtered, evaporated and flash chromatographed on silica gel (Dichloromethane: hexane: EtOAc: MeOH, 200: 50: 42.5: 7.5) . The obtained semi-purified product is Kromasil C-18 with 65% acetonitrile / water as eluent. Purified by HPLC on a ram (20 x 250 mm) to give AP1701 (12 mg) and AP1702 (7.6 mg) Obtained. MS (FAB): (M + Na)⁺Calculated value: 1021.5765, measured value: 1021.5788 (AP1701) and 1 021.5797 (AP1702).Example 3.12 Compound 46-(R^C7= O, p-diethoxyphenyl)   Rapamycin (108 mg, 0.118 mmol) and 1,3-die in dichloromethane (2.0 mL) A solution of toxicbenzene (783 mg, 4.72 mmol) at −40 ° C. was added to trifluoroacetic acid (154 μL, 2.01 mmol) and stirred for 3 hours. Then, the reaction solution was washed with saturated NaHCO_Threewater Poured into a two-phase solution of the solution (15 mL) and EtOAc (15 mL). The organic layer was washed with a saturated aqueous NaCl solution ( 2 × 10 mL) and then washed with Na_TwoSO_Four, Filter, evaporate and filter on silica gel. Flash chromatography (dichloromethane: hexane: EtOAc: MeOH, 200: 50: 42.5: 7.5). The obtained semi-purified product was diluted with (dichloromethane: hexane: EtOAc: MeOH, 210: 65: 65: 10) as eluent by HPLC on a Rainin silica column (20 × 250 mm). Further purification yielded AP20808 (20 mg). MS (ES +): (M + Na)⁺1065.95.Example 3.13 Compound 47-(R^C7= Methylthiophene)   Rapamycin (105 mg, 0.115 mmol) and 3-methyi in dichloromethane (2.0 mL) A solution of luthiophene (445 μL, 4.60 mmol) at −40 ° C. was added to trifluoroacetic acid (150 μL, 1 .96 mmol) and stirred for 3 hours. Then, the reaction solution was washed with saturated NaHCO_Threewater Poured into a two-phase solution of the solution (15 mL) and EtOAc (15 mL). The organic layer was washed with a saturated aqueous NaCl solution ( 2 × 10 mL) and then washed with Na_TwoSO_Four, Filter, evaporate and filter on silica gel. Flash chromatography (dichloromethane: hexane: EtOAc: MeOH, 200: 50: 42.5: 7.5). The resulting material was purified using (dichloromethane: hexane: EtOAc: MeOH, 210 : 65: 65: 10) by HPLC on a Rainin silica column (20 x 250 mm) using eluent To give AP20809 (60 mg). MS (ES +): (M + Na)⁺1002.96.Example 3.14 Compound 48-(R^C7= N-methylpyrrole)   Rapamycin (51 mg, 0.056 mmol) in dichloromethane (2.0 mL) (198 μL, 2.23 mmol) at 0 ° C. was treated with zinc chloride (76 mg, 0.557 mmol); The temperature was raised to room temperature and left overnight. Then, the reaction solution was washed with saturated NaHCO_ThreeAqueous solution (15mL) And EtOAc (15 mL). The organic layer was washed with a saturated aqueous NaCl solution (2 × 10 mL). After washing, Na_TwoSO_Four, Filtered, evaporated and flash chromatographed on silica gel Chromatography (dichloromethane: hexane: EtOAc: MeOH, 100: 150: 150: 1) 0). The resulting material was diluted with (dichloromethane: hexane: EtOAc: MeOH, 210: 65: 65: 10 ) Was purified by HPLC on a Rainin silica column (20 x 250 mm) with eluent AP2 0810 (10 mg) was obtained. MS (ES +): (M + NH_Four)⁺981.05; MS (ES-): (M-H)^-961.69.   Characterization (identification) of the above C7 rapalogs by accurate mass spectrum and MMR did.Example 3.15 FP assay of FKBP binding affinity of C7 rapalog   The affinity of the various C7 rapalogs for FKBP was determined using the competitive FP method as described above. Assays were performed as described for the C24 rapalog. Rapamycin and C 14-desoxo-rapamycin (Luengo et al. 1994. Tetrahedron Lett. 35, Prepared as described in 6469-6472) was included in the assay as a control.   The affinity was determined by determining the IC50 and the fold loss of the affinity (= IC50 / rapamycin IC50). (Ratio) is reported below. See the table below under "Example of C7 rapalog". These days These large C7 substituents indicate that rapalog has a high affinity for human FKBP. This indicates that the reduction does not necessarily occur. Example 4.1 Rapalog modified with R ^C24 and R ^C30 : 24 (S), 30 (S) -tetrahydro Preparation of rapamycin (53)   Rapamycin (46 mg, 0.050 mmol) is dissolved in 2.0 mL of methanol, cooled to -78 ° C. And cerium (III) chloride heptahydrate (46 mg, 0.123 mmol) was added. 0.25 hr of this solution After stirring for a while, sodium borohydride (7.6 mg, 0.20 mmol) was added. 0.5 hours later The reaction mixture was partitioned between ethyl acetate (15mL) and 5% aqueous hydrochloric acid (2mL). Yes The organic phase was washed with water (2 mL) and brine (1 mL), dried over anhydrous magnesium sulfate, and filtered. And concentrated. Flash chromatography (silica gel, 15: 75: 50: 200 Tanol: ethyl acetate: hexane: dichloromethane) to give 35 mg of the desired product (76 %) As a white foam. Mass spectrum data: (ES + / NaCl / NH_Three) m / z 942. 21 (M + Na)⁺, 935.83 (M + NH_Four)⁺; (ES- / NaCl) m / z 963.04 (M + Cl)^-, 917.34 (M-H)^-. three References: Luengo, J.I .; Rozamus, L.W .; Holt, D.A. Tetrahedron Lett. 1994, 35, 6469-6472.Example 5.1 Preparation of rapalog modified with C24, C30 and C7   24 (S), 30 (S) -tetrahydrorapamycin (53) as prepared in Example 4 was Can be denatured at the C7 position using the technique illustrated in the C7 rapalog example of You. For example:7 (S)-(2 ', 4'- (Dimethoxy) benzyl-7-demethoxy-24 (S), 30 (S) -tetrahydrola Pamycin   24 (S), 30 (S) -tetrahydrorapamycin (20 mg, 0.022 mmol) was added to dichloromethane ( 1.0 mL). 1,3-Dimethoxybenzene (0.20 mL, 1.5 mmol) was added and the The solution was cooled to -60C. Trifluoroacetic acid (0.030 mL, 0.39 mmol) was added. The reaction mixture was stirred at -60 ° C for 1 hour, then ethyl acetate (10 mL) and saturated sodium bicarbonate were added. And 1 mL of aqueous solution. The organic phase was washed with water (2 mL) and brine (1 mL), Dried over anhydrous magnesium sulfate, filtered and concentrated. Flash chromatograph (Silica gel, 15: 75: 50: 200 methanol: ethyl acetate: hexane: dichloro Methane) gave 8 mg (35%) of the desired product as a white solid. Mass spectrum Data: (ES + / NaCl / NH_Three) m / z 1046.96 (M + Na)⁺, 1042.15 (M + NH_Four)⁺; (ES- / NaCl) m / z 1069.09 (M + Cl)^-. References: Luengo, J.I .; Konialian-Beck, A .; Rozamus, L.W .: Holt, D.A. J. Org. Chem. 1994, 59, 6512-6513.   By similar means, examples having other C7 substituents described elsewhere herein For example, an aryl group having another substituent, a heteroaryl, an -O-aliphatic group, -Tel or R^C7aOr R^C7bOther types of substituents described above for It is possible to produce 24 (S), 30 (S) -tetrahydrorapamycins containing it can. These compounds are reduced at the C24 and C30 positions of the appropriate C7 rapalog. Or by conversion at the C7 position of the appropriate C24, C30-tetrahydrorapalog You can also. An example will be described later.   Rapalogs modified with C24, C30 and C7 can be used with various other described herein. Position, for example, R^C13, R^C43, R^C28, R^C29, R^Four, "A", etc. May be different from rapamycin. As an example, instead of rapamycin, 13- Starting from F-rapamycin, 13-fluoro analogs of compounds 53-79 were obtained. You.Example 5.2 Compound 54, 55-(R^C7= Et) is as described in Example 4.1, except that Synthesized using compounds 27 and 28, respectively, instead of rapamycin.Example 5.3 Compound 56-(R^C7= IPr) as described in Example 4.1, except that Synthesized using compound 29 instead of pamycin.Example 5.4 Compound 57-(R^C7= Benzyl) can be prepared as described in Example 4.1 However, it is synthesized using compound 30 instead of rapamycin.Example 5.5 Compound 58, 59-(R^C7= -NH-CO-OMe) as described in Example 4.1. But synthesized using compounds 32 and 31, respectively, instead of rapamycin. You. Example 5.6 Compound 60-(R^C7= -NH-SO_Two-Me) is as described in Example 4.1. But synthesized using Compound 33 instead of rapamycin.Example 5.7 Compounds 61 and 62- (R^C7= Furanyl) as described in Example 4.1 But synthesized using compounds 34 and 35 instead of rapamycin, respectively. It is.Example 5.8 Compound 63, 64-(R^C7= Methylthiophene) was described in Example 4.1. Thus, except that compounds 36 and 37 are used instead of rapamycin, respectively. Is done.Example 5.9 Compound 65, 66-(R^C7= Ethylthiophene) was described in Example 4.1. Thus, but using compounds 38 and 39 instead of rapamycin, respectively. Is done.Example 5.10 Compound 67, 68-(R^C7= Tert-butylthiophene) As described, except that compounds 41 and 40 were substituted for rapamycin, respectively. And synthesized.Example 5.11 Compound 69, 70-(R^C7= O, p-dimethoxyphenyl) was prepared according to Example 4.1. With the exception that rapamycin is replaced by compounds 43 and 42, respectively. Is synthesized usingExample 5.12 Compound 71, 72-(R^C7= Indolyl) as described in Example 4.1 But synthesized using compounds 45 and 44 instead of rapamycin, respectively. It is.Example 5.13 Compound 73-(R^C7= O, p-diethoxyphenyl) is described in Example 4.1. Synthesized as described above, but using compound 46 instead of rapamycin.Example 5.14 Compound 74-(R^C7= Methylthiophene) was described in Example 4.1. Thus, it is synthesized using compound 47 instead of rapamycin.Example 5.15 Compound 75-(R^C7= N-methylpyrrole) was described in Example 4.1. As such, but synthesized using compound 48 instead of rapamycin.Example 5.16 Compound 76, 77-(R^C7= 2,4,6-trimethoxyphenyl) was prepared in Example 5 1, but with 1,3,5-trimethyl instead of 1,3-dimethoxybenzene. It is synthesized using toxicbenzene.6. Preparation of fluororapalogs Example 6.1  A new class of rapalogs, C13-fluoro-rapalog, Can be prepared.  In this example, the hydroxy moieties at positions 28 and 43 are protected prior to treatment with DAST. You. We have found that the bistriethylcysyl protecting group (as shown above) and the bis-tri The isopropyl cysyl protecting group was used. Based on user preferences or circumstances, And then consider the reaction conditions for the conversion before or simultaneously with the elimination of the protecting group. Thus, various other protecting groups can be used. The protected compound is then Treatment with drugs introduces the 13-fluoro substituent. The DAST reaction is, for example, shown above. It can be carried out at -42 ° C or at 0 ° C.   The 13-fluororapamycin is then modified at position 7 as desired to give R^C7aAlso Is R^C7b13-fluoro-C7 la having any of the various moieties already mentioned Groups of palogs can be manufactured. For example, 7- (o, p-dimethoxy) -13-fluoro Rorapalog (96 and 97) removes the protecting group after converting compound 78 with C7 Or after removal of the protecting group from compound 78, as shown below, is converted at C7. By doing so, it can be produced (and separately collected if desired).   13-F-rapamycin in place of rapamycin, in addition to denaturation at C7, Alternatively, for example, fluorination at C28, reduction at C24 and C30, C24 And fluorination at C30, modification at C-43 and the like. Can be subjected to various other chemical transformations such as to provide the corresponding 13-F analogs. it can. Example 6.2 Compound 81, 82-(R^C7= Et) is as described in Example 3.1 except that Synthesized using 13-F-rapamycin (79) instead of rapamycin.Example 6.3 Compound 83-(R^C7= IPr) as described in Example 3.2, except that Synthesized using 13-F-rapamycin (79) instead of pamycin.Example 6.4 Compound 84-(R^C7= Benzyl) can be prepared as described in Example 3.3 However, it is synthesized using 13-F-rapamycin (79) instead of rapamycin.Example 6.5 Compound 85, 86-(R^C7= -NH-CO-OMe) as described in Example 3.4. But synthesized using 13-F-rapamycin (79) instead of rapamycin. You.Example 6.6 Compound 87-(R^C7= -NH-SO_Two-Me) is as described in Example 3.5. But synthesized using 13-F-rapamycin (79) instead of rapamycin.Example 6.7 Compounds 88 and 89-(R^C7= Furanyl) as described in Example 3.6. But synthesized using 13-F-rapamycin (79) instead of rapamycin. It is.Example 6.8 Compound 90, 91-(R^C7= Methylthiophene) was described in Example 3.7. Thus, but using 13-F-rapamycin (79) instead of rapamycin. Is done.Example 6.9 Compounds 92 and 93-(R^C7= Ethylthiophene) was described in Example 3.8 Thus, but using 13-F-rapamycin (79) instead of rapamycin. Is done.Example 6.10 Compound 68, 69-(R^C7= Tert-butylthiophene) in Example 3.9 As described, except that 13-F-rapamycin (79) was substituted for rapamycin. And synthesized.Example 6.11 Compounds 94 and 95-(R^C7= O, p-dimethoxyphenyl) is obtained in Example 3.10 Except that 13-F-rapamycin (79) is used in place of rapamycin. Is synthesized usingExample 6.12 Compound 96, 97-(R^C7= Indolyl) is described in Example 3.11 But using 13-F-rapamycin (79) instead of rapamycin. Is done.Example 6.13 Compound 98-(R^C7= O, p-diethoxyphenyl) is described in Example 3.12. As described, but using 13-F-rapamycin (79) instead of rapamycin. And synthesized.Example 6.14 Compound 99-(R^C7= Methylthiophene) was described in Example 3.13. Thus, but using 13-F-rapamycin (79) instead of rapamycin. Is done.Example 6.15 Compound 100-(R^C7= N-methylpyrrole) is described in Example 3.14. Except that 13-F-rapamycin (79) is used instead of rapamycin. Synthesized.Example 6.20 28 Preparation of -F-rapamycin (107)   DAST was added to a solution of rapamycin (71 mg, 0.078 mmol) in methylene chloride (1 mL) at -78 ° C. (21 mL, 0.156 mmol) and the reaction was stirred for 2 h before adding MeOH to quench the reaction. Stopped. The reaction mixture was warmed to room temperature and stirred for 30 minutes. This is saturated NaHCO_Three It was poured into a two-phase solution of an aqueous solution (20 mL) and EtOAc (30 mL). The organic layer was washed with another saturated NaH CO_ThreeAqueous solution (2 × 20 mL), then washed with a saturated aqueous NaCl solution (2 × 10 mL),_TwoSO_FourDry Dry, filter and evaporate. Flash chromatography of the resulting residue on silica gel Luffy (hexane: EtOAc, 1: 1 to 1: 2). Mass spectrum, fluorine NMR is C28 It was shown to be fluorinated rapamycin. Stereoisomers are reversed phase chromatography ー (C18 column, MeOH: H_TwoO, 80:20) and various F-28 rapalogs Can be used in place of rapamycin for the synthesis of the class. Embodiment 7 FIG. Human T cell proliferation assay: mitogenic assay for human immunosuppressive activity   Primary human peripheral blood mononuclear cells from healthy donors were subjected to Ficoll-Hypaque centrifugation. Separate as recommended by the manufacturer (Pharmacia), wash with RPMI complete medium, and Counting was performed using rypan blue. 1.2 × 10^FiveMedium containing the cells (120 μL). , Continuous rapamycin or rapalog in medium (final ethanol concentration <0.5%) Each well of a 96-well tissue culture plate containing 120 μL of medium containing diluent Distribute to The plate is incubated at 37 ° C. for 1 hour. Separately, anti-human CD3 anti The second 96-well plate to which the body was applied was washed with the medium and pre-cultured above. Transfer to a plate coated with 200 μL of cell solution. After culturing was continued at 37 ° C for 72 hours, 50 μCi Add 20 μL of / H 3H-thymidine to each well. After culturing overnight (12-16 hours) Cells are harvested using an automated multiple cell harvester and Beckman liquid scintillation The cellular radioactivity is counted using a ration counter. Four replicate measurements It is shown as the average value obtained from. Growth inhibition IC50, 3H-thymidine specific cells Chemicals that produce a 50% reduction in uptake (100% corresponds to uptake in the absence of compound) Determined by compound concentration.Example 8: AF / IS values of representative rapalogs   R^C7aOr R^C7bIs a substituted aryl or heteroaryl moiety of the general formula II Three types of rapalogs were tested for immunosuppressive activity using human peripheral lymphocyte proliferation assay. And Candida albicans, Cr in the broth macro dilution assay described above Antitrue against clinical isolates of yptococcus neoformans and Aspergillus fumigatus Bacterial activity was compared to rapamycin. From data obtained in a series of experiments The AF / IS values were calculated and are shown in the following table. Example 9: Cloning of FRB domain homolog from Cryptococcus neoformans   Align known FRAP / RAFT / RAPT / TOR proteins and nucleotide sequences Amplifies FRAP region encompassing FRB domain by identifying short conserved regions Degenerate PCR primers were designed to perform The sequences used are human, mouse, G, S. cerevisiae and C. albicans. Primer 174 (WYKAWHNW Annealing to the region encoding DLELAVPGT) and 176 (annealing to the region encoding DLELAVPGT). Kneeling) is shown below: Here, Y = C or T, R = A or G, and N = A, C, G or T.   Using these primers, C.I. neoformans lambda cDNA library (B350 One strain, a part of FRAP homolog derived from Stratagene library # 937052) was amplified . `` Touchdown '' PCR using Taq polymerase (Boehringer Mannheim) Use the buffer conditions and "hot start" as recommended by this enzyme manufacturer. Was. The cycling regime was for 5 minutes at 94 ° C (during which the enzyme was added); Second, 60 ° C for 40 seconds, 72 ° C for 90 seconds] at a 60 ° C annealing temperature reduced by 0.3 ° C for each cycle. 9 cycles; then 2 cycles of [94 ° C. 40 seconds followed by 50 ° C. 40 seconds]; and then 72 C for 10 minutes. A single product of the expected size (about 1074 bp) was obtained, Into the pCRII vector (In Vitrogen) using the TA Cloning Kit (Invitrogen). Cloned. Four clones were sequenced by dideoxy sequencing. They have one change at one position in one clone (encoding TTT → CTT, Phe → Leu) (This change may reflect pure species polymorphisms or PCR errors) And turned out to be identical.   C. Neoformans FRAP homologue nucleotide sequence and predicted protein sequence Is shown below. The positions of the above sequence changes are underlined.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/496 A61K 31/496 31/513 31/513 31/7048 31/7048 45/00 45/00 A61P 31/10 A61P 31/10 43/00 43/00 (31) Priority claim number 60 / 050,353 (32) Priority date June 20, 1997 (June 20, 1997) (33) Priority claim Country United States (US) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, R , TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE , HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU (72) Inventor Cracson, Timothy P. USA, Mass. Rosamouth, Leonard, United States 02142, Somerville, Leonard Street 24 142 (72) Mitchell Grant Way 39, Bedford, Massachusetts 01730, United States of America 39 (72) Inventor Jan, Wu United States of America , Massachusetts 02167, Chestnut Hill, Jamon de pound Parkway 34, apartment main cement 3 (72) inventor Gilman, Michael Georgette United States, Massachusetts 02168, Newton, Chestnut Su Treat 550

Claims (1)

[Claims] 1. A method of treating or preventing a pathogenic fungal infection in a mammalian individual, comprising: Administering to the individual a composition comprising at least one non-immunosuppressive antifungal rapalog The method including the process. 2. Claims wherein the composition comprises an antifungal effective amount of a non-immunosuppressive antifungal rapalog. The method of claim 1, wherein the method comprises: 3. 3. The method according to claim 1 or claim 2, wherein the mammal individual is a human patient. 4. 4. The method according to claim 3, wherein the mammal individual is an immunocompromised patient. 5. Claims wherein the patient is immunocompromised as a result of drug or radiation therapy 5. The method according to claim 4. 6. The patient is or is not a recipient of a tissue or organ transplant 5. The method of claim 4, wherein the method is in the process of being prepared. 7. The method according to claim 4, wherein the rapalog is administered in combination with the administration of the immunosuppressant. Law. 8. The patient is immunized as a result of diabetes, HIV infection, or another disease or disorder 5. The method of claim 4, wherein the method is unprotected. 9. Pathogenic fungal infection is aspergillosis, including invasive pulmonary aspergillosis; Brass, including resident or rapidly progressive infections and central nervous system blast mycosis Tomycosis; eg, kidney stones, urinary tract obstruction, kidney transplantation or poorly managed diabetes mellitus Candidiasis, including retrograde candidiasis of the urinary tract, in patients with cancer; other chemotherapy Coccidioidomycosis, including chronic illness that does not respond well to cryptography; cryptocox Disease; histoplasmosis; for example, craniofacial mucormycosis and pulmonary mucormycosis Mucormycosis including; Paracoccidioidomycosis; and Sporotricosis The method according to any one of claims 1 to 8, which is selected from the group consisting of: Law. 10. A mammalian individual with a fungus that is resistant to one or more other antifungal therapies A method for treating or preventing pathogenic fungal infections of the present invention, comprising an antifungal effective amount of Rapallo Administering to the individual a composition comprising the drug. 11． The fungus is amphotericin B, an analogue thereof or another polyene macrolide; Flucytosine; griseofulvin; or imidazole or 11. The method according to claim 10, wherein the method is resistant to one or more lyazoles. 12． If imidazole or triazole is clotrimazole, miconazole, Toconazole, econazole, butconazole, oxyconazole, terconazo Claim 11, wherein the isol, itraconazole or fluconazole. the method of. 13. Combining a composition containing rapalog with at least one other antifungal agent The method according to any one of claims 1 to 12, which is administered to a subject. 14. Another antifungal agent is amphotericin B, an analog thereof or another polyene macro. Ride antibiotics; Flucytosine; Griseofulvin; or, for example, clotrima Sol, miconazole, ketoconazole, econazole, butconazole, ox Such as ciconazole, terconazole, itraconazole or fluconazole 14. The method according to claim 13, which is an imidazole or a triazole. 15． A method for treating or preventing a pathogenic fungal infection in a mammalian individual, comprising: At least one compound represented by the general formula or a pharmaceutically acceptable derivative thereof Administering to the individual a composition comprising: Where: And   R^C7aAnd R^C7bIs H and the other is -H, halogen, -OR¹, -S R¹, -OC (O) R¹, -OC (O) NHR¹, -NHR¹, -NR¹R^Two, -NHC ( O) R¹, -NH-SO_Two-R¹Or -R^TwoWhere R^TwoIs aliphatic, hetero-fatty Aliphatic, aryl, heteroaryl, or alkylaryl;   R^C30Is halogen, -OR^ThreeOr (= O),   R^C24Is = O, -NR^Four, = NOR^FourOr = NNHR^Four, -NHOR^FourIf Is -NHNHR^Four, -OR^Four, -OC (O) R^FourOr -OC (O) NR^Four,halogen Or -H;   R^C13Is H, halogen, -OR^Five, -OC (O) R^Five, -OC (O) NHR^Five, -SR^Five , -SC (O) R^Five, -SC (O) NHR^Five, -NR^FiveR^Five', Or -N (R^Five) (CO) R^Five'And   R^C14Is = O, -OR⁶, -NR⁶, -H, -NC (O) R⁶, -OC (O) R⁶Also Is -OC (O) NR⁶And   R^ThreeIs H, -R⁷, -C (O) R⁷Or -C (O) NHR⁷Or C28 and C30 A cyclic moiety (eg, a carbonate forming a 5- or 6-membered ring),   R^C28Is halogen or -OR^ThreeAnd   R^C29Is H, OH or OMe;   Here, unless otherwise specified, each ring substituent exists in either stereochemical configuration. And R¹, R^Four, R^Five, R⁶, R⁷, R⁹, R^TenAnd R¹¹Is it Each independently selected from H, aliphatic, heteroaliphatic, aryl or heteroaryl. And then   R⁸Is H, halogen, -CN, = 0, -OH, -NR⁹R^Ten, -OSO_TwoCF_Three , -OSO_TwoF, -OSO_TwoR^Four', -OCOR^Four', -OCONR^Four'R^Five', Or- OCON (OR^Four') R^Five'With the proviso that the compound is not rapamycin. 16． Wherein the compound is at least one non-immunosuppressive antifungal rapalog. 16. The method according to claim 15, wherein 17． 17. The method according to claim 15 or 16, wherein the mammal individual is a human patient. 18． 18. The method according to claim 17, wherein the patient is immunocompromised. 19. Claims wherein the patient is immunocompromised as a result of drug or radiation therapy 19. The method according to claim 18. 20. The patient is or is not a recipient of a tissue or organ transplant 19. The method of claim 18, wherein said method is in the process of being prepared. twenty one. The method according to claim 18, wherein the rapalog is administered in combination with the administration of the immunosuppressant. Law. twenty two. The patient is immunized as a result of diabetes, HIV infection, or another disease or disorder 19. The method of claim 18, wherein the method is unprotected. twenty three. Pathogenic fungal infection is aspergillosis, including invasive pulmonary aspergillosis; Brass, including resident or rapidly progressive infections and central nervous system blast mycosis Tomycosis; eg, kidney stones, urinary tract obstruction, kidney transplantation or poorly managed diabetes mellitus Candidiasis, including retrograde candidiasis of the urinary tract, in patients with cancer; other chemotherapy Coccidioidomycosis, including chronic illness that does not respond well to cryptography; cryptocox Disease; histoplasmosis; for example, craniofacial mucormycosis and pulmonary mucormycosis Mucormycosis including; Paracoccidioidomycosis; and Sporotricosis The method according to any one of claims 15 to 22, which is selected from the group consisting of: Law. twenty four. Claims wherein the fungus is resistant to one or more other antifungal therapies. 15. The method according to clause 15. twenty five. The fungus is amphotericin B, an analogue thereof or another polyene macrolide; Flucytosine; griseofulvin; or imidazole or 25. The method according to claim 24, wherein the method is resistant to one or more lyazoles. 26. If imidazole or triazole is clotrimazole, miconazole, Toconazole, econazole, butconazole, oxyconazole, terconazo Claim 25, wherein the isol, itraconazole or fluconazole. the method of. 27. Combining the composition containing rapalog with at least one other antifungal agent The method according to any one of claims 15 to 26, wherein the method is administered to a subject. 28. Another antifungal agent is amphotericin B, an analog thereof or another polyene macro. Ride antibiotics; Flucytosine; Griseofulvin; or, for example, clotrima Zole, miconazole, ketoconazole, econazole, butconazole, ox Such as ciconazole, terconazole, itraconazole or fluconazole 28. The method according to claim 27, which is an imidazole or triazole. 29. If the compound is an R other than methoxy^C7aClaim 15 containing part Law. 30. The compound is a compound represented by the following general formula or a pharmaceutically acceptable derivative thereof. 16. The method of claim 15, wherein the method is: Where R^C7aAnd R^C7bRepresents that one is H and the other is a substituted or unsubstituted alkyl Nil, aryl, heteroaryl or -Z-aliphatic, -Z-aryl, -Z- Heteroaryl or -Z-acyl (where Z and Z 'are each independently Is O, S or NH, and acyl is -CHO,-(C = O) -aliphatic,-(C = O) -aryl,-(C = O) -heteroaryl,-(C = O) -Z'-aliphatic,- (C = O) -Z'-aryl, including-(C = O) -Z'-heteroaryl) To be elected. 31. R^C7aAnd R^C7bIs H and the other is -OEt, -O-propyl,- O-butyl, -OCH_TwoCH_Two-OH, -O-benzyl, -O-substituted benzyl (eg, , 3-nitro-, 4-chloro-, 3-iodo-4-diazo-, 3,4-dimethoxy -, And 2-methoxy-), -S-Me, -S-phenyl, -O (CO) Me, -allyl, -CH_TwoC (Me) = CH_Two, -OCH_Two-CCH, -OCH_Two-C C-Me, -OCH_Two-CC-Et, -OCH_Two-CC-CH_Two-OH, or -2 , 4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, furanyl, Chosen from Ofeniel, methylthiophenyl, pyrrolyl and indolyl Or the pharmaceutically acceptable derivative thereof. 32. The compound is a compound represented by the following general formula or a pharmaceutically acceptable derivative thereof. 16. The method of claim 15, wherein the method is: Where R^C7aAnd R^C7bRepresents that one is H and the other is a substituted or unsubstituted alkyl Nil, aryl, heteroaryl or -Z-aliphatic, -Z-aryl, -Z- Heteroaryl or -Z-acyl (where Z and Z 'are each independently Is O, S or NH, and acyl is -CHO,-(C = O) -aliphatic,-(C = O) -aryl,-(C = O) -heteroaryl,-(C = O) -Z'-aliphatic,- (C = O) -Z'-aryl, including-(C = O) -Z'-heteroaryl) To be elected. 33. R^C7aAnd R^C7bIs H and the other is -OEt, -O-propyl,- O-butyl, -OCH_TwoCH_Two-OH, -O-benzyl, -O-substituted benzyl (eg, , 3-nitro-, 4-chloro-, 3-iodo-4-diazo-, 3,4-dimethoxy -, And 2-methoxy-), -S-Me, -S-phenyl, -O (CO) Me, -allyl, -CH_TwoC (Me) = CH_Two, -OCH_Two-CCH, -OCH_Two-C C-Me, -OCH_Two-CC-Et, -OCH_Two-CC-CH_Two-OH, or -2 , 4-Dimethoxyphenyl, 2,4,6-trimethoxyphenyl, furanyl, thiophene Claims selected from Niel, methylthiophenyl, pyrrolyl and indolyl 33. The method of claim 32. 34. R^C13Or R^C28One or both of F may be of any stereochemical configuration 16. The method of claim 15, wherein the method comprises: 35. R^C7a35. The method according to claim 34, wherein is a part other than OMe. 36. R^C7aAnd R^C7bIs an aryl or heteroaryl The described method. 37. R^C24And R^C30Are both OH which may be in any stereochemical configuration 16. The method according to claim 15, wherein 38. R^C13Or R^C3038. The method of claim 37, wherein both are F. 39. R^C7a39. The method according to claim 37 or claim 38, wherein is a part other than OMe. . 40. R^C7aAnd R^C7bIs an aryl or heteroaryl Or the method of paragraph 38. 41. A rapalog represented by the following general formula or a pharmaceutically acceptable derivative thereof: Where: And   R^C7aAnd R^C7bIs H and the other is -H, halogen, -OR¹, -S R¹, -OC (O) R¹, -OC (O) NHR¹, -NHR¹, -NR¹R^Two, -NHC ( O) R¹, -NH-SO_Two-R¹Or -R^TwoWhere R^TwoIs aliphatic, hetero-fatty Aliphatic, aryl, heteroaryl, or alkylaryl;   R^C30Is halogen, -OR^ThreeOr (= O),   R^C24Is = O, = NR^Four, = NOR^FourOr = NNHR^Four, -NHOR^FourAlso Or -NHNHR^Four, -OR^Four, -OC (O) R^FourOr -OC (O) NR^Four,Halo Or -H,   R^C14Is = O, -OR⁶, -NR⁶, -H, -NC (O) R⁶, -OC (O) R⁶Also Is -OC (O) NR⁶And   R^ThreeIs H, -R⁷, -C (O) R⁷Or -C (O) NHR⁷Or C28 and C30 A cyclic part   R^C28Is halogen or -OR^ThreeAnd   R^C29Is H, OH or OMe;   Here, unless otherwise specified, each ring substituent exists in either stereochemical configuration. And R¹, R^Four, R^Five, R⁶, R⁷, R⁹, R^TenAnd R¹¹Is it Each independently selected from H, aliphatic, heteroaliphatic, aryl or heteroaryl. Bare; and   R⁸Is H, halogen, -CN, = 0, -OH, -NR⁹R^Ten, -OSO_TwoCF_Three, -OSO_TwoF, -OSO_TwoR^Four', -OCOR^Four', -OCONR^Four'R^Five'Or -O CON (OR^Four') R^Five'It is. 42. R^C7aAnd R^C7bIs a part other than -OMe. Rapalog according to paragraph 41. 43. R^C24And R^C3042. The rapalog according to claim 41, wherein both are -OH. 44. R^C7aAnd R^C7bIs a part other than -OMe. Rapalog according to clause 43. 45. R^C2842. The rapalog according to claim 41, wherein 46. R^C2843. The rapalog according to claim 42, wherein 47. R^C2844. The rapalog of claim 43 wherein is F. 48. R^C2846. The rapalog of claim 44 wherein is F. 49. A compound represented by the following general formula or a pharmaceutically acceptable derivative thereof:Where: And   R^C7aAnd R^C7bIs H and the other is -H, halogen, -OR¹, -S R¹, -OC (O) R¹, -OC (O) NHR¹, -NHR¹, -NR¹R^Two, -NHC ( O) R¹, -NH-SO_Two-R¹Or -R^TwoWhere R^TwoIs aliphatic, hetero-fatty Aliphatic, aryl, heteroaryl, or alkylaryl;   R^C13Is H, halogen, -OR^Five, -OC (O) R^Five, -OC (O) NHR^Five, -SR^Five , -SC (O) R^Five, -SC (O) NHR^Five, -NR^FiveR^Five', Or -N (R^Five) (CO) R^Five'And   R^C14Is = O, -OR⁶, -NR⁶, -H, -NC (O) R⁶, -OC (O) R⁶Also Is -OC (O) NR⁶And   R^ThreeIs H, -R⁷, -C (O) R⁷Or -C (O) NHR⁷Or C28 and C30 A cyclic part   R^C28Is halogen or -OR^ThreeAnd   R^C29Is H, OH or OMe;   Here, unless otherwise specified, each ring substituent exists in either stereochemical configuration. And R¹, R^Four, R^Five, R⁶, R⁷, R⁹, R^TenAnd R¹¹Is it Each independently H, aliphatic, heteroaliphatic, aryl or heteroaryl Selected from; and   R⁸Is H, halogen, -CN, = 0, -OH, -NR⁹R^Ten, -OSO_TwoCF_Three, -OSO_TwoF, -OSO_TwoR^Four', -OCOR^Four', -OCONR^Four'R^Five'Or -O CON (OR^Four') R^Five'And   Where R^C24, R^C30And R^C7All substituents except rapamycin R is equal to^C7aIs a part other than OMe. 50. A compound other than the compound shown in Table II represented by the following general formula or a pharmaceutically acceptable salt thereof Derivatives acceptable for: Where: And   R^C7aAnd R^C7bIs H and the other is -H, halogen, -OR¹, -S R¹, -OC (O) R¹, -OC (O) NHR¹, -NHR¹, -NR¹R^Two, -NHC ( O) R¹, -NH-SO_Two-R¹Or -R^TwoWhere R^TwoIs aliphatic, hetero-fatty Aliphatic, aryl, heteroaryl, or alkylaryl;   R^C30Is halogen, -OR^ThreeOr (= O),   R^C24Is = O, = NR^Four, = NOR^FourOr = NNHR^Four, -NHOR^FourIf Is -NHNHR^Four, -OR^Four, -OC (O) R^FourOr -OC (O) NR^Four,halogen Or -H;   R^C13Is H, halogen, -OR^Five, -OC (O) R^Five, -OC (O) NHR^Five, -SR^Five, -SC (O) R^Five, -SC (O) NHR^Five, -NR^FiveR^Five', Or -N (R^Five) ( CO) R^Five'And   R^C14Is = O, = OR⁶, -NR⁶, -H, -NC (O) R⁶, -OC (O) R⁶Also Is -OC (O) NR⁶And   R^ThreeIs H, -R⁷, -C (O) R⁷Or -C (O) NHR⁷Or C28 and C30 A cyclic part   R^C28Is halogen or -OR^ThreeAnd   R^C29Is H, OH or OMe;   Here, unless otherwise specified, each ring substituent exists in either stereochemical configuration. And R¹, R^Four, R^Five, R⁶, R⁷, R⁹, R^TenAnd R¹¹Is it Each independently selected from H, aliphatic, heteroaliphatic, aryl or heteroaryl. Bare; and   R⁸Is H, halogen, -CN, = 0, -OH, -NR⁹R^Ten, -OSO_TwoCF_Three, -OSO_TwoF, -OSO_TwoR^Four', -OCOR^Four', -OCONR^Four'R^Five'Or -O CON (OR^Four') R^Five'And   Where R^C7aIs a part other than OMe. 51. 51. The compound of claim 50 which is a non-immunosuppressive antifungal rapalog. 52. 52. One or more compounds according to any one of claims 41 to 51. Combining the pharmaceutically acceptable carrier or diluent and optionally one or two An antifungal composition comprising the above pharmaceutically acceptable excipient. 53. 52. The method of claim 52, further comprising an antifungal effective amount of a non-rapalog antifungal agent. The antifungal composition according to the above. 54. The non-rapalog antifungal agent is amphotericin B, an analog thereof or another polyether. Flucytosine; griseofulvin; or Lotrimazole, miconazole, ketoconazole, econazole, butconazole , Oxyconazole, terconazole, itraconazole or fluconazo 53.The method according to claim 53, which is an imidazole or a triazole such as Antifungal composition. 55. The antifungal composition according to any one of claims 52 to 54, comprising the composition. An antifungal product comprising a package insert describing the antifungal use of the article. 56. 51. One or more compounds according to any one of claims 42 to 50 A pharmaceutical composition comprising the compound in an aggregate immunosuppressive amount. 57. 55. One or more compounds according to any one of claims 42 to 54 Combination comprising a compound and one or more non-rapalog immunosuppressive compounds Adult. 58. Non-rapalog immunosuppressive compounds comprise FK506 and cyclosporin A and Claims selected from the group consisting of these analogs, as well as rapamycin 56. The pharmaceutical composition according to paragraph 57.