MXPA99002972A - Novel 3, 5, and/or 6 substituted analogues of swainsonine, processes for their preparation and their use as therapeutic agents - Google Patents

Abstract

The invention relates to novel 3, 5, and/or 6 swainsonine analogues, processes for their preparation and their use as therapeutic agents. The invention also relates to pharmaceutical compositions containing the compounds and their use as therapeutics.

Description

NEW ANALOGS 3, 5 AND / OR 6-SUBSTITUTED FROM S AINSONINE, PROCESSES FOR ITS PREPARATION AND ITS USE AS THERAPEUTIC AGENTS FIELD OF THE INVENTION The present invention relates to novel swainsonin analogs, to processes for their preparation and to their use as therapeutic agents.

BACKGROUND OF THE INVENTION The carbohydrate structures present in human tumor cells have been associated with the invasion of cancer and metastasis (Dennis et al., Science 236: 582, 1987; Demetriou et al., J. Cell Biol. 130: 383, nineteen ninety five) . These structures include the N- and O-linked carbohydrate side chains, branched to GlcNAcβ (Tl-6), of the cell surface glycoproteins. The Golgi enzymes required for its synthesis are ß (Tl-6) N-acetylglucosaminyltransferase V (ie, GlcNAc-TV), and the core 2 ß (Tl-6) N-acetylglucosaminyltransferase (ie, 2 GlcNAc-T) of core), respectively. These REF .: 29834 enzymes are regulated in human carcinomas (Fernandes et al., Cancer Res. 51: 718-723, 1991), a phenomenon that has been associated with the activation of the ras signaling pathway (Dennis et al., Science 236: 582-585, 1987, Dennis et al Oncogene 4: 853-860, 1989)). Additionally, overexpression of GlcNAc-TV in the epithelial cells results in morphological transformation and tumor formation in mice (Demetriou et al, J. Cell Biol. 130: 383-392, 1995). Therefore, the GlcNAc-TV, as well as the enzymes that deliver substrates acceptor to GlcNAc-TV (ie, GlcNAc-TI, a-mannosidase II and 2 core GlcNAc-T of the O-linked path) are targets for anti-cancer pharmaceutical products. Although there are currently no available inhibitors of GlcNAc-T, an a-mannosidase II lead inhibitor, swainssin has been tested in preclinical and human trials. The swainsonin e-s an indolizidine alkaloid found in _la Swainsona canescens Australian (Colegate et al., Aust J. Chem 32: 2257-2264, 1979), the plants North Americans of the genus Astragalus and Oxytropis (Molyneux RJ and James LF., Science 215: 190-191, 1981), and also fungi Rhizoctonia leguminicola (Scheneider et al., Tetrahedron 39: 29-31, 1983). The capacity of the a - sine to inhibit the activity of a - mannosidase II seems to be responsible for its interesting inmodulation and cancer suppression activity. Swainsonin is believed to function as an enzyme inhibitor because it can mimic the glycosylate cation intermediate generated during the hydrolytic cleavage of mannopyranosides (Goss, PE et al., Clin. Cancer Res. 1: 935-944 , nineteen ninety five) . The blocking of swainsonin of a-mannosidase II is before GlcNAc-TV and prevents the expression of N-linked carbohydrates, branched to GlcNAcβ (Tl-6). Murine tumor cells treated with swainsonin have been found to be less metastatic both in organ colonization and in spontaneous metastasis assays in mice (Dennis J.; Cancer Res. 46: 5131-5136, 1986 and Humphries et al. ., Proc. Nati, Acad. Sci. USA 83: 1752-1756, 1986). Swainsonin has also been found to block the invasion of tumor cells through the extracellular matrix in vitro (Yegel et al., Int., J. Cancer 44: 685-690, 1989 and Seftor et al. Melanoma Res. : 53-54, 1991). Swainsonin administered either orally or by mini-osmotic bombs to athymic nude mice inhibited the growth rate of human MeWo mel'anoma and HT29m colon carcinoma tumor xenografts in mice (Dennis et al., J. Nati Cancer Inst. 81: 1028-1033, 1989 and Dennis et al., Cancer Res., 50: 1867-1872, 1990). The phase 1 chemical trials of swainsonin have been done, which indicates that they are effective in the treatment of human tumors. (Goss et al., Cancer Res., 54: 1450, 1995). Although the side effects in humans are mild, some of these can be associated with the inhibition of swainsonin from the lysosomal storage of carbohydrates. Swainsonin has positive effects on cellular immaturity in mice (reviewed in Humphries M.J. and Olden K., Pharmacol Ther, 44: 85-105, 1989, and Olden et al., Pharmacol Ther 50: 285-290, 1991)). In particular, swainsonin has been shown to alleviate tumor suppression associated chemically and chemically induced (Hiño et al., J. Antibiot, (Tokyo) 38: 926-935, 1985), increases the activities of NK cells (Humphries et al. ., Cancer Res. 48: 1410-1 15, 1988), and of LAK cells (Yagita M and Saksela E., Scand., J. Immunol., 31: 275-282, 1990), and increases the proliferation of cells of the Bone Marrow (BM) and Spleen (White et al., Biochem Biophys, Res. Com., 150: 615-625, 1988; Bowlin et al. Cancer Res 49, 4109-4113, 1989 and White et al., Cancer Commun. 3: 83-91, 1991). SW has also been shown to be hemorrhaging in mice after treatment with both cycle-specific and nonspecific chemotherapeutic agents (Oredipe et al., J. Nati. Cancer Inst. 83: 1149-1156, 1991). Japanese Patent Application No.

J61277685 describes indolizidine derivatives which are reported to be useful as immune regulators, which can be administered orally or parenterally at a dose of about 0.1-100 ml / kg per day. Also, it is reported that indolizidine derivatives can be used in combination with antitumor agents, antimicrobial or anti-inflammatory agents. Carbonyloxy substitutions at carbons 2 and 8 of swainsonin have been reported to reduce inhibitory activity by 2-3 orders of magnitude by Jack Bean and lysosomal mannosidases of MDAY-D2 tumor cells in vitro. However, the 2-p-ni trobenzyloxy, 2-octanoyloxy- and 2-butanoyloxy-derivatives of swainsonin retained full activity as inhibitors of Golgi oligosaccharide processing in viable MDAY-D2 tumor cells. The inhibition of oligosaccharide processing was reduced by the esterase inhibitor, diethyl-p-nitrophenyl-phosphate, suggesting that while the compounds are relatively poor inhibitors of mannosidase in vitro, the compounds enter the cell at a comparable rate to that of the swainsonin and they are converted to swainsonin by cellular integer. The most lipophilic esters, 2-benzoyloxy-swainsonin, 2-toluoyloxy-swainsonin, 8-pal i toi loxi-swainsonin and 8-myristinoyloxy-swainsonin, showed at least 10-fold higher IC5 values for the inhibition of Golgi oligosaccharide processing , probably due to an entry efficiency of the compounds in the tumor cells. The metastatic activities of swainsonin and two analogs were tested and showed that they correlate with IC5o values for the inhibition of Golgi oligos.accharide processing in cultured tumor cells. In vivo, SW and analogs were administered intraperitoneally to mice and found to have comparable activities as stimulators of bone marrow cell proliferation (Dennis et al., Biochemical Pharmacology 46: 1459-1466, 1993). The selected analogs of swainsonin, in particular, the 2-substituted analogs and methods for preparing the analogs are described in U.S. Patent No. 5,466,809.

BRIEF DESCRIPTION OF THE INVENTION The present inventors have studied the reaction profiles catalyzed by the anosidase inhibitors, atomic charge distributions of the cation of mannopyranosyl (an intermediate in the reaction catalyzed by mannosidases) and derivatives of swainsonin, and the chemical topography of the cavity of union of mannosidase II. They found that swainsonin analogs that more closely mimic true species of the transition state (ie, cation of mannopyranosyls) in place of the mannosyllium cation intermediate, provided improved inhibitory potency. In particular, the selective derivatization of swainsonin in one or both of positions 3 and 5 with the electron withdrawing groups provided swainsonin analogues that are ideally suited for use as drugs and prodrugs having improved pharmacological properties. The present inventors have found that selective derivatization at position 6 also provides analogs having improved pharmacological properties. Therefore, the present invention relates to a compound of Formula I • wherein (1) R1, R2 and R3 are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, or R1 and R2 together or R2 and R3 together form a carbocyclic or heterocyclic ring; (2) W, W 'and W "are the same or different and represent hydroxyl, alkoxy, thiol, thioalkyl, thioaryl, halo or amino, or one or more of W and'? and W 'and W "form together a carbocyclic or heterocyclic ring; or one or more of R1 and W, R2 and ', R3 and W'? form a spiro ring system; (3) X, X ', Y, Y1, Z and Z' are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, alkoxy, aryloxy, hydroxyl, thiol, thioaryl, amino , ammonium, halogen, carboxylic acid or esters or thioesters thereof, ketone, aldehyde, carbonate, carbamate, amide, azide, imide, imine, imidazole, acetal, ketal, nitrile, diazo, nitro, hydrazine, and hydrazide, hydrazone, hydroxamic acid, hydroxylamine, epoxide, alkoxy or aryloxyamines, sulfate, sulphonic or sulfinic acid or esters thereof, sulfonamide, phosphate or phosphonate acids or esters thereof, silyl, sulfoxide, sulfone, oxime, guanidino, phosphonate, thioamide, thiocarbamate, thiocyanate, thioketone, thiourea, thioethers, triazole, urea, xanthate, cyano, nitrile, -SR 9, wherein R 9 is alkyl, cycloalkyl, alkenyl, alkynyl or monocyclic unsaturated hydrocarbons, and -OR where R is alkyl, cycloalkyl, alkenyl , alkynyl, or hydr monocyclic unsaturated carbons; or (i) X and Y, X 'and Y, X * and Y, or X' and Y 'together form a carbocyclic heterocyclic ring, or Y and Z, Y and Z', or Y 'and Z' can form together a carbocyclic or heterocyclic ring; (ii) one or more of X and X 'together, Y and Y' together, and Z and Z * together form a spiro ring; or (iii) one or more of X and X 'together, Y and Y' together, and Z and Z 'together represent = 0, = S, or = NR, where R4 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl unsaturated monocyclic hydrocarbons, aryl, alkoxy, hydroxyl, or = CR5R6, wherein R5 and R6 are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, monocyclic unsaturated hydrocarbons, or aryl; with the proviso that X, X ', Y, Y', and Z, Z 'can not all be hydrogen, and salts and optically active and racemic forms of a compound of Formula I.

In one embodiment of the invention, the compounds of Formula I are provided wherein R 1, R 2, R 3, X, X ', Y, Y' are hydrogen, W, W and W 1 'are not hydroxyl. In another embodiment of the invention, compounds of Formula I are provided wherein when R1, R2, R3, X, X ', Z and Z' are not hydrogen, and W, W 'and W' 'are hydroxyl, and and Y 'together can not be two ions or one of Y and Y' can not be alkoxy. The present invention also provides a process for the preparation of a compound of Formula I as defined herein, of a pharmaceutical formulation comprising a compound of Formula I as an active agent. The invention further relates to a method for stimulating the immune system, treating prolif- erative disorders, or microbial infections in a patient, which comprises administering an effective amount of a compound of Formula I, the invention also refers to to the use of a compound of Formula I in the preparation of a medicament for stimulating the immune system and / or for treating prolific disorders, and microbial infections.

The present invention also relates to a use of a compound of Formula I which is esterified to the free hydroxyls as a prodrug. These and other aspects of the present invention will become apparent with reference to the following detailed description and accompanying drawings. In addition, if it refers to the present to several publications, which are incorporated in this way by reference in its entirety.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will be better understood with reference to the drawings in which: > Figure 1 is a schematic diagram of a reaction for preparing a novel analogue of the invention; Figure 2 is a schematic diagram of a reaction for preparing a novel analogue of the invention; Figure 3A is a schematic diagram of a reaction to prepare a new analogue of the invention; Figure 3B is a schematic diagram of a reaction for preparing a new analogue of the invention; Figure 4 is a schematic diagram of a reaction for preparing a new analogue of the invention; Figure 5 is a schematic diagram of a reaction for preparing a new analogue of the invention; Figure 6 is a schematic diagram of a reaction to prepare a new analogue of the invention; Y Figure 7 is a schematic diagram of a reaction for preparing a new analog of the invention.

DETAILED DESCRIPTION OF THE INVENTION 1. COMPOUNDS OF THE INVENTION Hereinafter and in the following, the term "alkyl" alone or in combination refers to a linear branched hydrocarbon radical, typically containing from 1 to 20 carbon atoms, preferably from 1 to 15. Typical alkyl groups include, but are not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, pentyl, hexyl and imi .. The term "alkenyl", alone or in combination, is refers to a branched, unsaturated branched group having a typical 2 to 20 carbon atoms and at least one double bond. Examples of these groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 1,3-butadienyl, hexenyl, pentenyl, and the like. The term "alkynyl", alone or in combination, refers to a linear or branched, unsaturated group having from 2 to 20 carbon atoms and at least one triple bond. Examples of these groups include, but are not limited to, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 1-pentynyl, and the like. The term "cycloalkyl" refers to cyclic hydrocarbon groups and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The terms "cycloalkenyl" and "cycloalkynyl" refer to monocyclic, unsaturated hydrocarbons having an endocyclic double bond, or a triple bond. The compounds of Formula I that have more than one multiple bond are cycloalkadiene, cycloalcatriene, etc. The term inclusive for any cyclic hydrocarbon having any number of these multiple bonds is unspecified mpnocyclic hydrocarbons. Examples of monocyclic unsaturated hydrocarbons are cyclohexene, cyclopentadiene, and cyclooctadiene. The term "aryl", alone or in combination, refers to a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group. An aryl group may be optionally substituted as described herein. Examples of aryl groups and substituted aryl groups are phenyl, benzyl, p-nitrobenzyl, p-me toxibenzyl, biphenyl, and naphthyl. The term "alkoxy" alone or in combination, refers to an alkyl or cycloalkyl linked to the parent molecular moiety through an oxygen atom. The term "aryloxy" refers to an aryl linked to the molecular portion of origin through an oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, propoxy, vinyloxy, allyloxy, butoxy, pentoxy, hexoxy, cyclopentoxy, and cyclohexoxy. Examples of aryloxy soh phenyloxy groups, O-benzyl, ie benzyloxy, O-p-nitrobenzyl and O-p-methyl-benzyl, 4-n-phenyloxy, 4-chlorophenyloxy, and the like. The term "halo" or "halogen" alone or in combination, refers to a member of the fluorine, chlorine, bromine or iodine family. The term "amino", alone or in combination, refers to a chemical functional group where a nitrogen atom (N) is attached to three substituents which is any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl with the general chemical formula '-NR7R8, wherein R7 and R8 can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl. Optionally a substituent on the nitrogen atom can be a hydroxyl group (-OH) to give an amine known as hydroxylamine. Examples of amino groups are -amino (-NH 2), methylamine, ethylamine, dimethylamine, cyclopropylamine, benzylamine, allylamine and hydroxylamine, cyclohexylamirium (-NHCH (CH 2) 5), piperidine. (-N (CH2) 5) and benzylamino (-NHCH2CeH5). Some amines may contain the basic skeletal structure of swainsonin to give analogues such as: The term "thioalkyl", "thiocycloalkyl", "thioalkynyl", "thiocycloalkenyl", "thiocycloalkynyl", "thiocyclohetylenyl" alone or in combination, refers to a chemical functional group where the sulfur atom (S) is attached to a monocyclic, unsaturated, alkyl, cycloalkyl, alkenyl, or alkynyl hydrocarbon group. The compounds have the general chemical formula -SR9 wherein R9 is a monocyclic, alkyl, cycloalkyl, alkenyl, alkynyl, or unsaturated hydrocarbon group. Examples of thioalkyl groups are thiomethyl, thioethyl, thiopropyl, thiopropenyl, thiobutyl, thiohexyl, thiocyclopentyl, thiomethoxymethyl, thiocyclohexyl, thioalyl, and thiochloromethyl. - The term "thioaryl", alone or in combination, refers to a chemical functional group where a sulfur atom (S) is attached to an aryl group with the general chemical formula -SR where R is an aryl group which may be substituted . Examples of thioaryl groups are thiophenyl, para-chlorothiophenyl, thiobenzyl, 4-methoxy-thiaphenyl, 4-n-thio-phenyl, and para-nitro thiobenzyl. A chemical functional group of "carboxylic acid", alone or in combination, has the formula -COOH and examples of compounds of Formula I which contain a carboxyl group are the following.

The carboxylic acid esters have the chemical functional group R1: LCOOR12 where R11 represents the primary skeletal structure of a compound of Formula I and R12 is alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl. A lactone is a cyclic ester where R11 and R12 represent the same teter. Preferred esters of carboxylic acid (-C02R12) include methyl esters (-C02CH3), ethyl esters (-CO2CH2CH3), propyl esters (-C02CH2CH2CH3), allyl esters (-C02CH2CH = CH2), butyl esters (-C02CH2CH2CH2CH3) and benzylic esters (-CO2CH2C6H5). Examples of the compounds of the invention having only one ester group are the following: Where, for example, R 'is CH3, CH2CH3, CH2CH3CH3, CH2 CH2CH2 CH CH3, CH2CeH5. Other examples of esters of the compound of the Formula I of the invention include the following: Where, for example, R is methyl, ethyl, propyl, propenyl, butyl, pentyl, hexyl, phenyl or benzyl. The thioesters have the general formula R13COSR14 where R13 represents the main backbone of a compound of the general formula I, and R14 is an alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of thioesters are analogous to those provided for the esters of carboxylic acids presented above. The term "amides", alone or in combination, refers to a chemical functional group of the formula R15CONR16R17, where R15 represents the major backbone of the compounds of Formula I, and R16 and R17 are any combination of hydrogen, alkyl, cycloalkyl , alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of amide substituents from compounds of Formula I include: -CONH2 / -CONHCH3, -CON (CH3), -CONHCH2CH3, -CON (CH2CH3) 2, -CONHCH2CH2CH3, -CONHCH2CH = CH2, -CONHC6H5, -CONHCH2C6H5 , -CONHCH2CH2OH, CON (CH2CH2OH) 2, Examples of the compounds of the Formula I containing an amide substituent include: where R and R "are permutations of hydrogen, methyl, ethyl, hydroxyethyl, propyl, hydroxypropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl, for example, or wherein R and R" - of the basic amide formula can form a lactam ring such as: Other lactam rings of interest include structures where both R and R 'of the basic amide formula form part of the basic skeleton of the swainsonin of a compound of Formula I, "such as: where R ", for example, may be hydrogen, methyl, ethyl, hydroxyethyl, propyl, butyl, hexyl or benzyl. Thioamides have the general formula where R represents the backbone of a compound of Formula I, and R19 and R20 can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. A thiolactam is a cyclic thioamide where R18 and R19 represent the same tetramer. Examples of thioamides are analogous to those described for the above amides.

Sulfonamides have the general formula OR where R2? represents the general structure of the compounds of the general formula I, R22 and R23 can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl. Examples of thioamides are analogous to those described for previous amides. The hydrazides have the general formula R24C (O) NR25NR26R27, where R25 represents alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl, one of R24, R26 or R27 represent the backbone of a compound of Formula I, and the other of R24, R26 or R27, may be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, or aryl. Examples of hydrazide substituent groups wherein R24 represents the main backbone of the compound of Formula I include hydrazide (-C (0) NHNH2), dimethyl hydrazide (-C (O) NHN (CH3) 2, or benzyl hydrazide ( -C (0) NHNHCH2C6H5) Examples of substituent groups of hydrazide wherein R26 or R27 represent the backbone of a compound of Formula I including CH3C (O) NHNH-, CH3CH2C (0) NHNH-, CH3CH2CH2CH2C (O) NHNH- or CSH5C (O) NHNH- Hydrazines have the general formula: R R "'\ / N-N / \ R * R" where R, R ', R "and R'" may be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of hydrazine substituents include: -NHNH2, -NHNHCH2C6H5 and -NHN (CH3) 2 • Hydrazones have the general formula: RR "* \ / ON-N / \ R * R" where one of R, R ', R1' and R '' 'represent the main backbone of a compound of Formula I, and the other of R, R', R "and R" 'can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons or aryl. Examples of compounds of Formula I with hydrazone substituents which may or may not be cyclic and form part of the swainsonin backbone of a compound of Formula I include the following: The ureas have the general formula: wherein one of R, R ', R "and R' '' represents the major backbone of a compound of Formula I, and the other of R, R ', R" and R'1' can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons or aryl. Examples of urea substituents and urea-containing compounds of Formula I include: Thioureas have the general formula wherein one of R, R ', R "and R' '' represents the major backbone of a compound of Formula I, and the other of R, R ', R" and R "' can be any combination of alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of thiourea substituents and thiourea-containing compounds of Formula I are analogous to those provided above for ureas.

The term "ketones" refers to a chemical functional group of the formula R28COCR29, wherein R28 represents the major backbone of a compound of Formula I, and R29 is alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of ketones that can be used in the compounds of the invention include methyl-ketones (-COCH3), methylen-methyl-ketones (-CH2COCH3), ethylene-methyl-ketones (-CH2CH2COCH3), ethyl-ketones (- C0CH2CH3), propyl ketones, vini Icetonas, butyl ketones (-COCH2CH2CH2CH3), hexyketones, cyclohexylketones, cyclopentyl ketones, phenylketones and benzyl ketones. Compounds of Formula I which contain cyclic ketone groups include the following: Thioketones have the general formula where R represents the main backbone of a compound of Formula I, and R 'is alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. The examples for thioketones are analogous to those given above for ketones. The carbamates have the general formula: where R and R "represent the main backbone of a compound of Formula I, and the other of R and R 'are hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl, and R1 is hydrogen, alkyl , cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl or R and R 'represent the same compound of Formula I. Examples of carbamate substituents (-NR'C02") for the compounds of Formula I include 'O-allyl carbamates (-NHC02CH2CH = CH2), O-ethyl-carbamates' (-NHCO2CH2CH3), O-tert-butyl-carbamates (-NHC02C (CH3) 3) and O-benzyl-carbamates (-NHCO2CH2C6H5). Examples where both R and R "take part of the major backbone of a compound of Formula I (ie, swainsonin) include: The thiocarbamates have the general formula where one of R and R'1 represent the major backbone of a compound of Formula I, and the other of R and R "represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl and R 'is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. The examples for thiocarbamates are analogous to those given above for the carbamates. Xanthates have the general formula: where R and / or R * are the main structure of a compound of Formula I. Examples of xanthates (-SC (S) OR ') wherein R contains the main backbone of a compound of Formula I (ie, swainsonin) include O-methyl xanthates (-SC (S) OCH3), O-ethyl'-xanthates (- SC (S) OCH2CH3) or O-benzyl-xanthate (-SC (S) OCH2CH3). Examples of xanthates (-OCS2R), where R 'contains the major backbone of a compound of Formula I (ie, swainsonin) S-methyl-xanthates (-OCS2CH3), S-ethyl-xanthates (-0CS2CH2CH3) or S -benzyl-xanthate (-OCS2CH2CH3).

Sulfoxides have the general formula R30SOR31, where R30 and / or R31 represent the backbone of a compound of Formula I. Examples of sulfoxides of interest include those where R30 represents the backbone of a compound of Formula I (i.e. , swainsonina), and R 31 includes, for example, methylsulphoxides (-SOCH3) methylene-methylsulphoxides (-CH2S0CH3), ethylene-methylsulphoxides, (-CH2CH2SOCH3), eti 1-sulfoxides (-SOCH2CH3), butyl sulfoxides (-SOCH2CH2CH2CH3 ), hexyl sulphoxides, cyclohexyl sulphoxides, cyclopentyl sulfoxides, allyl sulphoxides, phenylsulphoxides and benzyl sulphoxides. Other sulfoxides of interest include those where both R 30 as R are part of the main backbone of a compound of Formula I (i.e., swainsonin), to give cyclic sulfoxides such as: Sulfones have the general formula where R and / or R 'represent the main backbone of a compound of Formula I. The examples of sulfones are analogous to the sulfoxides described above. The epoxides (or oxiranes) - are 3-membered cyclic ethers having the general formula: where one of R, R ', R "and R' '' represent the main backbone of a compound of Formula I, and the other of R, R ', R" and R "' can be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Some examples of epoxides include: Similarly, the 4-, 5- and 6-membered saturated cyclic ethers that can be used in the compounds of Formula I include trimethylene oxide ((CH2) 3?), Tetrahydrofuran ((CH2) 0), and tetrahydropyran rings ((CH2) 50). The ammonium salts have the general formula. wherein one of R, R ', R "and R"' 'is a backbone of a compound of Formula I and the other of R, R', RIf and R'1 * is hydrogen, alkyl, cycloalkyl, alkenyl , alkynyl, unsaturated monocyclic hydrocarbons, or aryl, and X "is a suitable counterion such as chloride (Cl"), bromide (Br "), or acetate (CH3C02"). Examples of ammonium salts include trimethylammonium chloride (-N (CH3) 3C1), methyl-piperidylammonium bromide (-N (CH3) (CH2) 5Br) or benzyldiethyl ammonium chloride (-N (CH2C6H5) (CH2CH3) 2C1). Thiols (also known as mercaptans) have the general formula R37-SH, where R; is a main skeleton of a compound of the Formula I. The nitro compounds have the general formula R38-N02 where R38 is a backbone of a compound of Formula I. Organic enzymes have the general formula R39-N3, where R39 is a backbone of a compound of the Formula I. Hydroxylamines have the general formula R40-NR41 (OH), where R40 is the major backbone of a compound of Formula I and R 41 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl. Examples of hydroxylamine substituents (-NR75 (0H)) include hydroxylamino (-NH (OH)), N-methylhydroxylamine (-N (OH) CH3)), N-ethylhydroxylamine (-N (OH) CH2CH3)) or N -benzylhydroxylamine (-N (OH) (CH2C6H5)). Alkoxy or aryloxy amines have the general formula R42-NR43 (OR44), where R42 is a major backbone of a compound of Formula I, R43 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl, and R44 is alkyl or aryl. Examples of alkoxy or aryloxyamine substituents (-NR (OR44)) include methoxylamine (-NH (OCH3)), N-ethylmethoxylamine (-N (OCH3) CH2CH3)) or N-benzyl-ethoxylamine (-N (CH2CH3) ( CH2C6H5)). The nitriles have the general formula R 45 -C N, where R 45 is the main backbone of a compound of the Formula I. The thiocyanates have the general formula R46-SCN, where R46 is the main backbone of a compound of the Formula I. The imines (also known as Schiff bases) have the general formula: * "• where R is a backbone of a compound of Formula I, and R 'and R "may be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, or aryl.

Sulfinic acids have the general formula R47-S02H, where R47 is a backbone of a compound of Formula I. Sulfonic acids have the general formula R8-S03H, where R48 is a backbone of a compound of Formula I . Sulfonic acid esters have the general formula: examples of sulfonic acid esters, where R 'contains the main backbone of a compound of Formula I, ie, the skeleton of swainsonin, contains tosylates (p-CH3C6H4S03-) and mesylates (CH3SO3-). Other examples where R contains the basic skeleton of the compound of Formula I, ie, the skeleton of swainsonin contains methyl esters (-SO3CH3), ethyl esters (-S03CH2CH3) or benzylic esters (-S03CH2CsH5). The triazoles have the general formula: where 'one of R, R1 and R' 'is a basic skeleton of a compound of Formula I, and another of R, R' and R '' may be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, hydrocarbons monocyclic unsaturated, or aryl. Examples of compounds of the invention that include triazoles are the following: The imides have the general formula wherein one of R, R ', R "is a backbone of a compound of Formula I, and the other of R, R' and R" may be any combination of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl , unsaturated monocyclic hydrocarbons, or aryl. Examples of compounds of Formula I, wherein an imide forms part of the main backbone of a compound of Formula I include: The imidazole rings that can be used in the compounds of Formula I have the general formula: Examples of the swainsonin analogs of the invention having an imidazole ring include: The term "carbocyclic" or "carbocyclic ring system" refers to molecular rings where the structure is constructed by joining the carbon atoms only and includes, but is not limited to, any bicyclic monocyclic or bicyclic ring of 3 to 7 members. or tricyclic of 7 to 14 members, or polycyclic of up to 26 members, any of which may be saturated, partially unsaturated, or aromatic. Examples of carbocyclic rings include substituted or unsubstituted cycloalkyl, monocyclic unsaturated hydrocarbons, and aryl as described herein, including, but not limited to, benzene and naphthalene.

Heterocyclic rings are molecular rings where one or more carbon atoms have been replaced by heteroatoms (atoms that are not carbons) such as, for example, oxygen (0), nitrogen (N) or sulfur (S), or combinations thereof. same. Examples of heterocyclic rings include ethylene oxide, tetrahydrofuran, thiophene, piperidine (piperidinyl group), pyridine (pyridinyl group), and caprolactam. A carbocyclic or heterocyclic group may be optionally substituted at the carbon or nitrogen atoms with for example, alkyl, phenyl, benzyl, or thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom may form a carbonyl group, or a heterocyclic group can be fused with a phenyl group. , A spiro ring is defined as two rings that originate from the same atom (the spiro center). A spiro ring is represented schematically.

Some of the examples of swainsonine analogs of the invention containing spiro-rings include: One more of R1, R2, R3, W, W ', W,?, X, X', Y, Y ', Z and / or Z', alone or together, containing functional groups available as described herein they may be substituted with one or more of the following: alkoxy, hydroxyl, thiol, thiol, SR9 where R9 is alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons, thioaryl, amino, ammonium, halogen, carbocyclic acid, or the latter, ketone, aldehyde, carbonate, carbamate, amide, azide, imide, imine, imidazole, acetal, ketal, nitrile, diazo, nitro, hydrazine, hydrazine, hydroxamic acid, oxime, hydroxylamine, sulfate, sulphonic or sulfinic acid, or ester, sulfonamide , phosphate or phosphanate, acids or ester, silyl, sulfoxide, sulfone, oxime, guanidino, phosphonate, thioamide, thiocarbamate, thiocyanate, thioketone, thiourea, triazole, cyano, nitrile, urea or xanthate. The term "one or more" used herein preferably refers to from 1 to 3 substituents, preferably 1 to 2 substituents. Examples of substituted radicals are described herein, and include, but are not limited to -CH2R50 where R50 is alkyl, aryl, amino, -CR51 where R51 is halogen, in particular trifluoromethyl, and -CH20R52, where R52 is alkyl or aril. In one embodiment of the invention, the compounds of Formula I are provided, where W, W 'and W "are the same and represent hydroxyl, in another embodiment of the invention, a compound of Formula I is provided, wherein R1, R2 and R3 are the same and represent hydrogen. In still a further embodiment of the invention, the compounds of Formula I are provided where R1, R2 and R3 are the same and represent hydrogen, and W, W and W "are the same and represent hydroxyl.

In particular, the invention contemplates. the compounds of Formula I, wherein: (a) R1, R2 and R3 represent hydrogen, and W, W 'and W "represent hydroxyl, and Z and Z' represent hydrogen; (b) R1, R2 and R3 represent, and W, W 'and W "represent hydroxyl, and X and X' represent hydrogen; - (c) R1, R2 and R3 represent hydrogen, and W, W 'and W1' represent hydroxyl, and X, X ', Z and Z' represent hydrogen; (d) R1, R2 and R3 represent hydrogen, and W, W 'and W "' represent hydroxyl, Y and Yf represent hydrogen, (e) one of Y and Y 'represents methyl, hydroxymethyl, ethyl, phenyl, benzyl, benzyloxymethyl, or fluoromethyl; (f) one of X and X 'represents methyl which may be substituted such as thiomethyl, fluoromethyl or methoxy; (g) W "and R3 are the same and represent halogen, preferably fluorine; ) Y and Y 'are the same and represent halogen, preferably fluoro.

Preferably, the compounds of Formula I of the invention are those where: (a) R1, R2 and R3 represent hydrogen, W, W 'and Wt'- represent hydroxyl, Z and Z' represent hydrogen, one of X and X ', which may be substituted, is alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, -CH2OR52, where R52 represents alkyl or aryl, and the other of X and X 'is hydrogen, or X and X' represent together = 0, and one of Y and Y ', which may be substituted, is alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino , halogen, carboxylic acid esters, thiol esters, .CH2R52, where R52 represents alkyl or aryl, benzyl, and the other of Y and Y 'is hydrogen.; (b) R1, R2 and R3 represents hydrogen, W, W 'and W "represents hydroxyl, Y and Y' represents hydrogen, X and X ', which may be substituted are the same or different and represent hydrogen, alkyl, aryl , alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2OR52, where R52 represents alkyl or aryl, and Z and Z "are the same or different and represent alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or CH2R52 where R52 represents alkyl or aryl, with the proviso that at least one of X and X 'and at least one of Z and Z * can not be hydrogen; (c) R1, R2 and R3 represents hydrogen, W, W' and W 'represents hydroxyl, X and X' represents hydrogen, Y, Y ', Z and Z' are the same or different and represent hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, ester is carboxylic acid, thiol, benzyl, or pyridinyl esters, or -CH2R52 where R52 represents alkyl or aryl, which may be substituted, provided that at least one of Y and Y 'and at least one of Z and Z' it can not be hydrogen; more preferably one of Y and Y 'and one of Z and Z' represents alkyl, aryl, hydroxyl, thiol, thioalkyl, benzyl, pyridinyl, or -CH2OR50, where R50 represents alkyl or aryl, which may be substituted, and the another of Y and Y 'and Z and Z' represents hydrogen; (d) R1, R2 and R3 represent hydrogen, W, W 'and W "represents hydroxyl, X and X' represent hydrogen, one of Y and Y ', which may be substituted, represents alkyl, aryl, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2R52 where R52 represents alkyl or aryl, and the other of Y and Y ', which may be substituted, represents hydrogen, alkyl , aryl, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2OR52, where R52 represents alkyl or aryl; (e) R1, R2 and R3 represents hydrogen, W, W 'and W "represents hydroxyl, Y, Y', Z and Z 'represents hydrogen, one of X and X' represents alkyl, aryl, alkoxy, hydroxyl, thiol , thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2OR52 where R52 represents alkyl or aryl, which may be substituted, and the other of X and X 'which may be substituted substituted represents hydrogen, alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl or pyridinyl esters, or -CH2OR52, where R52 represents alkyl or aryl, or X and X 'jointly represent = 0; (f) R1, R2 and R3 represent hydrogen, W, W and W 'represent hydroxyl, Z and Z' represent hydrogen, and X and Y, X 'and Y', or X and Y 'together form a heterocyclic ring of 6. members containing one or two of O, S, or N. Particularly preferred compounds of the invention are compounds of Formula I, wherein: 1. One of Y and Y 'and one of Z and Z' represents alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, benzyl, pyridinyl, or -CH20R52 where R52 represents alkyl or aryl, which may be substituted, and the other of Y and Y 'and ZY z' represents hydrogen. 2. R1, R2 and R3 represent hydrogen, W, W 'and W "represent hydroxyl, X and X', Z and Z 'represent hydrogen, and one of Y and Y' represent methyl, ethyl, phenyl, or benzyl which may be substituted, preferably trifluoromethyl, hydroxymethyl, and benzyloxy ethyl, and the other of Y and Y 'represents hydrogen; 3. R1, R2 and R3 represents hydrogen, and W represents hydroxyl, and W 'and W "represent halogen, preferably fluoro; X, X ', Z and Z' represent hydrogen, and one of Y and Y 'represent methyl, ethyl, phenyl, or benzyl, which may be substituted, preferably trifluoromethyl, hydroxymethyl, and benzyloxymethyl and the other of Y and Y' represents hydrogen; 4. One of Y and Y 'is hydrogen and the other of Y and Y' and methyl, and one of Z and Z 'is hydroxymethyl, -COCH2CH3. CN, -CH2NH2, -CH2NHAc, or -CH2NHCRd0 = NH where R60 is alkyl or aryl; 5. One of Z and Z * is -CONR70R71, where R70 and , 71 are the same different and represent hydrogen, alkyl, or aryl, -COOH, -COOC2H5, methyl, or CH2OH, or z and Z 'together form a spiro ring; or 6. X and Y form a carbocyclic or heterocyclic ring of the formula R75-R76-R77-R78-R79 where R75 and R79 are part of the skeleton of swainsonin and one more of R76, R77 and R78 represent CH, QH2, O, S, or N. Selected compounds of the Formula I are the following: (5R) -5-me t ilswainsonin, formate salt of (5R) -5-methylswainsonin, (5S) -5-met ilswainsonin, (5R) -8-epi-5-methylswainsonin, (5S) -5-etilswainsonin, (5S, 6S) -6-hydroxymethyl-5-methylswainsonin, (5R) -5-benzyloxymethylswainsonin, (5S) -5-hydroxymethylsilycin, (5R, 6R) -6-hydroxymethyl-5-ethylswainsonin, (5S) -5 -hydroxymet ilswainsonin, ethyl (14,24, 5S, 6S, 8S, 8aR) -1,2,8-trihydroxy-5-methyloctahydro-6-indolizinecarboxylate.

It will be appreciated that, due to the asymmetrically substituted carbon atoms in Formula I, there may be a compound of Formula 1, in, and isolated in, optically active and racemic forms. It is to be understood that the present invention lows a compound of Formula I, as a mixture of diastereomers, as well as in the form of a linear ter-ore, and that the present invention encompasses a compound of Formula I as a mixture of enantiomers , as well as in the form of an individual enantiomer. It will be appreciated that, the (S) -isomer and the (R) -isomer are convertible by easy epimerization of the chiral centers, and that a preparation containing the compound of the Formula I as a mixture of the (S) - and (R) -isomers of Formula I are within the scope of the invention. Therefore, the present invention contemplates all optical isomers and racemic formulas thereof of the compounds of the present invention and the formulas of the compounds shown herein are intended to encompass all possible optical isomers of the compounds represented A) Yes. The present invention also contemplates salts and esters of the compounds of Formula I of the invention. In particular, the present invention includes pharmaceutically acceptable salts. By pharmaceutically acceptable salts are meant those salts which are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response, and the like and are in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art and are described, for example, in S.M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66: 1-19. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, canfersul fonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanate, glycerophosphate, hemisulfate, heptonate, hexanoate, bromohydrate, hydrochloride, iodhydrate, 2-hydroxy-ethanesulphonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulphonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluensul fonate, undecanoate, salts of valerate and the like. Representative alkaline earth metal or alkali metal salts include cations of sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine, including, but not limited to, ammonium, tetramethyl ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

II. PROCESSES FOR PREPARING COMPOUNDS The compounds of Formula I of the present invention can be prepared by using the procedures and techniques well known and appreciated by one skilled in the art. By way of illustration, descriptions of some methods that can be used to prepare the compounds of Formula I of the invention are disclosed herein. The compounds of Formula I, wherein R 1, R 2 and R 3 represent hydrogen, W, W 'and W "represent hydroxyl, and X, X', Z and Z 'represent hydrogen can be synthesized in a variety of ways by adapting synthetic, organic chemistry practices common to known synthetic intermediates. For example, as shown schematically in Figure 1, the known alcohol acid 2 (BP Bashyal, Tetrahedrom 43 (13): 3083-3093 (1987)) can be oxidized to provide the corresponding aldehyde which is then reacted (Wittig reaction) with a variety of commonly available or synthesized phosphorans or phosphonate derivatives (3 and 4, respectively) to give the α, β-unsaturated ketone of type 5 where the group X can be any chemical group such as methyl, chloromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, hexyl, phenyl, benzyl, etc. Catalytic hydrogenation of 5 followed by removal of the isopropylidene protecting group under normal conditions then gives the desired derivatives of 5-substituted swainsonin. Further manipulations of functional groups such as oxidation, reduction, nucleophilic additions or substitutions, etc., of the new substituents can further increase the number of derivatives of the limited number of Wittig reagents originally used to construct the nucleus molecule. Alternatively, the reduction of the ketone 5 to the corresponding aminoalcohols 6 can give mixtures of 5- and 5'-swainsonin derivatives -substituted after a Mitsunobu-style cyclization reaction, to close the 6-membered ring, followed by the usual catalytic hydrogenation to cyclize the 6-membered ring, and the final removal of isopropylidene (Figure 2). The concept of displacing a leaving group, generated from an alcohol function, with an amine as in 6 in order to cyclize the 6-member ring of the swainsonins can be performed by a variety of strategies including, for example, group protection amino with a benzyloxycarbonyl group (CBZ) followed by the mesilization of the free hydroxyl and the nucleophilic displacement of the mesyl group by the amine generated during a catalytic hydrogenation step which simultaneously cyclizes both rings in the (compounds required of Formula I, and which is apparent to anyone skilled in the art of synthetic organic chemistry There are many possible synthetic routes that can be used to prepare swainsonine analogues 5, 5 '-disubstituted using some of the concepts described above, eg the reduction of the azido group in two followed by the production of the resulting amine with a suitable reducing group such as fluoroenylmethoxycarbonyl or (Fmoc) gives alcohol 7. Oxidation followed by a Wittin reaction using phosphorans or phosphonates as described above gives ketone 8. Selective reduction of alkene with palladium oxide and subsequent removal of the amine protecting group using piperidine for example, it leads to the formation of a cyclic imine that can be reacted with any nucleophile to provide the 5,5'-disubstituted swainsonin analogues after the final catalytic hydrogenation and the removal of isopropyl idene (Figure 3B). Alternatively, substituents at the 5-position of the swainsonin can be introduced by reacting the known amide 9 with suitable Wittig reagents. Additional modifications such as oxidative hydroboration or simple reduction of new alkene 10 can also give a number of new 5-subtype derivatives (Figure). Swainsonin analogs 3, 5-disubstituted, ie, compound of Formula I, wherein R1, R2 and R3 represent hydrogen, W, W 'and W "represent hydroxyl, and Z and Z' represent hydrogen can also be prepared by __ a variety of methods . For example, the temporary protection of the amine 11 with a Fmoc group followed by the gentle reduction of the anomeric benzyl group under neutral conditions gives the corresponding hemiacetal 12 which then temporarily spontaneously generates a cyclic iminium complex 13 in the deprotection of the amine using a soft base such as piperidine which then reacts rapidly with any nucleophile present to give the swainsonine analogue 3, 5-disubstituted, protected. The treatment with mild acid and then remove the protective group of isopropylidene to give the desired 3, 5-disubstituted swainsonine analogues (Figure 3A). Synthetic routes for preparing the compounds of Formula I, wherein R 1, R 2 and R 3 represent hydrogen, W, W 'and W "represent hydroxyl, and Z and Z' represent hydrogen; R1, R2 and R3 represent hydrogen, W, W 'and W1' represent hydroxyl and X and Xt represent hydrogen; and R1, R2 and R3 represent hydrogen, and W, W 'and W "represent hydroxyl, and Z and Z' represent hydrogen; R1, R2 and R3 represent hydrogen and W, W 'and W "represent hydroxyl, are shown in Figures 3A; Figures 4, 5 and 6; and Figure 7, respectively. The reactive groups used to prepare the compounds of the invention can be blocked using appropriate protecting groups. Appropriate blocking and unblocking schemes are known to one skilled in the art (see T. W. Greene, Protective groups in Organic Synthesis, John Wiley &Sons, New York, 1981). In general, the paricular protecting groups are selected, which adequately protect the reactive groups in question during the subsequent synthesis steps and which are easily removed under conditions that will not cause degradation of the desired product. By way of example, ethers, acetals, ketals and esters may be used to protect the isolated hydroxyl groups. In particular, suitable protecting groups that can be used in the process of the invention include O-benzyl, O-p-methoxybenzyl, O-acetoxy, O-haloacetoxy, O-benzoyloxy, and O-allyl. The removal of the protecting groups can be carried out using procedures known in the art. For example, a p-methoxybenzyl group can be removed using ceric ammonium nitrate in acetonitrile and water.

Appropriate methods for replacing a free hydroxyl group with alkoxy, halo, or amino in the blocked / claimed compounds to produce the compounds wherein, for example, W, W and / or W 'are alkoxy, aryl, halo-, or amino , are well known to one skilled in the art. In particular, a free hydroxyl group can be converted to an alkoxy or aryloxy group by reacting with an alkyl or aryl halide in the presence of a base. To replace the free hydroxyl with a halo group, the free hydroxyl compound is first reacted with typical anhydride, mesyl chloride or tosyl chloride, in the presence of a pyridine-like base, to block the hydroxyl with a leaving group such as triflate, mesyl or tosyl, respectively. The blocked hydroxyl is then replaced by O-benzoate, with inversion, by the treatment with sodium benzoate in dimethylformamide (DMF). The O-benzoate is then deesterified, again blocked by a suitable triflate-like leaving group which, treatment with tributyl ammonium halide1, is replaced, with emulsion, by the respective halide, or in the treatment with sodium azide is it replaces, with inversion, by azido, and subsequently by amino in reduction. An alkoxy group can be added by dissolving the compound with a free hydroxyl in DMF and adding it to a flask under an inert atmosphere containing a base (eg, sodium hydride) at low temperature (from 0 ° C to 10 ° C) . After stirring, for a few minutes, benzyl bromide in DMF is added dropwise at low temperature, for example from 0 ° C to 10 ° C. The reaction mixture is further stirred at room temperature for 2 to 24 hours. Conventional treatment of the reaction mixture produces the alkoxy (benzyl) compound. A halo group, for example, fluoro, can be added by dissolving a compound with a free hydroxide in dichloromethane (DCM) together with a base similar to pyridine. After cooling to low temperature (-10 ° C to -60 ° C), an appropriate amount of triflic anhydride, or mesyl chloride, or tosyl chloride is added dropwise. The reaction is allowed to stir at a temperature between 0 ° C to 25 ° C. Conventional treatment of the reaction mixture produces the esterified compound. The treatment of this derivative with sodium benzoate in DMF is carried out immediately, which replaces the leaving group with O-benzoate with inversion. The free hydroxyl is released by treatment with a base (e.g., sodium methoxide) and then re-blocked by a suitable leaving group such as triflate (repeating the method described above). To obtain an inverted fluoride derivative, the triflate is treated with anhydrous tetraalkylammonium fluoride (preferably tetra-n-butyl) or potassium fluoride in a suitable solvent (for example, diethyl ether, tetrahydrofuran or crown ether). For the introduction of an amino group, the triflate can be treated with either sodium azide or benzylamine in DMF. The product can be obtained with an azido or benzylamide group, with reversal, which in the reduction with palladium in carbon in a hydrogen atmosphere gives the free amino group. Suitable methods for the introduction of a thiol group into the compounds of Formula I (for example, where W, W ', W' ', X, X', X ', Y,?', Z and / or Z 'are thiol) are well known to one skilled in the art. For example, a thiol group can be added by nucleophilic substitution of an alkyl halide of sulfonyl ester for example using sodium sulphide hydride (NaSH), or by nucleophilic substitution of a halide or sulfonate ester using thioacetic acid to give a thioacetate group which is then unblocked to a free thiol in the treatment with sodium methoxy in methanol by converting it into a Bunte salt using thiosulfate (S203"2) and finally hydrolyzing the Bunte salt with an acid, or by treating the hydroxyl group with a fluoropyridinium salt, and N, N-dimethyl-thiocarbamate (Hojo: Yoshino: Mukaiyama Chem. Lett, (1977)) 133: 437), or by oxidizing a hydroxyl to a ketone then converting it to a thioketone with Lawson's reagent, and reducing a thiol with sodium borohydride. For review, see (Wardell, in Patai "The Chemistry of Thiol Group, p6tWriley: New York, 1974, pp. 179-211.) Methods for introducing a thiyl or a thioaryl group into the compounds of Formula I (for example, where W, W ', W' ', X, X', X ', Y, Y', Z, and / or Z 'are thiyl or thioaryl) are well known to one skilled in the art. by its nucleophilic substitution of an alkyl halide or sulfonyl ester, for example, with alkyl or aryl thiolate salts, or with alkyl or aryl thiols, in the presence of a base such as 1,8-diazabicyclo [5.4. 0] undecene (DBU), by alkylating the thiols with alkyl or aryl halides or sulfonate esters, or by treating a hydroxyl group with an alkyl or aryl halide in the presence of tetramethylthiourea followed by sodium hydride (Fujisaka; Fujiwara; Norisue; Kajigaeshi Bull, Chem. Soc. Jpn. 1985, 58: 2529) or by treating an alcohol with tributyl phosphine and an N- (thioaryl) succinimide in benzene (Waters Tetrahedron Lett, 1977, pp. 4475 and reference cited therein). For a review, see Peach, in Patai "The Chemistry of the Tiol Group, pt 1: Wiley: New York, 1974, pp. 721-735 In addition, the appropriate methods to replace a blocked or unblocked hydroxyl group with a hydrogen in Compouof Formula I are well known to one skilled in the art For example, alkyl halides or sulfonyl esters such as tosylates can be selectively reduced with lithium aluminum hydride or a variety of other metal hydride reducing agents in different solvents such as ether or diglyme A large list of methods capable of achieving this transformation is given in J. March "Advanced Organic Chemistry, Reactions, Mechanisms and Structure", 4th Edition, 1992, pp. 438-446 and cited references therein, some alkyl or aryl groups, particularly those which may contain unsaturations or other chemical functional groups such as halo, carboxyl, hydroxyl, alkoxy, azido or amino, 'for example, they can be additionally derivatized by chemical processes such as by oxidation, hydroxylation, hydrolysis, nitration, hydroboration, sulfation, amination, amidation, esterification, • alkylation, halogenation, epoxidation, carbonylation, haloformilation, reduction, carbon-carbon chain extension by Gringnard or Wittig reactions for example, to introduce new or additional functional groups in any final compound. These transformations can be achieved by one skilled in the art of synthetic organic chemistry. If necessary, the products of the processes described above can be purified by conventional methods such as column chromatography. Compouof Formula I with available hydroxyl group can be converted to epi-isomers by inversion of SN2. For example, the free hydroxyl can be reacted with benzyl chloride and pyridine to give O-mesyl (methylsulfonyl), which in the treatment with sodium benzoate in DMF (dimethylformamide) produces a compound where the free hydroxyl group is replaced by epi-O-benzoate. Deesterification using NaOMe in methanol results in a compound of Formula I, where the free hydroxyl is replaced by epihydroxyl. Similarly, this SN2 inversion method can be used to displace a hydroxyl by an azido group or halo group (F, Cl, I, Br) in its epi-isomers. The compouof Formula I described above can be converted to salts using conventional procedures. For example, where one of X, X ', Y, Y', Z, and Z 'in a compound of Formula I is a carboxylic acid, the compound can be converted to a salt by treating with a molar equivalent of hydroxide of sodium or potassium hydroxide. Where one of X, X ', Y, Y', Z, and Z 'in a compound of Formula I is an amine, the compound of Formula I can be converted to a salt by treating with acetic acid, hydrochloric acid, or formic acid.

Compounds of Formula I, with free hydroxyl groups can also be converted to esters using conventional processing. for example, the compounds of Formula I can be dissolved in DCM and pyridine. After cooling (0 ° C to 5 ° C), benzoic anhydride or benzoyl chloride is added dropwise to DCM and pyridine. The reaction is allowed to stir at room temperature for 2 or 24 hours. Conventional treatment produces the esterified derivatives. The optical antipodes of the oxygen can be prepared from the corresponding racemic forms by normal optical resolution techniques, comprising, for example, the separation of diastereomeric salts from those compounds of Formula I characterized by the presence of a group basic amino, and an optically active acid, or by synthesis of the optically active precursors.

III. UTILITY OF THE COMPOUNDS OF THE INVENTION The compounds of Formula I are inhibitors of oligosaccharide processing and in particular are mannosidase inhibitors. The general inhibition of mannosidase can be tested by measuring the inhibition of Jack Bean, a-mannosidase, and lysosomal α-mannosidase. Inhibition of mannosidase can also be tested using a cytotoxicity assay of L-PHA. The assay is based on the finding that the specific binding of the toxic lectin of L-PHA plant to transformed cell lines such as MDAY-D2 tumor cells is a specific measure of the inhibition of oligosaccharide processing. The measurement of IC5o in the toxicity test of L-PHA reflects the ability of the compound to be introduced into the cells and effect the inhibition of oligosaccharide processing. It is a general selection for cell activity that measures cell entry, inhibition of the target enzyme, a-mannosidase II in the Golgi, and the resulting cell phenotype. Therefore, a compound of the invention can be tested for its ability to inhibit the processing of N-linked oligosaccharides by culturing cells grown in the presence of L-PHA and the compound; measure the amount of proliferation of the cells; and determining the ability of the compound to inhibit the processing of the N-linked oligosaccharides by comparing the amount of proliferation of the cells with the amount of proliferation observed for the cells cultured in the presence of L-PHA alone. Transformed cells that can be used in this assay include MDAY-D2, L1210, CHO, B16, melanoma tumor cells, and human tumor cells such as SW 480, LS174TG, HT-29, WiDr, T2, MDA-231 , MCF7, BT-20, Hs578T, K562, Hs578T, SK-BR-3, CY 6T, MDA-468, H23, H157, H358, H1334, H1155, H28, H460, HMESOL, H187, H510A, N417, H146, H1092, H82, (Restifo, NP et al., J. Exper. Med. 177: 265-272, 1993). The amount of proliferation of the cells can be measured using conventional techniques. for example, cell proliferation can be measured by measuring the incorporation of labeled thymidine. More particularly, the radioactively labeled thymidine may be added for about 2-5 hours, preferably 3-4 hours and the cells may be harvested and the radioactivity counted using a scintillation counter. The conditions for carrying out the above test will be selected with respect to the nature of the compound and the cells employed. For example, if the transformed cells are MDA6-D2 tumor cells at a concentration of about 1-4 x 104 cells, preferably 2 x 104 can be used. The MDAY-D2 cells are generally grown for about 10 to 30 hours, preferably 18 to 20 hours, followed by the addition of L-PHA at a concentration of about 10-50 μg / ml, preferably 20- 30 μ / ml, more preferably 25 μg / ml. The following L-PHA assay can be used to assess the inhibition of oligosaccharide processing (ie Golgi α-mannosidase II) in viable cells. MDAY-D2 tumor cells are inoculated into 96-well micro-test plates at 2 x 104 cells / well, which contain serial dilutions of the compound to be tested in MEM plus 10% FCS. The cells are cultured for 18-20 hours, followed by the addition of L-PHA at 25 μg / ml for an additional 24 hours. Cell proliferation is measured by adding 0.5 μCi / well of 3H-thymidine for 3-4 hours, collecting on glass fiber discs using a Titertek counter, and counting the discs in a liquid scintillation counter. The apparent IC5o values for the test compounds are the concentration of the drugs that show 50% protection from the toxicity of L-PHA, that is 50% of 3H-thymidine incorporated compared to the cells grown in the absence of L -PHA. The ability of the compounds of Formula I in which the free hydroxyls have been esterified, to be converted into more active compounds in the cells can be measured by performing the L-PHA toxicity assay in the presence of a stearase inhibitor such as diethyl-p-nitrophenyl phosphate. For example, the esterase inhibitor diethyl-p-nitrophenyl-phosphate can be added to the MDAY-D2 cells in the assay method described above approximately 4 hours before the a-mannosidase inhibitors. An increase in IC50 in the toxicity test of L-PHA in the presence of diethyl-p-nitrophenyl phosphate indicates that the compound requires activation by esterases and would therefore be useful as a prodrug. This method can be used to select prodrugs and can be used to identify substances that inhibit all steps in the path of the N-linked oligosaccharides before β-4-Gal trans-ferase. The compounds of Formula I have valuable pharmacological properties and provide immunomodulatory, antimicrobial and cancer suppressive effects. In particular, the compounds are useful in the prevention, treatment and prophylaxis of tumor growth and tumor metastasis. The antimestatic effects of the compounds of the invention can be demonstrated using a lung colonization assay. For example, melanoma cells treated with a compound can be injected into mice and the ability of "give" melanoma cells to colonize the lungs in the mice can be examined by counting tumor nodules in the lung after death. The suppression of tumor growth in mice by the compound administered orally or intravenously can be examined by measuring tumor volume. The compounds of Formula I have particular application in the prevention of tumor recurrence after surgery, i.e., as adjuvant therapy. The compounds of the invention are especially useful in the treatment of various forms of neoplasia such as leukaemias, lymphomas, melanomas, adenomas, sarcomas and solid tissue carcinomas in patients. In particular, the composition may be useful for treating malignant melanoma, pancreatic cancer, cervical cancer, cancer of the kidney, stomach, lung, rectum, chest, intestine, gastric, liver, thyroid, neck, cervix, salivary gland, leg, tongue, lip, bile duct, pelvis, mediastinum, urethra, bronchogenic, vesicle, esophagus and colon, and caposi sarcoma which is a form of cancer associated with patients infected with HIV with acquired immunodeficiency syndrome (AIDS). The compounds may also be useful for other antiproliferative conditions such as atherosclerosis and viral infections, in particular AIDS. The compounds of Formula I can be used to stimulate the proliferation of bone marrow cells, and can be used as a hemorrhagic agent, in particular after chemotherapy or radiotherapy. The myeloproliferative activity of a compound of Formula I can be determined by injecting the compound into mice, killing the mice, removing the cells from the bone marrow and measuring the ability of the compound to stimulate the proliferation of the bone marrow by directly counting the Bone marrow cells and when measuring clonogenic progenitor cells in the methylcellulose assays. The compounds of the invention are immunomodulatory and in particular have immunostimulating properties. Thus, the compounds of Formula I can be used in cases where a patient has been immunocompromised such as patients infected with HIV, or other viruses or infectious agents including bacteria and fungi, in patients undergoing bone marrow transplants, and in patients with clinical or tumor-induced immunosuppression. The compounds also have an antiviral effect and in particular in viruses enveloped in membranes such as retroviruses, influenza viruses, cytomegalovirus and herpes viruses. The compounds of the invention can also be used in the treatment of inflammation. The following compounds of the invention show significant inhibition of Golgi α-mannosidase activity on lysosomal mannosidase activity; (a) Compounds of Formula I wherein R1, R2 and R3 represent hydrogen, W, W 'and W' represent hydroxyl, Y, Y ', Z and Z' represent hydrogen, and one of X and X ', representing methyl, phenyl, benzyl, which may be substituted, preferably fluoromethyl or hydroxymethyl, and the other of X and X 'represents hydrogen; (b) Compounds of Formula I, wherein R1, R2 and R3 represent hydrogen, W, W 'and W "represent hydroxyl, X and X', Z and Z 'represent hydrogen, and one of Y and Y' represent methyl, ethyl, phenyl, benzyl which may be preferably substituted trifluoromethyl, hydroxymethyl and benzyloxymethyl and the other of Y and Y 'represents hydrogen; and (c) Compounds of Formula I, wherein R 1, R 2 and R 3 represent hydrogen, W, W 'and W "represent hydroxyl, and Y, Y' represent hydrogen, X and X 'are the same or different and, they represent hydrogen, alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2OR52 where R52 represents alkyl or aryl, which may be substituted, and Z and Zt are the same or different and represent alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, amino, halogen, carboxylic acid esters, thiol, benzyl, pyridinyl, or -CH2OR52 esters, where R52 represents alkyl or aryl , with the proviso that at least one of X and X 'and at least one of Z and Z' can not be hydrogen. Particularly preferred compounds are (5S) -5- (hydroxymethyl) swainsonin, (5S) -5-met ilskinsonin, (5S) -5-et ilswainsonin, (5R) -5-methylswainsonin, (5S) -5-benzyloxymethylswainsonin , (5R) -5-benzyloxymethylsilycin, or (5R) -5- (hydroxymethyl) swainsonine. These compounds are particularly well suited for incorporation into pharmaceutical compositions for use in the treatment of the conditions mentioned herein since they have improved pharmacological properties and selectivity avoids the clinical side effects that may be exhibited by swainsonin. The term "patient" refers to a warm-blooded animal such as a mammal that is afflicted with a particular disease state or condition as described herein. Examples of animals within the scope of the meaning of the term are dogs, cats, rats, mice, horses, cattle, sheep, and humans.

The compounds of Formula I can be converted using standard methods in the pharmaceutical composition. The pharmaceutical composition contains the compounds either alone or in combination with other active substances. These pharmaceutical compositions may be for oral, topical, rectal, parenteral, local, inhalant, or intracellular use. Therefore, they exist in solid or semi-solid form, for example, pills, tablets, creams, gelatin capsules, capsules, suppositories, soft gelatine capsules, liposomes.

(For example, see the United States Patent Serial No. 5,376,452), gels, membranes and tubules.

For parenteral and intracellular uses, those forms for intramuscular or subcutaneous administration, or forms for inclusion or intravenous or intracellular injection can be used, and therefore can be prepared as solutions of the compounds or as a powder of the active compounds that are to be mixed with one or more pharmaceutically acceptable excipients or diluents, suitable for the above uses and with an osmolarity that is compatible with physiological fluids. For local use, these preparations in the form of creams or ointments for topical use or in the form of sprays should be considered. For inhalant uses, preparations in dew forms, for example nose dew, should be considered. The pharmaceutical compositions can be prepared by methods known per se for the preparation of pharmaceutically acceptable compositions that can be administered to patients, and such that an effective amount of the substances they combine in a mixture with a pharmaceutically acceptable carrier. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985). Based on this, the pharmaceutical compositions include, but are not limited to, the compounds in association with one or more pharmaceutically acceptable carriers or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids. . The compounds are indicated as therapeutic agents either alone or in combination with other therapeutic agents or other forms of treatment (eg, chemotherapy or radiotherapy). . For example, the compounds can be used in combination with antiproliferative agents, antimicrobial agents, immunostimulatory agents, or anti-inflammatory agents. In particular, the compounds can be used in combination with antiviral and / or antiproliferative agents such as interferons. The compounds of the invention can be administered concurrently, separately, sequentially with other therapeutic agents or therapies. In general, a dose range of the compuestost in the composition is contemplated for administration in human medicine from about 0.001 to 50 mg / kg of body weight daily. In the case of intravenous compositions, the dose is for example about 0.1 to 0.6 mg / kg / day, and for oral compositions the dose is about 0.5 to 6 mg / kg / day. The amounts of the drugs supplied to produce 10-lOOx serum levels, the IC 50 for the inhibition of polysaccharide processing in the L-PHA assay are preferably used.

It will also be appreciated that it may be necessary to deviate from the amounts mentioned and in particular to do so as a function of the body weight of the animal to be treated, the particular disease to be treated, the nature of the route of administration and the desired therapy. In addition, the type of animal and its individual behavior towards the medicine or the nature of its formulation and the interval time in which it is administered may also be the indicative use of amounts different from those mentioned. In this way, it may be sufficient, in some cases, to handle agreements of the minimum amounts mentioned above while in other cases the upper limit mentioned must be exceeded. Where it is administered in larger quantities, one can contemplate dividing these into several administrations during the course of the day. The following non-limiting examples are illustrative of the present invention: EXAMPLES Example 1 SYNTHESIS OF SWAINSONINE 5-SUBSTITUTE ANALOGS A. Synthesis of (5S) -5-met ilswainsonin (GD28) and 5 (R) -5-Metilswainsonin (GD20) Benzyl--azido-, 6,7,9- (tetradeoxy-2, 3-0-isopropylidene-a-D-mannone-6-enopyranosi or-8-ulose (GDLZI).

Pyridinium chlorochromate (776 mg, 3.6 mmol) was added to a vigorously stirred suspension of flame-dried 3 A molecular sieves (3 g) and benzyl-4-azido-2,3-isopropylidene-aD-mannopyranoside (500 mg, 1.49 g. mmol) in anhydrous methylene chloride (50 mL). After 30 minutes, the oxidation was finished, the slurry was loaded on top on a column of silica gel (50 g) and the product was eluted with ethyl acetate.

Hexanes 1: 1. The eluent containing aldehyde was concentrated, the residue was dissolved in anhydrous benzene (30 mL), the solution was cooled to 0 ° C, and triphenylphosphoranylidene-2-propanone (1.2 g, 3.77 mmol) in anhydrous tetrahydrofuran (30 mL) was added. The solution was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, the residue was chromatographed (16 g of silica gel, ethyl acetate: hexanes 1: 3) and gave GDLZ1. (340 mg, 61%) as a syrup that crystallizes spontaneously.

Benzyl-4-azido-4, 6,7, 0-tetradeoxy-2, 3-0-isorpopoylidene-D / L-glycero-D-man-a-none-, 6-enopyranoside (GDLZ18).

Sodium borohydride (150 mg) was added to a stirred solution of crude GDLZ17 (1.46 g, approximately 3.91 mmol) in methylene chloride methanol 1: 1. After 30 minutes, the reaction was terminated, the solution was concentrated to dryness, the residue was chromatographed (34 g of silica gel, ethyl acetate: hexanes 1: 2), to give GDLZ18. (1.38 g, 94%).

Benzyl -4- (N-benzyloxycarbonyl) amino-4,6,7,9-tetradeoxy -2, 3-O-isopropylden-D / L-glycero-D-mann-a-nonapyranoside (GDLZ21) A suspension of GDLZ21 (550 mg, 1.47 mmol) and 10% palladium on carbon (50 mg) in 95% methanol was stirred under hydrogen at atmospheric pressure overnight. The catalyst was completely filtered, sodium hydrogen carbonate (0.5 g) was added; and to the stirred suspension was added benzyl chloroformate (0.5 ml), in portions over a period of 2 h. The mixture was filtered, the filtrate was concentrated, and chromatographed. (ethyl acetate: hexanes 2: 3). The product (649 mg, 90%) was obtained as a syrup that crystallizes slowly.

Benzyl-4- (N-benzyloxycarbonyl) mino-4, 6,7,9-tetradeoxy-2,3-isopropylidene-8-0-tosyl-D / L-glycero-D-mann-a-nonapyranoside (GDLZ22 ). 4-Toluenesul fonyl chloride (140 mg, 0.73 mmol) was added to a solution of GDLZ21 (43 MG, 88 μmol) in anhydrous pyridine and allowed to stir overnight. The solution was cooled to 0 ° C and the excess reagent was hydrolyzed with water (1 ml). The solution was transferred into water (50 mL) and the product was extracted with ethyl acetate (4 x 10 mL). The combined extracts were neutralized with NaHCO3 solution, washed with water, dried and concentrated. The residues were purified by column chromatography (10 g of silica gel, 2: 3 ethyl acetate: hexanes) and gave GDLZ22 (49 mg, 87%) as a colorless syrup.

Benzyl-4,6,7,8, 9-pentadeoxy-4, 8- (N-benzyloxycarbonyl) amino-2,3-O-isopropylidene-L and -D-glycero-D-manno-n-a-nanopyranoxide (GDLZ29A and GDLZ29B) Solid potassium tert-butoxide was added (100 ml) to a stirred solution of GDLZ22 (380 mg, 594 μmol) in anhydrous tetrahydrofuran (20 ml). During the night the reaction was finished. The suspension was concentrated, the residue was transferred into water (50 ml) and the products were extracted with ethyl acetate (4 x 20 ml). The combined extracts were washed with water, dried, and concentrated. The isomeric mixture was resolved and the isomers were purified by column chromatography (silica gel 18, ethyl acetate: hexanes 1: 4). The fast migrating isomer (GDLZ29A), 78.5 mg, 28%), and the slower migrating isomer (GDLZ29B, 87.2 mg, 31%) and the unresolved mixture (47.3 mg, 17%) were obtained as colorless syrups. (5S) -1, 2-0-Isopropylidene-5-methylswainsonin (GDLZ27).

Palladium on carbon (10%, 80 mg) was added to a solution of compound GDLZ9A (84 mg, 180 mmol), in 95% ethanol (6 mL), and the suspension was stirred under hydrogen at atmospheric pressure. After 1.5 h, the starting material was consumed, indicating that the first reduction step (removal of benzylcarbamate) was completed. The suspension was then acidified by the addition of 1M hydrochloric acid (180 μl) and further hydrogenated overnight. The ion exchange resin (Dowex 1 x 8 100, or OH-form, 1 g) was stirred for 5 minutes, completely filtered together with the catalyst, the filtrate was concentrated and gave the crude acetonide (38 mg, approx. %). (5S) -5-Methylswainsonin (GD 28) The compound GDLZ27 (25 mg, 110 ml) was dissolved in 70% aqueous trifluoroacetic acid (3 ml) and stirred at room temperature overnight. The solution was concentrated to dryness, the residue was dissolved in water (0.5 ml), and the free base was generated by the addition of a strongly basic ion exchange resin (BioRad, AG 1-X8 20-50 mesh, OH form The solution was removed from the resin, and the resin was extracted with water (5 x 0.5 ml) The extracts were mixed, filtered and lyophilized The product was obtained as a white solid (13.0 mg, 63%). ). (5R) -1, 2-0- isopropylidene-5-metilswainsoni.na (GDLZ34) Palladium on carbon carbon (10%, 37 mg) was added to a solution of the compound GDLZ29B (210 mg, 01.0.45 mmol) in 95% ethanol (14 ml), and the suspension was stirred under hydrogen at atmospheric pressure. After 3 h the starting material was consumed. The suspension was acidified by the addition of 1M hydrochloric acid (450 ml) and hydrogenated for 3 days. The ion exchange resin (Dowex 1X8 100, OH form, 3 g) was added and stirred for 5 minutes.The suspension was filtered and the filtrate was concentrated to give crude acetonide (136 mg, quantitative).

Formate salt of (5R) -5-methylswainsonine (GD19) It was dissolved in (5R) -1,2-isoproopylidene-5-methylswainsonin (63 mg, 0.28 mmol) in 50% trifluoroacetic acid and the solution was stirred at? room temperature for three days. The solution was concentrated, the residue was purified by reverse phase HPLC using a 20 mM ammonium formate buffer (pH 3.5). The fractions containing the product were lyophilized several times to remove all traces of the buffer and produced (5R) -5-met i Iswainsonin as the "formate" salt (GD19). (5R) -5-Methylswainsonin (GD20) .

An aqueous solution of GD19 was eluted through a column of ion exchange resin, basic, recently regenerated (DOWEX 1x8-100, 50-100 mesh, hydroxyl form). The eluent containing a free base (GD20) was combined and concentrated.

B. Synthesis of (5S) -5-E ilswainsonin l-Bromo-2-butanol (GDLZ103) Carbon tetrabromide (26.6 g, ~ "" 8 ~ 0 mmol) and tri-phenol-1-phosphate (2.1 g, 80 mmol) were added successively to 1,2-butanediol (7.2 g, 80 mmol) in anhydrous pyridine at 0 °. C, and the solution was stirred at room temperature overnight. The mixture was concentrated and the residual oil was added dropwise to 1: 5 ethyl acetate: hexane, (220 mL), vigorously stirred. The solution was decanted from the precipitate, concentrated and chromatographed (silica gel, ethyl acetate: hexanes 1: 3), and gave GDL2103 (11.5 g, 90%). 2-Butanonyl Triphenylphosphonium Bromide (GDLZ105) Pyridinium chlorochromate (20 g, 93 mmol) was added to a suspension of 3 Å molecular sieves, flame dried (15 g) and GDLZ 10 3 (115.5 g, 75 mmol) in anhydrous methylene chloride, and the mixture was stirred for 1 hour, the coffee slurry was loaded onto the top of a column of silica gel (40 g), and the product was eluted using 1: 5 ethyl acetate: hexanes. The eluates containing ketones were combined, concentrated and the residue was reacted with fine triphenyl phosphate (12 g, 46 mmmol) in chloroform (20 mL). The solution formed overnight was added slowly in stirred diethyl ether (300 mL) and the precipitate was filtered. The residue was crystallized from methylene chloride (50 mL) by the addition of hexanes. GDLZ105 (3.539 g, 11.4%) was obtained as colorless crystals.

Triphenylphosphoranylidene-2-butanone (GDLZ113) GDLZ105 in fine powder (2.5 g, 6.05 mmol) was added to 10% sodium carbonate solution, aqueous (150 mL), and stirred vigorously overnight. The solid formed was completely filtered, washed thoroughly with water, and dried in vacuo in a dryer overnight. GDLZ113 (1.9 g, 94%) was obtained as a completely white, electrostatic powder.

Benzyl -4-azido-4, 6,7,9, 10 -pen adeoxy -2, 3-0-isopropylidene-a-D-man-dec-6-enopyranoside-8-ulose (GDLZ102) A slurry of flame-dried 3 A molecular sieves (1 g), benzyl-4-azido-2, 3-0-isopropylidene-aD-mannopyranoside (133 mg, 0.40 mmol), and pyridinium chlorochromate (0.8 g, 3.71 mmol) in anhydrous methylene chloride (40 mL) was stirred vigorously for 30 minutes. The mixture was loaded to the top of a column of silica gel (16 g) and the product was eluted using 1: 1 ethyl acetate: hexanes. The eluent was concentrated, the residue was dissolved in anhydrous benzene-tetrahydrofuran 1: 1 (10 mL), and GDLZ113 (180 mg, 0.541 mmol) was added. After stirring overnight, the mixture was concentrated, the residue was chromatographed (12 g of silica gel, ethyl acetate: hexanes 1: 5), and gave GDLZ102 (95 mg, 61%) -like a lightly syrup. yellow.

Benzyl-4 -azido-4, 6,7,9, 10-pen-adeoxy-2, 3-γ-isopropylidene-D / L-glycero-D-man-a-dec-6-enopyranoside (GDLZ115).

Sodium borohydride (55 mg, 1.45 mmol) was added to a solution of GDLZ102 (800 mg, 2.06 mmol) in methanol (25 mL), and the mixture was stirred for 30 minutes. The solution was concentrated to dryness, the residue was chromatographed (ethyl acetate, hexanes 1: 5-1: 2), and gave GDLZ115 (560 mg, 70%) as a colored syrup.

Benzyl -4- (N-benzyloxycarboni1) -amino-4,6,7,9,10-pen adesoxy-2, 3-O-isopropylidene-D / L-glycero-D-manno-a-decopyranoside (GDLZ116). % palladium on carbon (approximately 100 mg) was added to a solution of GDLZ115 (560 mg, 1.44 mmol) in ethanol (25 mL), and the mixture was stirred under hydrogen at atmospheric pressure overnight. The catalyst was completely filtered, sodium carbonate acid was added (0.5 g), and the mixture was stirred while benzyl chloroformate (500 μL) was added in portions via a syringe over a period of 1 hour. The suspension was then filtered, the filtrate was concentrated, and the residue was chromatographed (ethyl acetate: hexanes 1: 2). GDLZ116 '(500 mg, 69.5%) was obtained as a colorless foam.

Benzyl -4 - (N-benzyloxycarbonyl) -amino-4,6,7,9,10-pen-adeoxy-2, 3-O-isopropylidene-β-O-tosyl-D / L-glycero-D-man-a -decopyranoside (GDLZ117).

A solution of GDLZ119 (500b mg, 1.02 mmol) and 4-toluenesulfonyl chloride (430 mg, 2.3 mmol) in anhydrous pyridine (25 mL) was stirred. at room temperature overnight. The excess reagent was hydrolyzed by the addition of water (1 mL). The solution was transferred into water (300 mL), and the product was extracted using ethyl acetate (4 x 50 L). The combined extracts were washed with 1 M hydrochloric acid, neutralized with aqueous sodium bicarbonate solution, washed with water, and dried and concentrated. The residue was chromatographed (ethyl acetate: hexanes 1: 2) and gave GDLZ117 (586 mg, 89%) as a colorless syrup.

Benzyl -4, 6,7,8,9, 10-hexadeoxy-4, 8- (N-benzyloxycarbonyl) imino-2,3-O-isopropylidene-L- and -D-glycero-D-man-aD-decopyranoside (GDLZ118A and GDLZ118B).

A solution of GDLZ117 (586 mg-, 0.91 mmol) and potassium tert-butoxide (110 mg, 0.98 mmol) in anhydrous tetrahydrofuran was stirred at room temperature overnight. The solution was concentrated and the residue was chromatographed (ethyl acetate: hexanes 1: 4-1: 2). The products were rechromatographed, and the fastest migration isomer (GDLZ118A, 130.2 mg, 30%), as well as the slow migration isomer (GDLZ118B, 139 mg, 32%) were obtained as colorless syrups. (5S) -5-E il-1, 2-O-isopropilenswainsonin (GDLZ119). % palladium on carbon (approximately 45 mg) was added to a solution of .GDLZ118A (139 mg, 288 μmol) in 95% ethanol and the mixture was stirred under hydrogen at atmospheric pressure overnight. The Tic showed complete production of the carbamate. The mixture was acidified by the addition of 1 M hydrochloric acid (250 μL) and further hydrogenated. During the night a new product (tic) was formed. The catalyst was completely filtered and the filtrate was eluted through a column of basic ion exchange resin (8 mL, AG 1X8 20-50 mesh, OH form "-). The eluate containing GDLZ119 was concentrated and the residue was concentrated. purified by HPLC (ammonium formate 20 mm, aqueous, 50% -50% MeOH pH 9.0, 7 mL / min, Waters ODS 25 x 100 mm, detection uv 206 nm) The products were obtained as a formate salt (7 mg, 8.5%). (5S) -5-Ethylswainsonin (GD 38) A solution of GDLZ119 (7 mg, 29 μmol) in tetrahydrofuran: 6 M hydrochloric acid 1: 1 (1 mL) was stirred overnight. The solution was concentrated, the residue was taken up in water (1 mL) and eluted through a basic ion exchange column (10 mL, OH- form). The eluate containing the free base was lyophilized and gave GDLZ125 (2.8 mg, 48%) as a colorless foam.

Synthesis of (5R) - (5S) -5 Hydroxymethyl) swainsonine (5R) -5-Hydroxymethylsilycin (5S) -5-Hydroxymethylsilycin 3-Benzyloxy-l-bromo-2-propanol (GDLZ132) Thin phenylphosphine X 6.82 g, 26 mmol) and carbon tetrabromide (8.63 g, 26 mmol) were added to a solution of 3-benzyloxy-1,2-propanediol (4.72, 25.9 mmol) in anhydrous pyridine at 0 °. C, and stirred overnight at room temperature. The solution was concentrated and the residue was added dropwise to 1: 5 ethyl acetate: hexanes, vigorously stirred (200 mL) to precipitate trif nylphosphine oxide. The supernatant was decanted, concentrated, and the residue was chromatographed (60 g of silica gel, ethyl acetate: hexanes 1: 3). The product was obtained as a colorless oil (5.1 g, 80%). 3-bensyloxyacetonyl bromide Trifenilfos onio (GDLZ135) Pyridinium chlorochromate (8.5 g, 39.4 mmol) was added to a slurry of the compound GDLZ 132 (5.1 g, 20.8 mmol) and 3 A molecular sieves recently dried to the flame ((9 g) in anhydrous methylene chloride, and a The suspension was stirred under argon at room temperature, the reaction was complete, after 1 hour.The coffee slurry was loaded directly on top of a column of silica gel (50 g) and the product was eluted using ethyl acetate: Hexanes 1: 2 The eluent containing the product was concentrated, the residue was diluted with chloroform (10 mL) and reacted with triphenylphosphine (5.5 g) overnight at room temperature The thick solution obtained was diluted dropwise in diethyl ether (20 mL) stirred vigorously, and the compound GDLZ135 precipitated as a completely white solid.The product was filtered by suction and dried in vacuo overnight.The product (7.68 g, 73%) was reacted further. without purification. 3-benzyloxy-l-triphenyl os oranylden-2-propanone (GDLZ138) The fine powder compound GDLZ135 (1.0 g, 1.98 mmol) was added to a 10% aqueous solution of sodium carbonate (30 ml) and the mixture was stirred vigorously at room temperature. During the night, the starting material dissolved and the product precipitated. The suspension was filtered by suction and the completely white residue was washed thoroughly with water. The residue was then dried in vacuo over Drierite. The product (817 mg, 97%) was used for the next reaction without further purification.

Benzyl-4-azido-9-0-benzyl-4, 6, 7-trideoxy -2, 3-0-isopropylidene-a-D-mannone-6-enopyranoside-8-ulosa (GDLZ150) A suspension of 3 Å molecular sieves dried to flame (2 g), pyridinium chlorochromate (1.5 g, 6.96 mmol), and benzyl-4-azido-2,3-isopropylidene-aD-mannopyranoside (466 mg, 1.39 mmol) was stirred at room temperature for 30 minutes. The brown mixture was then charged to the top on a column of silica gel (18 g, ethyl acetate: hexanes 1: 2) and the aldehyde was diluted. The fractions containing the product were combined and concentrated. The residue was dissolved in anhydrous benzene (20 mL), and GDLZ138 (1.0 g, 2.3 mmol) was added, and the mixture was stirred at room temperature overnight. The suspension formed was concentrated, the residue was chromatographed (35 g of silica gel, ethyl acetate: hexanes 1: 3), and gave 150 g (500 mg, 75%) as a colorless syrup.

Benzyl-4-N- (benzyloxycarbonyl) amino-9-O-benzyl-4,6, 7-trideoxy-2,3-O-isopropylidene-D / L-glycero-D-mann-a-nonapyranoside (GDLZ166) A solution of GDLZ150 (834 mg, 1.74 mmol) and boron sodium hydride (66 mg, 1.74 mmol) in methanol was stirred at room temperature for 2 hours. (20 mL). The solvent was evaporated and the residue was chromatographed (33 g of silica gel, ethyl acetate: hexanes 1: 3). The reduced glycoside (554 mg, 66%) was then dissolved in 95% ethanol (20 mL), 10% palladium on carbon (approximately 50 mg) was added, and the solution was basified with two drops of triethylamine. The mixture was then stirred under nitrogen at atmospheric pressure for 3 hours, the catalyst was stirred thoroughly, sodium hydrogen carbonate (400 mg) was added to the filtrate and stirred while benzyl chloroformate (250 μL, 1.75 mmol) was added to the filtrate. portions during a period of 2 hours. The solids were completely filtered, the filtrate was concentrated and the residue was chromatographed (EtOAc-hexanes 1: 1). GDLZ166 (557 mg, 54.8% of GDLZ150) was obtained as a colorless syrup.

Benzyl-4-N- (benzyloxycarbonyl) amino-9-O-benzyl-4,6, 7-trideoxy-2, 3-O-isopropylidene-8-O-t.osyl-D / L-glycero-D-hand -a-nonapyranoside (GDLZ169) 4-Toluenesul fonyl chloride (500 mg, 2.6 mmol) was added to a solution of GDLZ166 (557 mg, 953 μmol) in anhydrous pyridine (15 mL) and the mixture was stirred at room temperature overnight. The excess reagent was hydrolyzed by the addition of water (1 mL), and the solution was transferred into water (200 mL). The product was extracted using ethyl acetate (3 x 50 mL), the combined extracts were washed with 1 M hydrochloric acid, neutralized with aqueous, saturated NaHCO3, washed with water, dried and concentrated. The crude product was chromatographed (30 g of silica gel, ethyl acetate: hexanes, 1: 3-1: 2) and gave pure GDLZ169 (574 mg, 80.8%).

Benzyl-9-O-benzyl-4, 6,7,8-tetradeoxy-4, 8- (N-benzyloxycarbonyl) amino-2,3-isopropylidene-8-L- and -D-glyceryl-D-mannitol -nonapyranoside (GDLZ170A and GDLZ170B) Potassium tert-butoxide (90 mg, 802 μmol) was added to a solution of GDLZ169 (574 mg, 770 μmol) in anhydrous tetrahydrofuran (25, mL), and the mixture was stirred at room temperature under argon overnight. The suspension was transferred into ethyl acetate (100 mL), washed with water and brine, dried and concentrated. The isomeric mixture was purified by column chromatography (33 silica gel, ethyl acetate: hexanes 1: 3-1: 2), and the various tereomers were resolved using Preparative HPLC (22:78 ethyl acetate: hexanes, 8 mL / min, 25 x 100 mm, Waters Silica) The fastest migration isomer GDLZ170A (141.5 mg, 32%) and the slowest migration isomer GDLZ170B (157.6 mg , 35.7%) were isolated as colorless syrups. (5R) -5-Hydroxymethyl-l, 2-O-isopropylidenskinsonin (GDLZ162) The compound GDLZ170A (38 mg, 66 μmol) was hydrogenated in 95% ethanol using 10% palladium in carbon (approximately 30 mg) and atmospheric pressure hydrogen under neutral conditions for the removal of the carboxylbenzyl group. Overnight the reaction was terminated, the mixture was acidified with 1 M hydrochloric acid (80 μL) and further stirred under nitrogen for 3 days. The suspension was filtered, the filtrate was concentrated and the product was isolated and purified by HPLC (0.1% NH3 in MeOH-0.1% NH3 30:70 in water, 2 mL / min, 10 x 150-mmBeckman Ultrasphere ODS). GDLZ172 (7.5 mg, 46.7%) was obtained as a colorless syrup. (5S) -5-Hydroxymethyl-1,2-O-isopropylidenskinsonin (GDLZ167) The compound GDLZ170b (57.6 mg, 100 μmol) was hydrogenated in 95% ethanol using 10% palladium on carbon (approximately 100 mg) and hydrogen at atmospheric pressure. The carboxybenzyl group was stirred overnight. The mixture was acidified with 1 M hydrochloric acid (150 μL) and further stirred under hydrogen for 2 days. The suspension was filtered, the filtrate was concentrated, and the product was isolated and purified by HPLC (0.1% NH3 in 0.1% MeOH NH3 at 30:70 water, 2 mL / min, 10 x 150 mm, Beckman Ultrasphere ODS ). GDLZ167 (9.0 mg, 37% as a colorless syrup was obtained. (5R) -5-Hydroxymethyl) swainsonine (GDLZ168 / GDLZ45) A solution of GDLZ162 (7.1 mg, 29.2 μmol) in tetrahydrofuran: 6M 2: 1 hydrochloric acid (1.5 L) was stirred at room temperature overnight. The solution was concentrated, the residue was dissolved in water (1 mL), and passed through a column of ion exchange resin, basic to generate the free base. The crude product was purified by HPLC (0.1% NH3 in MeOH-0.1 NH3 in water 3:97, 2 mL / min, 10 x 150 mm Beckman Ultrasphere ODS) and gave pure GDLZ168 (3.7 mg, 62.3 -s). (5S) -5-Hydroxymethyl) swainsonine (GD 46) A solution of GDLZ167 (9.0 mg, 37 μmol) in tetrahydrofuran: 6 M hydrochloric acid 1: 1 (2 mL) was stirred at room temperature overnight. The solution was concentrated, the residue was dissolved in MeOH: water 1: 1 (2 L), basified using ion exchange resin and passed through a Sep-Pak C-18 column (Waters). The crude product was purified by HPLC (0.1 NH 3 in MeOH-0.1% NH3 in water 7:93, 2 mL / min, 10 x 150 smm Beckman Ultrasphere ODS) and gave GDLZ172 (5.7 mg, 75.8%).

Example 2 Synthesis of analogs of s ainsonma 5, 6-di substitutes Benzyl-4-amino-4-deoxy-2, 3-O-isopropylidene-a-D-mannopyranoside (1): To a stirred, cooled solution (ice bath at 0 ° C) of Benzyl-4-azido-4-deoxy-2, 3-0-isopropylidene-aD-mannopyranoside (1.0 g, 3.0 mmol) in dry THF (10 g). mL) LiAlH4 (140 mg, 3.8 mmol) was added in small portions. The reaction was allowed to warm to room temperature slowly. After 4 hours, the TLC indicated complete consumption of the starting material and formation of a new individual product. The reaction was quenched with 5% NH 4 Cl (10 mL) and then treated by liquid-liquid solution (H 20 / CH 2 C 12). On drying (MgSO4) and concentration of the combined organic extracts, the desired amine 1 was obtained as a white, crystalline solid (0.90 g, 2.9 mmol) in 97% yield.

Benzyl-4-benzyloxycarbonylamino-4-deoxy-2, 3-0-isopropylidene-a-D-mannopyranoside (2): To a stirred, cooled solution (ice bath at 0 ° C) of 1 (215 mg, 0.70 mmol) in THF: 10% NaHC03 (1: 1) (15 mL) was added benzyl chloroformate (0.11 L, 0.75 mmol) drop by drop. The reaction was then allowed to warm to room temperature slowly. After stirring for 3 hours, the TLC indicated complete consumption of the starting material and formation of a new individual product. The majority of the THF was removed by rotary evaporation and CH2Cl2 and water were added to the remaining aqueous mixture. After liquid / liquid extraction (H20 / CH2CL2), the combined organic extracts were dried (MgSO4) and concentrated to 2 (306 mg, 0.69 mmol) in 97% yield as a white solid. The structure of that product was confirmed by 1 H NMR.

Benzyl-4-benzyloxycarbonylamino-4-deoxy-2, 3-0-isopropylidene-a-D-mannopyranoside (3): To a solution of DMSO (0.75 L, 10.6 mmol) in dry CH2C12 (10 mL) at -50 ° C was added oxalyl chloride (0.93 mL, 10.6 mmol) dropwise. Stirring was continued for 15 minutes. During that time, the temperature of the cooling bath has increased to minus 20 ° C. The solution was cooled to -50 ° C before the dropwise addition to the solution of 2 (1.51 g, 3.4 mmol) in dry CHC12 (15 mL). Stirring was continued at low temperature (-20 ° C to -50 ° C) for one hour before the addition of triethylamine (9 mL). The reaction was allowed to warm to room temperature and stirring was continued for an additional 15 minutes. Then water was added, followed by liquid-liquid extraction (H20 / CH2C12). The combined organic extracts were dried (MgSO4) and concentrated to give the crude aldehyde. This product, which seemed relatively clear from the TLC, was used in. the next step without further purification.

Knoevenagel product (4): To a stirred (5 ° C) stirred solution of ethylacetoacetate (0.9 mL, 7.1 mmol) in dry CH2C12 (20 mL), containing powdered molecular sieves of 3 (1 g), was added solution of 1 M of TiCl 4 in CH 2 Cl (7 mL, 7 mmol). And the addition of TiCl4, the solution turned yellow then slowly changed orange. To this solution was added pyridine (6 mL, 74 mmol) dropwise and resulted in a color change to brick red. Then it was added dropwise with continuous stirring to a solution of 3 in CH2C12 (20 mL). Stirring was continued for an additional 48 hours. The reaction was then treated by the addition of aqueous NaHCO3 (10 mL) followed by suction filtration through a glass fiber filter to remove a brown, pasty solid. The filtrate was extracted several times with CH2C12. The combined organic extracts were then dried (MgSO4) and concentrated to give a yellow-brown oil. Purification by chromatography (20-30% ethyl acetate in hexane) gave the desired product (570 mg) as a mixture of the cis and t-isomers. The structure of this product was confirmed by 1 H NMR. (5R, 6R) and (5S, 6S) 6-carboethoxy-5-methyl swainsonine acetonide (5): To a solution of 4 (570 mg, 1.03 mmol) in 40 mL of ethanol (95 -5-) was added Pd at 10% / C (50% wet) (712 mg). This mixture was shaken under H2 (balloon) for two days. At that time, the TLC showed complete consumption of the starting material. The Pd / c was then completely filtered using a glass fiber filter and fresh catalyst was added to the solution. HCl (1M, 1.1 mmol) was added and the mixture was stirred under H2 (balloon) for 4 additional days. The reaction gave a mixture of components including the desired product (70:30 mixture of the isomers (5R, 6R) and (5S, 6S)) as the main components. The structure and ratio of these isomers was inferred by 1 H NMR.

Ethyl (1R, 2R, 5S, 6S, 8S, 8aR) (5S, 6S) -1, 2, 8-trihydroxy-5-me iloctahydro-6-indolizine-sarboxila or- [6-carboxyethoxy-5-methylskinsonin (GD0036 )] The isolation of (GD0036) was achieved by the de-acetone of the isomeric mixture 5, the derivatization of the resulting triols (6) as the TMS ethers, the purification of 7 by preparatory GC, followed by acid hydrolysis of the TMS groups. This isomer (GD 0036), which gave a 1 H NMR consistent with the structure, was submitted for the enzyme assay. (5R, 6R) -6-hydroxymethyl-5-methylswainsonine acetonide and (5S, 6S) -6-hydroxymethyl-5-methylhexonidine acetonide (8): To a solution of isomer 5 (64 mg, 021 mmol) in dry THF was added 20 mg of LiAlH in small portions. This suspension was stirred overnight. At that time, the starting material has been completely consumed as inferred by TLC. Methanol (1 mL) was added to completely cool excess LiAlH4 and stirring was continued for 30 minutes. Ceuta (0.5 g) was added to this mixture and the methanol was removed by rotary evaporation. The dried Ceuta / product was then loaded onto a Si02 gel column. Dilution with EtOAc: MeOH: 10% NH 4 OH 27: 2: 1 gave the purified isomers together with the mixed fractions which were rechromatographed. The total recovery of (5R, 6R) 8 of all the fractions was 12 mg. The total recovery of (5S, 6s) 8 of all the fractions was 15 mg. The structure of these products was confirmed by 1 H NMR. (5S, 6S), and (5R, 6R) -6-hydroxymethyl-5-methylswainsonin GD40 GD 44 (5S, 6S) -6-Hydroxymethyl-5-methylskinsonin (5R, 6R) -6-Hydroxymethyl-5-methylskinsonin A solution of acetonide 8 (approximately 5 mg) in THF-HC1-6M > (2 mL) was stirred at room temperature for 2 days. The solutions were then concentrated and passed through a column of ion-exchange hydroxide resin using methanol as an eluent. The free base was then purified using HPLC. The recovery of each isomer was approximately 2-3 mg. "These samples, (5S, 6S) - 6-Hydroxymethyl-5-methylswainsonin (GD0040), and (5R, 6R) - 6-Hydroxymethi-1-5-methylskinsonin (GD0044) were submitted for the enzyme assay E emplo 3 (5R) -5-BENCILOXIMETILS AINSONINA (GD42) GD 42 (5R) -5-Benzyloxymethylsilycin (5R) -5-Benzyloxymethyl-l, 2-O-isopropylidenskinsonin (GDLZ177).

Sodium hydride (10 mg, 60% in mineral oil) was added in portions to a stirred solution of crude (5R) -5-hydroxymethyl-1, 2-0-isopropylenskinnyin (30.7 m = g, < 0.126 mmol) in anhydrous DMF containing benzyl chloride (200 mL). After stirring for 2 days methanol (1 ml) was added, and the solution was concentrated. The residue was purified by inverted phase HPLC and gave GDLZ177 (7.0 mg, approximately 17%). (5R) -5-Benzyloxymethylsilycin (GD42) The compound GDLZ177 (7.0 mg, 21 mmol) was dissolved in tetrahydrofuran (1 ml), 6 M hydrochloric acid (1 ml) was added, and the solution was stirred at room temperature for 2 days. The solution was concentrated to dryness, the residue was purified by reverse phase HPLC, and gave GD42 (2.3 mg, 38%) as a colorless residue. (5S) -5-Benzyloxymethyl-1,2-O-isopropylidenskinnyin (GDLZ252).

Sodium hydride (7 mg, 60% in mineral oil) was added in portions to a stirred solution of _ (5S) -5-hydroxymethyl-1, 2-O-isopropylidene-swainsonin (20.5 mg, 85 mmol) in Anhydrous DMF containing benzyl chloride (100 ml). After stirring for 2 days methanol (1 ml) was added, and the solution was concentrated. The residue was purified by inverted phase HPLC and gave GDLZ252 (10.4 mg, 36%) (5S) -5-BENCILOXIMETILSWAINSONIN (GD91).

GD 91 (5S) -5-Benzyloxymethylsilynesin Compound GDLZ252 (6.0 mg, 18 mmol) was dissolved in tetrahydrofuran (1 ml), 6 M hydrochloric acid (1 ml) was added, and the solution was stirred at room temperature for 2 days. The solution was concentrated to dryness, the residue was purified by inverted phase HPLC, and gave GD91 (4.9 g, 93%) of amorphous material.

EXAMPLE 4 (ÍS, 2S, 3R / S, 8R ", 8aS) -3-cyano-l, 2, 8- Trihydroxyoctahydroindolizine (GD 92) A process for the preparation of 3-cyano-swainsonin is summarized and shown schematically later.

(IR, 3S, 4S, 6R) -7-Aza-3-benzyloxy-4,5-isopropylidenedioxy-2-oxa-biscyclo [4,4,0] -decane (GDSC1009) To a solution of E-4-azido-4,6,7-tridesoxy-6-ene-2,3-0-isopropylene-aD-man-octadialdopyranoside (GDSC1005) (1.6 g, 4.46 mmol) in ethanol (25 mL ) was added 10% in palladium on carbon (80 mg, 50% wet). The reaction mixture was stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (1 to 10% methanol in dichloromethane gradient) to give GDSC1009 1.24 g (3.97 mmol) in 87.6% yield. (1R, 3S, 4S, 5S, 6R) -7- [N-tert-Butyloxysarbonyl) amino] -3-benzyloxy-4,5-O-isopropylenedioxy-2-oxa-bi-cyclo [4.4, 0] decane (GDSC1117) To a solution of (IR, 3S, 4S, 5S, 6R) -7-Aza-3-benzyloxy-4,5-isopropylidenedioxy-2-oxa- [4, 4, 0] -decane (GDSC1009) (1.40 g, 4.41 mmol) in dioxane / water (1: 1, 20 mL) was added 1N NaOH (10 mL), di-tert-butyl dicarbonate (2.89 g, 13.23 mmol) was added to this solution and the mixture was added. stirred at room temperature for 4 hours. The reaction mixture was partitioned between dichloromethane (50 ml) and water (60 L). The organic layer was washed with saturated NaCl (50 ml), and dried over MgSO4 and filtered, the filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography using 0-2% methanol in an dichloromethane as eluent to give GDSC1117 81.38 g, 74.9%). (1R, 3S, 4S, 5S, 6R) -7- [N -tert -Buyloxycarbonyl) amino] -3-hydroxy-4,5-O-isopropylenedioxy-2-oxa-bis-cyclo [4, 4, 0] decane (GDSC1127) To a solution of (IR, 3S, 4S, 5S, 6R) -7- [N- (tert-Butoxycarbonyl) amino] -3-benzyloxy-4,5-isopropylidenedioxy-2-oxa-bis-cyclo [4, 4, 0] -decano (GDSC1117) (1.2 g, 2.86 mmol) in ethanol (50 ml) was added 10% palladium on carbon (1.2 g., 50% wet) and a catalytic amount of acetic acid. The flask was evacuated by aspiration and purged with hydrogen 3 times. The resulting heterogeneous mixture was stirred under a hydrogen balloon for 8 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was then subjected to column chromatography on silica gel, eluting with a gradient of 1-5% methanol in dichloromethane to give GDSC1127, 0.810 g (2.46 mmol) in 86% yield as an α, β-anomeric mixture. . A minor product of this reaction was purified and identified as the acetonating product of GDSC1127 (approximately 6%).

Synthesis of GDSC1147 A solution of GDSC1127 (0.5 g, 1.52 mmol) in DMSO (3 mL) and acetic anhydride (3 L) was stirred at room temperature r argon for 14 hours, the solution was diluted with dichloromethane (25 mL), poured into solution of saturated NaHC03 (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated r reduced pressure. The residue was purified by column chromatography using 1% methanol in dichloromethane as eluent to give GDSC1147 (0.457 g) in 92% yield.

Synthesis of GDSC1149 GDSC1147 (215 mg, 0.657, mmol) was dissolved in 0.5 mL of dichloromethane. To this solution 4 ml of 5% TFA in water were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated r reduced pressure and co-evaporated twice with water (10 mL). After it was evaporated r high vacuum overnight, the residue was dissolved in 5 mL of 0.2N sodium methoxide and stirred at room temperature r argon for 20 hours. The reaction mixture was concentrated in a rotary evaporator. The orange residue was dissolved in a minimum amount of water and subjected to sequential purifications using Dowex 50WXx2-200 (H +) ion exchange resins and an AG 1 -X8 (OH "), followed by a purification of C-18 column. to give GDSC1149 (96 mg, 78) -like a crystalline compo Synthesis of 3-cyano swainsonin (GDSC3027) GDSC1147 (110 mg, 0.334 mmol) was dissolved in a mixture of 0.3 mL of dichloromethane, 3.2 mL of TFA and 0.8 mL of water. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in a rotary evaporator. The residue was dissolved in water (4 mL) and stirred with ion exchange resin AG 1-X8 (OH ") (0.5 g of dry resin) After 30 minutes, the mixture was filtered and the filtrate was concentrated The residue was dissolved in methanol (4 mL) and stirred with potassium cyanide (217 mg, 3.34 mmol ) for 12 hours The mixture was concentrated The residue was dissolved in 1 mL of water and filtered through a column of ion exchange resin AG 1X8 OH "(1.0 g), rinsed with water (12 mL). The filtrate was concentrated and the residue was purified with a C-18 column (1 g) using 10-50% methanol in water as eluent to give GDSC 3027 (56 mg) as a 1: 1 mixture of 3. -ciano-swainsonina.

(Boc) zO 1 N NaOH-Dioxar GDSCU27 DMSO, CICOCOCI DCM GD5C1147 GDSCI149 GDSC1127 GDSC3027 EXAMPLE 5 Inhibition of Golgi α-mannosidase II and lysosomal a-mannosidase by the compo of the invention.

The compo of the invention and swainsonin were added (10 μl) in 96-well Elisa plates followed by the addition of 200 mM sodium acetate, pH 5.6 and 25 μl of 10 mM p-nitrophenyl a-mannospyranoside. 15 μl of a-mannosidase (Sigma 38 U / ml) was added to each well and the plates were incubated for 60 minutes at 37 ° C. The reaction was stopped by the addition of 50 μl of 0.5 M sodium carbonate and the formation of p-nitrophenol was measured with a plate adjustment at 400 nM. The effects of the compo and swainsonin on the lysosomal mannosidase were measured by the addition (10 μl) of the compo in Elisa plates to 96 wells followed by the addition of sodium acetate at 200 mM, pH 5.0 and 25 μl of p -not trofeni 1-aD-mannopyranos gone 10 mM. 15 μl of lysosomal mannosidase (approximately 8mM / mL) was added to each well and the plates were incubated for 60 minutes at 37 ° C. The reaction was stopped by the addition to 50 μl of sodium carbonate 0.5 m and the formation of p-nitrophenol was measured as a plaque adjustment at 405. The activity of mannosidase II and the lysosomal mannosidase of the compo of formula I of the invention are shown in Table 1.

While the present invention has been described with reference to what is currently considered to be the preferred examples, it is to be rstood that the invention is not limited to the described examples. On the contrary, the invention is proposed to cover several modifications and equivalent arrangements included within the spirit and scope of the appended claims. All publications, patents and patent applications are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and indirectly indicated to be incorporated by reference in its entirety. .

Table 1 It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention. F Having described the invention as above, the content of the following is claimed as property:

Claims (32)

1. a compound of the formula I characterized in that (1) R1, R2, and R3 are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, or R1 and R2 together or R2 and R3 together form a carbocyclic or heterocyclic ring; (2) W, W 'and W "are the same or different and represent hydroxyl, alkoxy, thiol, thioalkyl, thioaryl, halo, or amino, or one or more of W and Wt' and W 'and W"' form together a carbocyclic or heterocyclic ring, or one or more of R1, and W, R2, W 'and R3 W "forms a spiro-ring system; (3) X, X ', Y, Y', z, and Z 'are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, unsaturated monocyclic hydrocarbons, aryl, alkoxy, aryloxy, hydroxyl, thiol, thioaryl amino, ammonium, halogen, carboxylic acid or esters or thioesters thereof, ketone, aldehyde, carbonate, carbamate, amide, azide, imide, imine, imidazole, acetal, ketal, nitrile, diazo, nitro, hydrazine, hydrazide, hydrazone hydroxamic acid, hydroxylamine, epoxide, alkoxy, or aryloxy, sulfate, sulfonic acid or sulfinic amines or esters thereof, sulfonamide, phosphate or phosphonate acids, or esters thereof, silyl, sulfoxide, sulfone, oxime, guanidino, phosphonate, thioamide, carbamate, thiocyanate, thioketone, thiourea, thioethers, thiazole, urea, xanthate, cyano, nitrile, -SR9 wherein R9 is alkyl cycloalkylalkenyl, alkynyl, or monocyclic unsaturated hydrocarbons, and -OR where R is alkyl, cycloalkyl, alkenyl, alkynyl, or hydroca monocyclic unsaturated hydrocarbons; or (i) X and Y, X 'and Y, X' and Y, or X 'and Y' may together form a carbocyclic or heterocyclic ring, or Y and Z, Y and Z1, or Y 'and Z' may form together a carbocyclic ring, or heterocyclic ring; (ii) one or more of X and X 'together, Y and Y' together, and Z and Z 'together, can form a spiro ring; or (iii) one or more of X and X * together, Y and Y 'together, and Z and Z' together represent = 0, = S, or = NR4 wherein NR4 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons aryl, alkoxy, hydroxyl, or = CR5R6 wherein R5 and R6 are the same or different and represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, monocyclic unsaturated hydrocarbons or aryl; with the proviso that X, X ', Y, Y', and Z, Z 'can not all be hydrogen. And salts and optically active and racemic forms of a compound of the formula I.

2. A compound of the formula I, characterized in that when R1, R2, R3, X, X ', Y, Y' are hydrogen, W, W ', and W "are not hydroxyl.

3. A compound of the formula I, characterized in that when R1, R2, R3, X, X ', Z and Z' are hydrogen, and W ', W' and W '' are hydroxyl, Y and Y 'can not be together = 0 or one of Y and Y 'can not be alkoxy.

4. A compound of the formula I according to claim 1, characterized in that W, W 'and W "are the same and represent hydroxyl.

5. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 are the same and represent hydrogen.

6. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 are the same and represent hydrogen, and W, W 'W are the same as hydroxyl.

7. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W 'and W "represent hydroxyl, and Z and Z' represent * hydrogen.

8. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W 'and W "represent hydroxyl, and X and X' represent hydrogen.

9. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W 'and W1' represent hydroxyl, and X, X ', Z and Z' represent hydrogen.

10. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W 'and W "represent hydroxyl, e represent hydrogen.

11. A compound of the formula I according to claim 1, characterized in that one of Y and Y 'represent ^ methyl, ethyl, phenyl, benzyl, trifluoromethyl, hydroxymethyl, or benzyloxymethyl.

12. A compound of the formula I according to claim 1, characterized in that one of X and X 'represents thiomethyl, fluoromethyl, or methoxy.

13 * A compound of the formula I according to claim 1, characterized in that W "and R ^ are the same represent halogen.

14. A compound of the formula I according to claim 1, characterized in that Y_ and Y_ 'are the same and represent halogen.

15. A compound of the formula I according to claim 1 'characterized in that R1, R2, and R3 represent hydrogen, W, W ?, and W "represent hydroxyl, Z and Z" represent hydrogen, one of X and X', which may be substituted, is alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, -CH2OR52 wherein R52 represents alkyl or aryl, and the other X and X 'is hydrogen, or X and X' represent together = 0, and, one of Y and Y ', which may be substituted, is alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen , esters of carboxylic acid, esters of thiol, benzyl, pyridinyl, -CH2OR52 wherein R52 represents alkyl or aryl, and the other of Y and Y 'is hydrogen.

16. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, Y and Y' represent hydrogen, X and X ', which can to be substituted, are, the same or different represent hydrogen, alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH2OR52 wherein R52 represents alkyl or aryl, and Z and Z 'are the same or different and represent alkyl, aryl, alkoxy, hydroxyl, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, - CH2OR52 wherein R52 represents alkyl or aryl, with the proviso that at least one of X and X 'and one of Z and Z' can not be hydrogen.

17. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, and X and X' represent hydrogen, Y, Y ', Z , and Z 'are the same or different and represent hydrogen, alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH2R52 where R52 represents alkyl, aryl with the proviso that at least one of Y and Y 'and one of Z and z1 can not be hydrogen.

18. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, and X, X', Z and Z 'represent hydrogen, and one of Y, and Y 'represent hydrogen, alkyl, aryl, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH2R50 where R50 represents alkyl, aryl and the other of Y and Y 'represents hydrogen, alkyl, aryl, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH R, 50 where R 50 represents alkyl, aryl

19. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, and Y, Y' Z and Z 'represent hydrogen, and one of X, and X 'represents hydrogen, alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH2R50 where R50 represents alkyl, aryl and the other of X and X 'represents hydrogen, alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol esters, benzyl, pyridinyl, or -CH2R50 where R50 represents alkyl, aryl or X and X 'together represent -o.

20. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, and Z and Z' represent hydrogen, and X, and Y, X 'and Y', X 'and Y, or X and Y' together form a 6-membered heterocyclic ring containing one or two of O, S, or N.

21. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, X, X', Z and Z 'represent hydrogen, and one of Y, and Y 'represent methyl, ethyl, -phenyl, benzyl, which may be substituted, preferably trifluoromethyl, hydroxymethyl, benzyloxymethyl, and the other of Y and Y' represents hydrogen.

22. A compound of the formula I according to claim 1, characterized in that R1, R2, and R3 represent hydrogen, W, represents hydroxyl, and W ', and W' represent halogen, preferably fluorine; X, X ', Z and Z' represent hydrogen, and one of Y and Y 'represents methyl, ethyl, phenyl, benzyl, trifluoromethyl, hydroxymethyl, benzyloxymethyl, and the other of Y and Y' represents hydrogen.

23. A compound of the formula I according to claim 1, characterized in that one of Y and Y 'is hydrogen and the other of Y and Y' is methyl, and one of Z and Z 'is hydroxymethyl, COCH2CH3, -CN, - CH2NH2, -CH2NHAc, or -CH2NHCR60 = NH where R60 is alkyl or aryl.

24. A compound of formula I according to claim 1, characterized in that one of Y and Y 'and one of Z and Z' represents alkyl, aryl, alkoxy, hydroxy, thiol, thioalkoxy, benzyl, pyridinyl, or -CH20R52 where R52 represents alkyl, or aryl, which may be substituted, and the other of Y and Y 'and Z and Z' represent hydrogen.

25. A compound of formula I according to claim 1, characterized in that one of Z and Z 'is -CONR70R71 where R > 70 and R71 are the same or different and represent hydrogen, alkyl or aryl, -COOH, -COOC2H5, methyl, or CH2OH, or Z and Z 'together form a spiro ring.

26. A compound of the formula I according to claim 1, characterized in that X and Y form a carbocyclic or heterocyclic ring of the formula R 7 5 7 6 -R-R '-R 7 £ -R 7 9 where R 75,7 9 are part of the queue of swainsonin and one or more of R76, R77, and R78 represent CH, CH2, O, S, or N.

27. A compound of formula I according to claim 1, which is (5R) -5-met ilswainsonin, formate salt of (5R) -5-methylswainsonin, (5S) -5-methylswainsonin, (5R) -8- Epi-5-methylswainsonin, (5S) -5-ethylswainsonin, (5S, 6S) -6-hydroxymethyl-5-methylswainsonin; (5R) -5-benzyloxymethylsilycin, (5R, 6R) -6-hydroxymethyl-5-methylskinsonin, (5R) -5-hydroxymethyl-beninsonin, (5S) -5-hydroxymethyl-swainsonin, (5R, 6R) -6-hydroxymethyl-1-5-met i 1-swainsonin, (5S) -5-benzyloxymethylsilycin, or (5R) -5-benzyloxymethyl-swainsonin.

28. A pharmaceutical formulation characterized in that it comprises a compound of the formula I as claimed in any of claims 1 to 27, as an active agent, and a pharmaceutically acceptable carrier, excipient or diluent.

29. A method for stimulating the immune system, for treating proliferative disorders, or microbial infections in a patient, characterized in that it comprises administering an effective amount of a compound of the formula I as claimed in any of claims 1 to 27.

30. The use of a compound of formula 1 as claimed in any of claims 1 to 27, in the preparation of a medicament for stimulating the immune system, and / or for treating proliferative disorders, and microbial infections.

31. A method for stimulating the immune system, treating proliferative disorders, or microbial infections, in a patient, characterized in that it comprises administering an effective amount of a compound of the formula I as claimed in claim 1, wherein R1, R2 ., and R3 represent hydrogen, W, W 'and W *' represent hydroxyl, Y, 'Y', Z and Z 'represent hydrogen, and one of X and X' represent methyl, phenyl, benzyl, hydroxymethyl, and the others of X and X 'represent hydrogen.

32. The use of a compound of the formula I as claimed in claim 1, wherein R1, R2, and R3 represent hydrogen, W, W ', and W "represent hydroxyl, and Y, Y' Z and Z 'represent hydrogen, and one of X, and X 'represents methyl, phenyl, hexyl which may be substituted, and the other of X and X' represents hydrogen, R1, R2, and R3 represent hydrogen, W, W 'and W' 'represent hydroxyl, X, X ', Z and Z' represent hydrogen, and one of Y and Y 'represent methyl, ethyl, phenyl, benzyl which may be substituted and the other of Y and Y' represents hydrogen; R1, R2, and R3 represent hydrogen, and W, W 'and W "represent hydroxyl, and Y and Y' represent hydrogen, X and X 'are the same or different and represent hydrogen alkyl, aryl, alkoxy, hydroxyl, thiol , thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, pyridinyl esters, or -CH OR 52 where R52 represents alkyl or aryl, which may be substituted, and one of Z and Z 'are the same or different and. they represent alkyl, aryl, alkoxy, hydroxy, thiol, thioalkyl, thioaryl, amino, halogen, carboxylic acid esters, thiol, benzyl, or pyridinyl esters, or -CH2OR52 where R52 represents alkyl or aryl, with the proviso that at least one of X and X 'and at least one of Z and Zt can not be hydrogen, in the preparation of a medicament for stimulating the immune system and / or for treating proliferative disorders and microbial infections.