WO2011151493A1 - Sp2 iminosugar derivatives as alfa-glycosidase inhibitors - Google Patents

Abstract

The invention relates to glycosylated derivatives of formula I, wherein the designations for the each substituent are indicated in the description. Said compounds can be used as α-glycosidase inhibitors.

Description

Sp ² imnoazúcar derivatives as inhibitors of a-glycosidases

The present invention relates to a new series of carbohydrate analogs, as well as methods for their preparation, pharmaceutical compositions comprising these compounds and their use in therapy.

PRIOR ART The potential of iminoazúcares as glycosyl hydrolase inhibitors in therapies directed to cancer, viral infections, tuberculosis, diabetes and glycosphingolipid storage disorders, has led to the discovery of many types of natural and synthetic structures that help Unravel both the mechanism of action of glycosidases and the development of new pharmaceutical products. However, although these compounds mimic critical molecular characteristics of the corresponding substrates, their selectivity for action against different isoenzymes is generally low, which represents a serious obstacle to drug development. This fact, together with the poor cellular permeability derived from its highly hydrophilic nature, is probably responsible for the failure that iminoazúcares have experienced in most clinical trials. Two representative examples of this type of compounds are alkaloids 1-deoxyinojirimycin and castanospermine, which are potent inhibitors of neutral oc-glucosidases (-glucosidases I and II) that participate in the processing of A / -glycoproteins in the endoplasmic reticulum (ER ). Since there is evidence that the abnormal glycosidation of glycoproteins and glycolipids plays a crucial role in several pathophysiological processes involved in tumor progression, both 1-deoxynojirimycin and castanospermine would be promising as anti-cancer agents if the aforementioned problems were resolved.

In this sense, they have developed amphiphilic prodrugs, such as 6-O-butanoylcastanospermine, to improve the ability to pass the cellular membrane; However, these compounds also inhibit lysosomial a- and β-glucosidase and intestinal glucoamylase, leading to many side effects.

The attempt to develop more selective inhibitors of RE-neutral glucosidases by chemically modifying natural alkaloids has proved fruitless. Alternatively, sp ² -imino-sugar derivatives have been developed that have allowed the synthesis of a new family of glycomimetics in which the typical endocyclic oxygen atom of the monosaccharides was replaced by a pseudoamide-type nitrogen atom {for example, carbamate, thiocarbamate, urea, thiourea or guanidine) groups with a sp ² character accused. The very effective overlap between the orbital p, which houses the pair of non-bond electrons of the nitrogen atom, and the orbital σ ^* of the pseudoanomeric C-0 bond, translates into a significant increase in the orbitical contribution to the anomeric effect, setting axial orientation in aqueous solution. Consequently, these compounds have stereochemical complementarity with glycosides, which translates into a very high α-anomeric selectivity in their inhibition of glycosidases. It should be noted that sp ² -iminoazúcares "reducing" bicyclic structure with 5-hydroxy-2-oxacastanospermina show a remarkable selectivity between different -glucosidases, with preference for neutral isoforms. On the other hand, epimerization at the hemiaminal center ("anomerization") is possible at the active site of glucosidases. Thus, the anomeric selectivity can change from α to β depending on the nature of the pseudoamid segment and the incorporation of substituents in the five vertices ring of the structure. In any case, the increased inhibitory activity of enzymes acting in neutral conditions (pH 7.3) with respect to acidic conditions (pH 5.2) is a general characteristic of these compounds, which can provide unique opportunities for the design of more selective inhibitors of Neutral α-glucosidases of ER, which would lead to more suitable compounds for the treatment of cancer without affecting the functioning of lysosomes. Therefore, it would be desirable to provide new compounds that are capable of inhibiting RE neutral neutral a-glucosidases selectively, and that are good drug candidates. The compounds should have good activity in pharmacological tests in vivo, good oral absorption when administered orally, as well as being metabolically stable and have a favorable pharmacokinetic profile. In addition, the compounds should not be toxic and have few side effects.

Explanation of the invention.

An aspect of the invention relates to the compounds of formula I

donde:

where:

X represents O, S or -NR ₅ ;

Y represents O or S;

Ri represents _Ci-i2 alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -COR _6, -CONR ₆ R _6, -COCONR ₆ R _6, -SR _6, -SOR ₆ -S0 ₂ R ₆ , -S0 ₂ NR ₆ R ₆ , -S0 ₂ NR ₅ COR ₆ , -NR ₆ R ₆ , -NR ₅ COR ₆ , -NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S ) NR ₆ R ₆ , -NR ₅ (C = NR ₅ ) NR ₆ R ₆ , -NR ₅ C0 ₂ R ₆ or -NR ₅ S0 ₂ R ₆₎ where Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl and C ₂ -i ₂ alkynyl are independently optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -COR6, -CONR ₆ R ₆ , or Cyi, where Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl and C ₂ -i ₂ alkynyl are independently optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Rs; or two Ri and R2 groups are optionally linked to form a 3 to 7 membered monocyclic ring that can be carbocyclic or heterocyclic in which case it can contain 1 to 4 heteroatoms selected from N, S and O, which can be saturated or partially saturated. unsaturated, and where one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO _{2 groups} , and which is optionally substituted by one or more R ₈ R ₃ and R ₄ independently represent hydrogen, Ci-2 alkyl , C ₂ -i2alkenyl, C ₂ -i2alkynyl, -COR ₆ , -CONR ₆ R ₆ , or Cyi, where Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl and C ₂ -i ₂ alkynyl are independently optionally substituted by one or more R ₇ and Cy is optionally substituted by one or more Ra;

each R5 represents hydrogen or d- ₁ 2 alkyl;

each R6 independently represents hydrogen, Ci-i2alquilo, halod- _i2 alkyl, Ci- _{12 alcoxiCi-i2} alkyl, hydroxyC _ii-2 alkyl, _cianoCi-i2 alkyl or Cyi, wherein Cyi is optionally substituted by one or more Rs;

Each R ₇ independently represents halogen, -CN, -NO2, -CORg, - CO2R9, -CONR9R9, -ORg, -OCORg, -OCONR9R9, -OCO2R9, -SR ₉ , -SORg, - SO2R9, -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9 _, -NR5CONR9R9, - NR5CO2R9, -NR ₅ SO ₂ Rg or Cy-ι, where Cyi is optionally substituted by one or more Rs;

hidroxiCi-i2alquilo, haloC-i-i2alquilo,

halógeno, -CN, -NO₂, -CORg, -CO2R9, -CONR9R9, -OR₉, -OCORg, -OCONR9R9, -OCO2R9, -SR₉, -SORg, -SO₂R₉, -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9

each Re represents independently

hydroxyCi-i2alkyl, haloC-i-i2alkyl,

Halogen, -CN, -NO ₂ , -CORg, -CO2R9, -CONR9R9, -OR ₉ , -OCORg, -OCONR9R9, -OCO2R9, -SR ₉ , -SORg, -SO ₂ R ₉ , -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9

o cianoCi-₁₂alquílo; y each R9 independently represents hydrogen, Ci- ₁₂ alkyl, halod- i2alquilo, Ci-i2alcoxiCi-i2alquilo,

or cyano- ₁₂ alkyl; Y

each Cyi independently represents a 3- to 7-membered monocyclic or 6 to 11-membered bicyclic ring which may be carbocyclic or heterocyclic in which case it may contain from 1 to 4 heteroatoms selected from N, S and O, where Cyi can be saturated or partially unsaturated, and can be attached to the rest of the molecule through any available C or N atom, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO _{2 groups} , with the proviso that the following compounds are excluded:

The present invention also relates to the salts and solvates of the compounds of formula I.

 Some compounds of formula I may have chiral centers, which may give rise to various stereoisomers. The present invention relates to each of the individual stereoisomers as well as their mixtures.

The compounds of formula i are glycosidases inhibitors and can therefore be useful in the treatment of diseases mediated by glycosidases

 Thus, another aspect of the invention relates to a compound of formula I

o una sal del mismo, donde:

or a salt thereof, where:

X represents O, S or -NR ₅ ;

Y represents O or S;

Ri represents Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl, C ₂ -i ₂ alkynyl, -COR ₆ , -CONR ₆ R6, -COCONR ₆ R ₆ , -SR ₆ , -SOR ₆ , -SO ₂ R ₆ , -S0 ₂ NR ₆ R ₆ , -S0 ₂ NR ₅ COR ₆ , -NR ₆ R ₆ ,

-NR ₅ C0 ₂ R6 or -NR5SO2R6, where C ₁₂ -alkyl, C ₂ -i ₂ -alkenyl and C ₂ -i ₂ -alkynyl are independently optionally substituted by one or more R ₇ ;

R2 represents hydrogen, Ci-i2alkyl, C ₂ -i ₂ alkenyl, C ₂ -i2alkynyl, -COR6, -CONR ₆ R6, or Cyi, where C -i2alkyl, C2-i2alkenyl and C-2-i2alkyl are independently optionally substituted by one or more R ₇ and Cy is optionally substituted by one or more Re;

or two Ri and R2 groups are optionally linked to form a 3 to 7 membered monocyclic ring that can be carbocyclic or heterocyclic in which case it can contain 1 to 4 heteroatoms selected from N, S and O, which can be saturated or partially saturated. unsaturated, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO _{2 groups} , and which is optionally substituted by one or more R ₈ R3 and R ₄ independently represent hydrogen, C2alkyl, C ₂ -i ₂ alkenyl, C2-i2alkynyl, -COR6, -CONR ₆ R6, or Cy-i, where Ci-i2alkyl, C ₂ -i ₂ alkenyl and C2-i2alkynyl are independently optionally substituted by one or more R ₇ and Cy-i is optionally substituted by one or more R ₈ ;

each R ₅ represents hydrogen or C1-2 alkyl;

o Cyi, donde Cy-ι está opcionalmente sustituido por uno o más R₈; each R6 independently represents hydrogen, Ci-i2alkyl, haloCi-

or Cyi, where Cy-ι is optionally substituted by one or more R ₈ ;

each R independently represents halogen, -CN, -N0 ₂ , -CORg, - CO2R9, -CONR9R9, -ORg, -OCORg, -OCONRgRg, -OC0 ₂ R ₉₎ -SR ₉ , -SOR ₉₎ - SO2R9, -SO2NR9R9 , -S02NR ₅ COR _9j -NR9R9, -NR5COR9 _, -NR5CONR9R9, - NR5CO2R9, -NR5SO2R9 or Cyi, where Cy is optionally substituted by one or more Re;

Each Rg independently represents CM2alkyl,

haloC-i-i ₂ alkyl, Ci-i ₂ alkoxyC- ₁₂ alkyl, halogen, -CN, -N0 ₂ , -COR ₉ , -C0 ₂ Rg, -CONR ₉ R ₉ , -ORg, -OCOR ₉ , - OCONR ₉ R ₉ , -OCO ₂ R ₉₎ -SR ₉ , -SORg, -SO ₂ R ₉ , -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9

each Rg independently represents hydrogen, Ci-i ₂ alkyl, haloCi- ₂ alkyl, or cyanoCi-i ₂ alkyl; Y

each Cyi independently represents a 3- to 7-membered monocyclic or 6 to 11-membered bicyclic ring which may be carbocyclic or heterocyclic in which case it may contain from 1 to 4 heteroatoms selected from N, S and O, where Cyi can be saturated or partially unsaturated, and may be attached to the rest of the molecule through any available C or N atom, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO2 groups, with the condition that the following compounds are excluded:

To be used in therapy.

 Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

 Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases mediated by a-glycosidases.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the Preparation of a medicament for the treatment of a selected disease of cancer, viral infections, tuberculosis, diabetes and glycosphingolipid storage disorders. Preferably, the disease is selected from cancer. Even more preferably, the disease is selected from lung, pancreas, colon, prostate, skin and breast cancer. And even more preferably, the disease is selected from breast cancer.

 Another aspect of the present invention relates to a process of preparing a compound of formula I as defined above, comprising:

(a) reacting a compound of formula il with a compound of formula III:

II III where A represents a halogen group; Z represents a nucleophile group; and where X, Y, R _t R ₂ , R3 and R ₄ have the meaning described above; or (b) reacting a compound of formula II with a compound of formula IV:

IV wherein R1 represents _Ci-i2 alkyl, C2-C2-i2alquiniio i2alquenilo or where each C1- _i2 alkyl, C ₂ alkenyl or C ₂ -i _2-2 alkynyl is optionally substituted independently by one or more R ₇ ; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R ₂ , R3 and R ₄ have the meaning described above; or

(c) reacting a compound of formula V with a compound of formula SAW:

V VI where B represents hydrogen or -COR6; C represents -NH ₂ , -SH or -CN; Ri represents Ci-i2alquilo, C2-i2aiquenilo or C2-i2alquinilo where each Ci-i2alquilo, C ₂ or C ₂ -i -i2alquenílo ₂ alkynyl is independently optionally substituted by one or more R _7; and where X, Y, R ₂ , R3 and R4 have the meaning described above; or

 (d) transform, in one or several stages, a compound of formula i into another compound of formula I.

como grupo o parte de un grupo, significa un grupo alquilo de cadena lineal o ramificada que contiene de 1 a 12 átomos de C. Ejemplos incluyen los grupos metilo, etilo, propílo, isopropilo, butilo, isobutílo, sec-butilo, te/t-butilo, ventilo, hexilo, heptilo, octilo, nonílo, decilo, undecilo y dodecilo. In the previous definitions, the term

as a group or part of a group, it means a straight or branched chain alkyl group containing from 1 to 12 C atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te / t groups -butyl, ventyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

A C ₂ -i ₂ alkenyl group means a linear or branched alkyl chain containing from 2 to 12 C atoms, and also containing from one to six double bonds. Examples include the groups ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1, 3-butadienyl, 1-pentenyl, 1-hexenyl, 1 -heptenyl, 1 -octenyl, 1 -nonenyl, 1-dedenyl, 1-undecenyl and 1-dodecenyl.

 A C-2-I2alkyl group means a linear or branched alkyl chain containing from 2 to 12 C atoms, and which also contains from one to six triple bonds. Examples include the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1,3-butadiinyl, 1 -pentinyl, 1-hexyl, 1-heptyl, 1-octactyl, 1 - groups noninyl, 1-decinyl, 1-undecinyl and 1-dodecinyl.

A C- ₂ alkoxy group, as a group or part of a group, means a -OC- ₂ alkyl group, where the d-alkyl part has the same meaning described previously. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, terf-butoxy, pentoxy, hexoxy, heptoxy, octoxy and nonoxy.

 A halogen radical or its abbreviation halo means fluoro, chloro, bromo or iodo.

A Ci-i2alcoxiCi- 2 -C group means a group resulting from the substitution of one or more hydrogen atoms of a C ₁ group - ₁₂ by one or more alkyl groups Ci- ₁₂ alkoxy as defined above, which may be identical or different . Examples include, among others, the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, terf-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2- ethoxyethyl, 1, 2-diethoxyethyl groups butoxy ethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 2-sec-butoxy ethyl, 3-tert-butoxypropyl and 4-methoxybutyl.

A group haloCi- ₁₂ alkyl means a group resulting from the substitution of one or more hydrogen atoms of a Ci ₂ alkyl group by one or more halogen atoms {i.e., fluoro, chloro, bromo or iodo), which can be Same or different. Examples include, among others, the trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2- iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl groups, 3-chloropropyl, 2,2,3, 3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4- fluorobutyl and nonafluorobutyl.

A hydroxyC-i ₂ alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci-i ₂ alkyl group with one or more hydroxy groups. Examples include, among others, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl and 1-hydroxybutyl.

A cyanoC-ii ₂ alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci-i ₂ alkyl group by one or more cyano groups. Examples include, among others, the cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-dicyanopropyl and 4- cyanobutyl groups. A Cyi group refers to a monocyclic heterocycle of 3 to 7 members or bicyclic of 6 to 1 1 members with the proviso that the ring is saturated or partially unsaturated. When Cy is bicyclic, the second ring can be saturated, partially unsaturated or aromatic. Cyi contains a total of 1 to 4 heteroatoms selected from N, O and S. Cyi can be attached to the rest of the molecule through any available C or N atom. When Cy is a bicyclic ring, it can be formed by two fused rings through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridge ring, or it can be formed by two rings joined through a single C atom forming a spirane type ring. In Cyi one or more C or S atoms of any saturated or partially unsaturated ring may optionally be oxidized forming CO, SO or SO _{2 groups} . The Cyi group may be optionally substituted as indicated in the definition of formula I, said substituents may be the same or different and may be located at any available position of any of the rings. Examples of Cyi groups include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, aziridinyl, azetidinyl, 4-diazepanyl, pyrrolidinyl, oxiranyl, oxetanyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolinyl, pyrrolinyl, pyrazolinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl, piperazinyl, homopiperazinyl, 2-oxo-azepanyl, 2-oxo-azetidinyl, 2-oxo-1, 2-oxopanyl-1, 2-oxopanyl-1, 2-oxzepanyl 2-oxo-piperazinyl, 2-oxo-piperidinyl, 3-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, 2-oxo-1, 2-dihydropyridyl, 2-oxo- 1, 2- dihydropyrazinyl, 2-oxo-1, 2-dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, tetrahydrofuranyl, 1, 2,3,6-tetrahydropyridinyl, 1, 2,3,6-tetrahydropyranyl, perhydroisoquinolinyl, 1-oxo-1, 2-dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 5-aza-bicyclo [ 2.1 .1] hexanyl, 2-aza-bicyclo [2.2.1] heptanyl, 6-aza-bicyclo [3.2.1] octanyl, octahydro-pyrrolo [1,2-a] pyrazinyl, 2H-spiro [benzofuran-3, 4'-piperidinyl3,3H-spiro [isobenzofuran-1, 4'-piperidinyl], 2,8-diazaspiro [4.5] decan-1 -onyl, 2,7-diazaspiro [4.5] decan-1 -onyl, 2-aza - bicyclo [2.2.1] heptan-6-onyl and 6-aza-bicyclo [3.2.1] octan-7-onyl. In the previous definition of Cyi, when the specified examples refer to a bicyclic ring in general terms, all possible arrangements of atoms are included.

 When in the definitions used throughout the present description for cyclic groups the specified examples refer to a ring radical in general terms, for example tetrahydrofuran, all possible binding positions are included, except that in the group definition corresponding, indicate any limitation in this regard, in which case such limitation applies. Thus, for example, in the definition of Cyi, which does not include any limitation with respect to the binding position, the term tetrahydrofuran includes 2-tetrahydrofuran and 3-tetrahydrofuran.

 The term "nucleophile group" refers to a species that reacts by releasing a pair of free electrons to another species by combining and covalently bonding with it. A nucleophile can be an anion or a neutral molecule with a pair of free electrons. Nucleophiles can be classified according to their chemical nature into carbon nucleophiles such as carbanions (such as organometallic reagents), oxygen nucleophiles such as water, alcohols, and salts of carboxylic acids, nitrogen nucleophiles such as amines and sulfur nucleophiles such as hydrogen sulphides, thiols, thiolates and sulphides. Examples of nucleophilic groups include, but are not limited to, water, methanol, ethanethiol, sodium propionate, 1-propanylamine, 1-octactylamine, 1, 1-diethylamine, 1-octanethiole, dimethyl sulfide, methyl magnesium bromide, trimethylaluminum, and trioctylaluminum.

The term "organometallic reagent" refers to a compound in which carbon atoms form covalent bonds, that is, they share electrons, with a metal atom. The characteristic of these compounds is the presence of bonds between metal and carbon atoms (which can be single, double or triple) and therefore those compounds in which a metal is attached to a molecule or fragment by an atom are not considered organometallic. other than carbon Formally, organometallic compounds are those that have, directly, links between metal atoms (or metalloids) and carbon atoms, M ⁺⁶ -C ^"6 , of greater or lesser polarity. that is, a compound is considered as organometallic if it contains at least one carbon-metal bond. Examples of organometallic reagents include, but are not limited to, methyl magnesium bromide, methyl magnesium chloride, methyl lithium, butyllithium, ethyl sodium, trioctylaluminum, ethyl mercury chloride, methyl magnesium iodide, dimethyl magnesium, methyl zinc chloride, dimethylcadmium and methylpotasium.

 The term "metal" refers to the metallic elements of groups 1, 2, 3 and 4 of the periodic table as well as to the transition elements. The oxidation state of metals varies between +1 and +7. Examples of metal include, but are not limited to, lithium, sodium, potassium, beryllium, magnesium, calcium, scandium, titanium, zirconium, vanadium, chromium, manganese, iron, osmium, nickel, palladium, platinum, copper, silver, gold, zinc, Cadmium, mercury, aluminum, tin and lead. Preferably the term metal refers to lithium, magnesium, titanium, palladium, platinum, copper, silver, gold, zinc, cadmium, mercury, alumino, tin and lead. More preferably, the term metal refers to lithium, magnesium, titanium, palladium, copper, silver, gold, zinc, aluminum and tin. And, even more preferably the term metal refers to lithium, magnesium and aluminum.

 The term "optionally substituted by one or more" means the possibility of a group being substituted by one or more, preferably by 1, 2, 3 or 4 substituents, more preferably by 1, 2 or 3 substituents and even more preferably by 1 or 2 substituents, provided that said group has sufficient available positions that can be substituted. If present, said substituents may be the same or different and may be located over any available position.

 When a non-aromatic cycle is as a substituent of a non-aromatic cycle, it may be replacing a hydrogen atom, or it may replace two hydrogen atoms on the same C atom thus forming a ring of the Spiranus type. Similarly, when a non-aromatic cycle is as a substituent of an alkyl, alkenyl or alkynyl group, it may be replacing a hydrogen atom, or it may replace two hydrogen atoms on the same C atom.

When two or more appear in a definition of a substituent groups with the same numbering (for example -CONR ₆ R6, -NR ₉ R ₉ , -CONRgRg, etc.), this does not mean that they have to be identical. Each of them is independently selected from the list of possible meanings given for said group, and therefore they can be the same or different.

 Throughout the present description, the terms "treatment" of a disease, "treating" a disease or other grammatically related expressions refer to both curative treatment and palliative treatment or prophylactic treatment of said disease.

 The invention thus relates to the compounds of formula I as defined above.

 In another embodiment, the invention relates to the compounds of formula 1 where X represents O.

 In another embodiment, the invention relates to the compounds of formula I where X represents S.

In another embodiment, the invention relates to the compounds of formula i where X represents -NR ₅ .

 In another embodiment, the invention relates to the compounds of formula I where Y represents O.

 In another embodiment, the invention relates to the compounds of formula I where Y represents S.

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O; Y

 And represents O.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O; Y

 And represents S.

In another embodiment, the invention relates to the compounds of formula 1 where Ri represents Ci-i2alkyl, C2-i2alkenyl, C2-i2alkynyl, -SRe, -NR ₆ R6, -NR ₅ COR ₆ , -NR ₅ <C = 0 ) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ (C = NR ₅ ) NR ₆ R ₆ , where Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl and C ₂ - i ₂ alkynyl are independently optionally substituted by one or more R ₇ .

In another embodiment, the invention relates to compounds of formula I wherein Ri represents Ci-^ alkyl, -SR ₆ , -NR ₆ R ₆ , -NR ₅ COR ₆ , - NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ {C = NR ₅ ) NR ₆ R6, where Ci-i ₂ alkyl, is optionally substituted by one or more R ₇ .

In another embodiment, the invention relates to the compounds of formula i where Ri represents Ci-i ₂ alkyl, -SRe or -NR ₆ R ₆ , where C ₁₂ alkyl is optionally substituted by one or more R ₇ .

In another embodiment, the invention relates to the compounds of formula I where R represents Ci-i2alkyl or -NR ₆ R ₆ , where Ci-i2alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O; Y

donde Ci-i₂alquilo, está opcionalmente sustituido por uno o más R₇. Ri represents Ci-i ₂ alkyl, -SR ₆ , -NR ₆ R ₆ , -NR ₅ COR ₆ , -

where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O; Y

Ri represents C ^^ alkyl, -SR ₆ or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O; Y

Ri represents Cii ₂ alkyl or -NR ₆ R6, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula i where:

Y represents O; Y Ri represents Ci-i ₂ alkyl, -SR ₆ , -NReRe, -NR ₅ COR ₆ , NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ ( C = NR ₅ ) NR ₆ R ₆ , where d- ^ alkyl, is optionally substituted by one or more R7.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O; Y

R1 represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R ₆ , where Cii ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O; Y

R1 represents Ci-i ₂ alkyl or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S; Y

Ri represents d. ^ Alkyl, -SR ₆ , -NR ₆ R ₆ , -NR ₅ COR ₆ , NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ (C = NR ₅ ) NR ₆ R ₆ , where Ci-i ₂ alkyl, is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I wherein:

 Y represents S; Y

R represents Ci- ₂ alkyl, -SRQ O -NR ₆ R6, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S; Y

R1 represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Cii ₂ alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula i where:

X represents O; Y represents O; Y

Ri represents Ci- ₁₂ aquíquio, -SR ₆ , -NR ₆ R ₆ , -NR ₅ COR ₆ , - NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or - NR ₅ (C = NR ₅ ) NR ₆ R ₆ , where d- ^ alkyl, is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O; Y

Ri represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I wherein:

 X represents O;

 Y represents O; Y

Ri represents Ci-^ alkyl or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S; Y

Ri represents Ci-i ₂ alkyl, -SR ₆ , -NR ₆ R6, -NR ₅ COR ₆ , NR ₅ (C = 0) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ <C = NR ₅ ) NR ₆ R ₆ , where C _1-2 alkyl, is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O;

 Y represents S; Y

Ri represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R6, where di ₂ alkyl, is optionally substituted by one or more R ₇ .

 In another embodiment, the invention relates to the compounds of formula i where:

X represents O; Y represents S; Y

está opcionalmente sustituido por uno o más R₇. Ri represents

is optionally substituted by one or more R ₇ .

In another embodiment, the invention relates to the compounds of formula I wherein R2 represents hydrogen, Ci-i2alkyl, -COR6, -CONR ₆ R6 or Cyi, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ .

In another embodiment, the invention relates to compounds of formula I wherein R2 represents hydrogen, Ci-i2alquilo or Cyi, wherein Ci-i2alquilo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re;

In another embodiment, the invention relates to the compounds of formula i where R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O; Y

R ₂ represents hydrogen, Ci- ₂ alkyl or Cy-i, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I wherein:

 Y represents O; Y

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cyi, where Ci-i2 alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S; Y

R2 represents hydrogen, Ci-Cy-ι i2alquilo or where _Ci-i2 alkyl is optionally substituted by one or more R and Cyi is optionally substituted by one or more R _8, preferably R ₂ represents hydrogen. In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O; Y

F½ represents hydrogen, Ci-i2alquilo or Cyi, wherein Ci-i2alquílo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, R2 preferably represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O; Y

está opcionalmente sustituido por uno o más R₇ y Cyi está opcionalmente sustituido por uno o más R₈, preferiblemente R₂ representa hidrógeno. R2 represents hydrogen, Ci-i2alkyl or Cy-i, where

is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

R1 represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R2 represents hydrogen, Ci-Cy-ι i2alquilo or where Ci-i2alquilo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, R2 preferably represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

R1 represents Ci-^ alkyl or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

está opcionalmente sustituido por uno o más R₇ y Cyi está opcionalmente sustituido por uno o más R₈, preferiblemente R₂ representa hidrógeno. R2 represents hydrogen,

is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I wherein:

X represents O; Ri represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

R ₂ represents hydrogen, Ci-i2 alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O;

R1 represents Cii ₂ alkyl or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

R2 represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O;

R1 represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R ₂ represents hydrogen, Ci-i2alkyl or Cy-ι, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O;

R1 represents Ci- ₁₂ alkyl or -NR ₆ R _6, where d- ^ alkyl is optionally substituted by one or more R _7; Y

R ₂ represents hydrogen, C ₁₂ alkyl or Cyi, where C ₁₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

Y represents S; Ri represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

está opcionalmente sustituido por uno o más R₇ y Cyi está opcionalmente sustituido por uno o más Re, preferiblemente R2 representa hidrógeno. R ₂ represents hydrogen, Ci-i2alkyl or Cy-ι, where

it is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

 Y represents S;

R1 represents Cii ₂ alkyl or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

R2 represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O;

R ₁ represents Ci-i ₂ alkyl, -SRe or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R2 represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cy is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 And represents O.

R ₁ represents Cii ₂ alkyl or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R2 represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen. In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 And represents S.

R represents C 2 -alkyl, -SRQ O -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

R ₂ represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Rs, preferably R ₂ represents hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 And represents S.

R represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen .

In another embodiment, the invention relates to the compounds of formula I wherein R 3 and R ₄ independently represent hydrogen or C _1. ^ Alkyl, where C -i ₂ alkyl is optionally substituted by one or more R ₇ .

In another embodiment, the invention relates to the compounds of formula I wherein R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O; Y

R ₃ and R independently represent hydrogen or d- ^ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

Y represents O; Y R3 and _R4 independently represent hydrogen or Ci-i2alquilo where _Ci-i2 alquiio is optionally substituted by one or more R _7, preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S; Y

donde Ci-i₂alquilo está opcionalmente sustituido por uno o más R₇, preferiblemente R₃ y R₄ independientemente representan hidrógeno. R ₃ and R ₄ independently represent hydrogen or

where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O; Y

R ₃ and R ₄ independently represent hydrogen or Ci-i2 alkyl, where Ci-i2alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S; Y

R ₃ and R ₄ independently represent hydrogen or Ci-i ₂ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

R1 represents Ci-i2alquilo, -SR 6 or -NR ₆ R 6, where _Ci-i2 alkyl, is optionally substituted by one or more R _7; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci-i2alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

o -NR₆R₆, donde está opcionalmente sustituido por uno o más R₇; y In another embodiment, the invention relates to the compounds of formula I where: Ri represents

or -NR ₆ R ₆ , where it is optionally substituted by one or more R ₇ ; Y

R ₃ and R ₄ independently represent hydrogen or Ci-i ₂ alkyl, where Ci-i2 alkyl is optionally substituted by one or more R ₇ , preferably R3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

 X represents O;

R1 represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

donde Ci-i2alquilo está opcionalmente sustituido por uno o más R , preferiblemente R3 y R₄ independientemente representan hidrógeno. R3 and _R4 independently represent hydrogen or

where Ci-i2alquilo is optionally substituted by one or more R, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

R1 represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

donde Ci-i₂alquilo está opcionalmente sustituido por uno o más R₇, preferiblemente R3 y R₄ independientemente representan hidrógeno. R3 and _R4 independently represent hydrogen or

where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O;

R1 represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R ₆ , where d- ^ alkyl, is optionally substituted by one or more R ₇ ; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where

Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

o -NR₆R₆, donde está opcionalmente sustituido por uno o más R₇; y Y represents O; Ri represents

or -NR ₆ R ₆ , where it is optionally substituted by one or more R ₇ ; Y

R ₃ and R ₄ independently represent hydrogen or Ci-i ₂ alkyl, where Ci-i2 alkyl is optionally substituted by one or more R ₇ , preferably R3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula i where:

 Y represents S;

R1 represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

donde Ci-i2alquilo está opcionalmente sustituido por uno o más R , preferiblemente R3 y R₄ independientemente representan hidrógeno. R3 and _R4 independently represent hydrogen or

where Ci-i2alquilo is optionally substituted by one or more R, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S;

R1 represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ; Y

donde Ci-i₂alquilo está opcionalmente sustituido por uno o más R₇, preferiblemente R3 y R₄ independientemente representan hidrógeno. R3 and _R4 independently represent hydrogen or

where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O;

R1 represents Ci-i2alquilo, -SR 6 or -NR ₆ R 6, where _Ci-i2 alkyl, is optionally substituted by one or more R _7; Y

R ₃ and R ₄ independently represent hydrogen or C ₂ alkyl, where Ci-2 alkyl is optionally substituted by one or more R ₇ , preferably R 3 and R ₄ independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O;

 Y represents O;

Ri represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Ci- ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where

Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S;

R1 represents Ci-i2alkyl, -SRe or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ; Y

R ₃ and R ₄ independently represent hydrogen or Ci-i2 alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S;

R1 represents Ci-i ₂ alkyl or -NR ₆ R ₆ , where Ci- ₂ alkyl is optionally substituted by one or more R ₇ ; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where _Ci-i2 alkyl is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen; Y R3 and _R4 independently represent hydrogen or Ci-i2alquilo where _Ci-i2 alkyl is optionally substituted by one or more R _7, preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

R ₂ represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Rs, preferably R2 represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where

Ci-i2alkyl is optionally substituted by one or more R ₇ , preferably R3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O;

R2 represents hydrogen, Ci - i2alqu¡lo or Cy-ι where Ci-i2alquilo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R _8, preferably R ₂ represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where Ci-i2alquilo is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents S;

R ₂ represents hydrogen, d- ^ alkyl or Cy-ι, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci-i2 alkyl is optionally substituted by one or more R ₇ , preferably R3 and R ₄ independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O;

 Y represents O;

R ₂ represents hydrogen, Ci-i2 alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci-i2alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S;

R ₂ represents hydrogen, C ₁₂ alkyl or Cyi, where d-alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen; Y

R 3 and R ₄ independently represent hydrogen or Ci-i ₂ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

R1 represents C ^^ alkyl, -SR ₆ or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cyi, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen; Y

R3 and _R4 independently represent hydrogen or alkyl Cii ₂ where Ci- ₁₂ alkyl is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I wherein:

R1 represents R ₁ represents

is optionally substituted by one or more R ₇ ; R2 represents hydrogen, Ci-Cy-ι i2alquilo or where Ci-i2alquilo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where Ci-i2alquílo is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

R1 represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ;

está opcionalmente sustituido por uno o más R₇ y Cyi está opcionalmente sustituido por uno o más R₈, preferiblemente R₂ representa hidrógeno; y R2 represents hydrogen, Ci-i2alkyl or Cyi, where

is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

dondeR3 and _R4 independently represent hydrogen or

where

C -i2alquilo is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

R1 represents R1 represents Ci -i ₂ alkyl or -NR ₆ R6, where Ci -i ₂ alkyl is optionally substituted by one or more R ₇ ;

R2 represents hydrogen, Ci-i2alquilo or Cyi, wherein Ci-i2alquílo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where Ci- ₁₂ alkyl is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I wherein:

Y represents O; Ri represents Ci-i2alkyl, -SR6 or -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ;

está opcionalmente sustituido por uno o más R₇ y Cyi está opcionalmente sustituido por uno o más Re, preferiblemente R2 representa hidrógeno; y R ₂ represents hydrogen, Ci-i2alqu¡lo or Cyi, where

it is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 Y represents O;

R1 represents R1 represents Ci-i2alkyl or -NR ₆ R6, where

is optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cyi, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or C. alkyl, where C ₁₂ alkyl is optionally substituted by one or more R ₇ , preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I wherein:

 Y represents S;

R represents C 2 -alkyl, -SRQ O -NR ₆ R6, where Ci-i2alkyl is optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, d- ^ alkyl or Cy-i, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S;

Ri represents Ri represents Ci -i ₂ alkyl or -NR ₆ R ₆ , where d. ^ Alkyl, is optionally substituted by one or more R7;

está opcionalmente sustituido por uno o más R7 y Cyi está opcionalmente sustituido por uno o más R₈, preferiblemente R₂ representa hidrógeno; y R2 represents hydrogen, Ci-i2alkyl or Cyi, where

is optionally substituted by one or more R7 and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

donde Ci-i₂alquilo está opcionalmente sustituido por uno o más R₇, preferiblemente R₃ y R₄ independientemente representan hidrógeno. R ₃ and R ₄ independently represent hydrogen or

where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ , preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O;

R represents Ci-i2alkyl, -SR6 or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, Ci-i2 alkyl or Cy-i, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where Ci-i2alquilo is optionally substituted by one or more R _7, preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents O;

R1 represents R1 represents Ci-i2alquilo or -NR ₆ R 6, where Ci-i2alquilo, is optionally substituted by one or more R _7;

R ₂ represents hydrogen, Ci-i ₂ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y R3 and _R4 independently represent hydrogen or Ci-i2alquilo where _Ci-i2 alquiio is optionally substituted by one or more R _7, preferably R ₃ and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S;

R1 represents Ci-i ₂ alkyl, -SR ₆ or -NR ₆ R ₆ , where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ ;

R ₂ represents hydrogen, Ci-i2alkyl or Cy-ι, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R ₂ represents hydrogen; Y

R ₃ and R ₄ independently represent hydrogen or Cii ₂ alkyl, where Ci- ₂ alkyl is optionally substituted by one or more R ₇ , preferably R 3 and R ₄ independently represent hydrogen.

 In another embodiment, the invention relates to the compounds of formula I where:

 X represents O;

 Y represents S;

R1 represents R1 represents Ci-i2alquilo or -NR ₆ R 6, where Ci-i2alquilo, is optionally substituted by one or more R _7;

R ₂ represents hydrogen, C ₁₂ alkyl or Cyi, where C ₁₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re, preferably R2 represents hydrogen; Y

dondeR ₃ and R ₄ independently represent hydrogen or

where

Ci-i2alquilo is optionally substituted by one or more R, preferably R 3 and R ₄ independently represent hydrogen.

In another embodiment the invention relates to the compounds of formula l selected from la-li:

 lg ih li where:

R2 represents hydrogen, Ci-Cy-ι i2alquilo or where Ci-i2alquilo is optionally substituted by one or more R ₇ and Cy is optionally substituted by one or more R _8, preferably R ₂ represents hydrogen.

In another embodiment the invention relates to the compounds of formula I selected from la-li:

 ig ih

 where:

R2 represents hydrogen, Ci-i2alkyl or Cy-ι, where Ci-i2alkyl is optionally substituted by one or more R ₇ and Cy is optionally substituted by one or more R ₈ , preferably R ₂ represents hydrogen; Y

R3 and _R4 independently represent hydrogen or Ci-i2alquilo where _Ci-i2 alkyl is optionally substituted by one or more R _7, preferably R ₃ and R ₄ independently represent hydrogen.

 Also, the present invention covers all possible combinations of the particular and preferred embodiments described above.

In another embodiment, the invention relates to compounds of formula i that produce more than 50% inhibition of a-glycosidase activity neutral at 100 μΜ, more preferably at 10 μΜ, even more preferably at 1 μΜ and still more preferably at 0.1 μΜ in a glycosidases inhibition assay such as that described in example 58.

 In another embodiment, the invention relates to a compound of formula 1 selected from the list of compounds described in examples 1 to 57.

 In another embodiment, the invention relates to compounds of formula I selected from:

 (5S, 6S, 7S, 8fí, 8afí) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

(5fí, 6fí, 7S, 8fí, 8afí) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

(5? SJfí ñ a ¾-5-0 <¾il-67 -trihydroxy-2-oxa-3-oxoindolizidine;

 (5S, 6S, 7S, 8f, 8añ) -5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

 (5S, 6S, 7S, 8ñ, 8añ) -5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine;

 {5S, 6S, 7S, 8fí, 8afí) -5- (4-Hydroxybutylamino) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine;

 (5S, 6S, 7S, 8f, 8añ) -5- (Pent-3-yl-amino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

(SS ^ fíJS ^ fí ^ a ^ -S-Butylamino-ej ^ -trihydroxy ^ -oxa-S-oxoindolizidine;

 (SS ^ fíJS.Sfí.Sa ^ -S-Octylamino-ex.S-trihydroxy ^ -oxa-S-oxoindolizidine;

 {5S, 6fí, 7S, 8fí, 8af?) - 5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine;

 (5S, 6S, 7S, 8ñ, 8afí) -5- (Octylthioureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

(5S, 6S, 7S _! 8fí, 8afí) -5- (Acetamido) -6.7 _! 8-trihydroxy-2-oxa-3-oxoindolizidine;

{5S, 6S, 7S, ^8: 8a ^/:) - 5- (butanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidina;?

{5S, 6S, 7S, 8fí, 8afí) -5- (Octanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8f, 8añ) -5- (Adamantane-1-carboxamido) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine;

; y

; Y

 Hept

In another embodiment, the invention relates to compounds of formula I selected from:

(5S, 6S, 7S, 8fí, 8afí) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

{5f?, 6f?, 7S, 8fí, 8afí) -5-Octylthio-6,7,8-tnhydroxy-2-oxa-3-oxoindolizidine; Y

(5fí, 6S, 7fí, 8fí, 8afí) -5-Octyl-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine.

 The compounds of the present invention contain one or more basic nitrogen and could therefore form salts with acids, both organic and inorganic. Examples of such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maieic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid , glycolic acid, succinic acid and propionic acid, among others. Some compounds of the present invention may contain one or more acidic protons and therefore may also form salts with bases. Examples of such salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, / V-methylglucamine, procaine and the like.

There is no limitation on the type of salt that can be used, provided that when used for therapeutic purposes they are pharmaceutically acceptable. Pharmaceutically acceptable salts are understood to be those salts that, in medical judgment, are suitable for use in contact with the tissues of humans or other mammals without causing undue toxicity, irritation, allergic response or the like. The salts pharmaceutically Acceptable are widely known to any person skilled in the art.

The salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or they can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt of a conventional form. The salts of the compounds of formula can be converted into other salts of compounds of formula I by ion exchange by means of an ion exchange resin.

 The compounds of formula I and their salts may differ in certain physical properties, but are equivalent for the purposes of the invention. All salts of the compounds of formula I are included within the scope of the invention.

 The compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term "solvate" refers to a complex of variable stocheometry formed by a solute (a compound of formula i or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as hydrate. Solvates of the compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.

 The compounds of formula I can exist in different physical forms, that is to say in amorphous form and crystalline forms. Also, the compounds of the present invention may have the ability to crystallize in more than one way, a characteristic known as polymorphism. Polymorphs can be distinguished by several physical properties well known to those skilled in the art, such as their X-ray dipfractograms, melting points or solubility. All physical forms of the compounds of formula, including all their polymorphic forms ("polymorphs"), are included within the scope of the present invention.

Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers. The diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by using conventional optical resolution techniques, to give optically pure isomers. This resolution can be made on synthesis intermediates that are chemical or on products of formula I. Optically pure isomers can also be obtained individually using enantiospecific synthesis. The present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereoisomers), whether they are obtained by synthesis or by physically mixing them.

The compounds of formula I can be obtained following the procedures described below. As will be apparent to one skilled in the art, the precise method used for the preparation of a given compound may vary depending on its chemical structure. Likewise, in some of the procedures detailed below, it may be necessary or convenient to protect reactive or labile groups by means of conventional protective groups. Both the nature of such protecting groups and the procedures for their introduction and removal are well known and form part of the prior art (see for example Greene TW and Wuts PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 ^to edition, 1999). Whenever a protective group is present, a subsequent deprotection stage will be necessary, which is carried out under the usual conditions in organic synthesis, such as those described in the reference mentioned above.

 Unless otherwise indicated, in the methods described below the meanings of the different substituents are the meanings described above in relation to a compound of formula I.

For the synthesis of a compound of formula I, the 5-hydroxy-2-oxa-3-oxocastanospermine derivative, obtained from the commercial D-glucurono-3-lactone in five steps, was chosen as the basic skeleton (see García Fernández, JM et al. Journal of Organic Chemistry 2000, 65, 136 and García Fernández, JM, et al. Journal of Organic Chemistry 2005, 2903, whose content is incorporated here by reference). It is based on the hypothesis that the fixed gauche-trans orientation of the oxygen atom equivalent to 0-6 in glucopyranosides (0-2 in the nomenclature of the indolizidines) could confer selectivity to the inhibitory activity of these compounds, in comparison with the Free spin scenario found in 1 - deoxinojirimycin or gauche-gauche orientation in castanospermina. The incorporation of axially oriented pseudoanomeric substituents guarantees α-anomeric specificity by eliminating mutarotation and, in addition, can be used to modulate inhibitory activity by promoting favorable interactions between amino acids near the active site of the enzyme and aglycone. Finally, the aglyconic portion can be chosen in a way that allows the hydrophilic / lipophilic balance of the molecule to be adjusted in order to improve permeability through cell barriers, essential for biomedical applications.

 In general, the compounds of formula I can be obtained in one or more stages by the method described in scheme 1:

 II III

 Scheme 1

where A represents a halogen group; Z represents a nucleophile group; and where X, Y, Ri, R ₂ , F¾ and R ₄ have the meaning described above. The reaction conditions for carrying out the transformation of a compound of formula il into a compound of formula I by reaction with a nucleophile of formula ili are the conditions of a conventional nucleophilic (SN) substitution.

Alternatively, some compounds of formula I can be obtained in one or more stages by the method described in scheme 2:

 IV

 Scheme 2

where Ri represents Cii ₂ alkyl, C ₂ -i ₂ alkenyl or C ₂ -i ₂ alkynyl, where each Ci-2-alkyl, C2-i-2-alkenyl or C2-i-2-alkynyl is independently optionally substituted by one or more R ₇ ; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R ₂ , R3 and R ₄ have the meaning described above. The reaction conditions for carrying out the transformation of a compound of formula II into a compound of formula I by the reaction of an organometallic compound of formula IV are the conditions of conventional organometallic chemistry.

 Also, some compounds of formula I can be obtained in one or more steps p

 v VI

 Scheme 3

where B represents hydrogen or -COR ₆ ; C represents -NH ₂ , -SH or -CN; R ₁ represents C ^^ alkyl, C ₂ -i ₂ alkenyl or C ₂ -i ₂ alkynyl, where each Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl or C ₂ -i ₂ alkynyl is independently optionally substituted by one or plus R ₇ ; and where X, Y, R2, R3 and 4 have the meaning described above. The reaction conditions for carrying out the transformation of a compound of formula V into a compound of formula I by reaction with a nucleophile of formula VI are the conditions of a conventional nucleophilic substitution (SN).

For the synthesis of examples 2, 7 and 1 1, 5-hydroxy-2-oxa-3-oxocastanospermine (scheme 4), easily obtained from commercial D-glucurono-3-lactone in five, was chosen as the basic skeleton stages

 MeOH / NaOMMee | l 99 ,, RR - = AAcc 10

955% / \ _11; = H

 Scheme 4

The synthesis of glycosylamines / V-substituted is normally carried out by dissolving sugar in methanol and reacting with an excess of amine. When an equimolecular solution of 5-hydroxy-2-oxa-3-oxocastanospermine and n-octylamine was reacted at 65 ⁹ C in methanol, the compound of example 2 was obtained. Both the anomer and β were formed in proportion 6: 1 relative, as observed by NMR of the reaction crude. Through the chromatographic column, the α anomer was obtained pure (example 2) with a 60% yield, being stable in aqueous solution at both neutral and acidic pH.

The per-O-acetylated thioglycoside analogue of castanospermine (example 7) was obtained as a mixture of the corresponding anomers and β in a 20: 1 ratio through the reaction of the corresponding sp ² -iminoazúcar tetra-Oacetate with octanotiol after selective activation of the hemiaminal center. with BF ₃ .OEt ₂ . The stereochemical result of this reaction is remarkable. The thiol addition proceeds under control of the generalized anomeric effect, leading to the α-anomer in the ⁸ C ₅ chair conformation as a major diastereoisomer. The minor β-anomer adopts the ⁵ ' ⁸ B boat conformation, placing the octiltio group in axial arrangement, thus fulfilling the effect anomeric Conventional deacetylation of with sodium methoxide in methanol led to the compound of example 7 in 92% yield.

 The C-glycosidation of 2-oxacastanospermine was carried out through the

5-fluoro derived from scheme 4, obtained from the corresponding per-O-acetylated by treatment with poly (hydrogen fluoride) pyridine (HF / pyridine).

The reaction of the aforementioned fluoro derivative with tri-n-octylaluminum in anhydrous toluene proceeded gently at 0 ^e C to give a mixture of the triacetates a and β in a 4: 1 ratio. The separation of the diastereoisomer α and subsequent deacetylation led to the compound of example 11.

 The compounds of formula II, III, IV and V are commercial or can be prepared by methods widely described in the literature, and can be conveniently protected.

 Also, some compounds of the present invention can be obtained from other compounds of formula I by transformation reactions of suitable functional groups, in one or more stages, using reactions widely known in organic chemistry under the usual experimental conditions.

 Such interconversions can be carried out on groups Y, Ri

R ₂ , R ₃ or R ₄ and include, for example:

the reduction of a nitro group to give an amino group, for example by treatment with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd / C; or, by treatment with sodium borohydride in the presence of NiCI ₂ , or SnCI ₂ ;

 the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions; or by reductive amination, that is, by treatment with an aldehyde or ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride;

the transformation of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of catalytic amounts of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine , optionally in the presence of a base such as triethylamine or pyridine; the transformation of an amine into an amide, carbamate or urea under standard conditions;

 alkylation of an amide by treatment with an alkylating agent under basic conditions;

 the conversion of an alcohol into an ether, ester or carbamate under standard conditions;

 the alkylation of a thiol to obtain a thioether, under standard conditions; partial or total oxidation of an alcohol to obtain ketones, aldehydes or carboxylic acids under standard oxidation conditions;

 the reduction of an aldehyde or ketone to alcohol, by treatment with a reducing agent such as sodium borohydride;

the reduction of a carboxylic acid or a carboxylic acid derivative to alcohol by treatment with a reducing agent such as diisobutylaluminum hydride or LiAIH ₄ ;

the oxidation of a thioether to sulfoxide or sulfone under standard conditions; the transformation of an alcohol into a halogen by treatment with SOCI ₂ , PBr ₃ , tetrabutylammonium bromide in the presence of P2O5, or Pl ₃ ;

 the transformation of a halogen atom into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating;

 the transformation of a primary amide into a -CN group or vice versa, of a -CN group into an amide by standard conditions.

 Likewise, any of the aromatic rings of the compounds of the present invention may undergo aromatic electrophilic substitution or aromatic nucleophilic substitution reactions, widely described in the literature.

 Some of these interconversion reactions are explained in more detail in the examples.

As will be apparent to those skilled in the art, these interconversion reactions can be carried out both on the compounds of formula I and on any suitable synthesis intermediate thereof. As mentioned above, the compounds of the present invention act by inhibiting the signaling pathway of the neutral RE-glycosidases selectively. Therefore, these compounds could be useful for the treatment of diseases in which the participation of RE-neutral glycosidases is important in mammals, including humans. Such diseases include, without limitation, cancer (see for example Wrodnigg, TM et al. Anticancer Agents Med. Chem. 2008, 8, 77; Nishimura, Y. Iminosugars: From Synthesis to Therapeutic Applications (Eds .: P. Compaín, OR Martin), Wiley-VCH: Weinheim, Germany, 2007; p. 269)), viral infections (see for example Duringl, D. Et al. Curr. Opin. Investig. Drugs 2007, 8, 125; Greimel, P. et al., Curr. Top. Med. Chem. 2003, 3, 513-523.), tuberculosis (see for example Wrodnigg, TM et al. Mini-Rev. Med. Chem. 2004, 4, 437), diabetes (see for example Mítrakou, A. et al. Diab. Med. 1998, 15, 657; Scott, LJ et al. Drugs, 2000, 59, 521) and storage disorders of glycosphingolipids (see for example Butters, TD et al. Chem Rev. 2000, 100, 4683; Fan, J.-Q. Iminosugars: From Synthesis to Therapeutic Applications (Eds .: P. Compain, OR Martin), Wiley-VCH: Weinheim, Germany, 2007; p. 225).

 As an example of cancer diseases that can be treated with the compounds of the invention, lung, pancreas, colon, prostate, skin and breast cancer can be mentioned. Preferably, breast cancer.

Biological assays that can be used to determine the ability of a compound to inhibit glycosidases, especially neutral a-glucosidase, are widely known. For example, a compound to be tested can be incubated in the presence of glycosidases to determine if there is inhibition of the enzymatic activity of glycosidases, as described in the test of example 59. The cytostatic and cytotoxic activity of the compounds of the present invention can be Assay using antiprolipherative activity assays against human breast carcinoma MCF-7 cell line (see for example the method described in El Hiani, Y. et al. Arch. Biochem. Bíphys. 2009, 486, 58, the content of which is here incorporated by reference). To select active compounds, the 100 μΜ assay should result in an activity of more than 50% inhibition in the test mentioned in example 59. More preferably, the compounds should have more than 50% inhibition at 10 μΜ; even more preferably more than 50% inhibition at 1 μΜ; and still more preferably more than 50% inhibition at 0.1 μΜ.

 The present invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and of not being harmful to who takes said composition.

 The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as is well known, will depend on the nature of the active ingredient and its route of administration. In principle, any route of administration can be used, for example oral, parenteral, nasal, ocular, rectal, and topical.

Solid compositions for oral administration include tablets, granules and capsules. In any case, the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active ingredient with excipients. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, manitol or calcium hydrogen phosphate; binding agents such as starch, gelatin or polyvinyl pyrrolidone; disintegrants such as sodium carboxymethyl starch or croscarmellose sodium; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may also be coated with suitable excipients and by known techniques in order to delay their disintegration and absorption in the gastrointestinal tract and thus achieve sustained action for a longer period of time, or simply to improve their organoleptic properties or their stability. The active ingredient can also be incorporated by coating on inert peilets through the use of natural or synthetic film-forming polymers. It is also possible to make soft gelatin capsules, in which the Active ingredient is mixed with water or oily medium, for example coconut oil, liquid paraffin or olive oil.

 Powders and granules can be obtained for the preparation of oral suspensions by adding water, mixing the active ingredient with dispersing or wetting agents; suspending and preservative. Other excipients can also be added, for example sweeteners, flavorings and dyes.

 Liquid forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Such compositions may also contain adjuvants such as wetting, suspending, sweetening, flavoring, preservative and pH regulating agents.

 Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions may also contain adjuvants, such as humectants, emulsifiers, dispersants and preservatives. They could be sterilized by any of the methods known or prepared as sterile solid compositions that will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile raw materials and keep them in these conditions during the entire manufacturing process.

 For rectal administration, the active ingredient may preferably be formulated as a suppository in an oily base, such as for example vegetable oils or solid semi-synthetic glycerides, or in a hydrophilic base such as polyethylene glycols (macrogol).

The compounds of the invention can also be formulated for topical application for the treatment of pathologies in areas or organs accessible by this route, such as eyes, skin and intestinal tract. Formulations they include creams, lotions, gels, powders, solutions and patches in which the compound is dispersed or dissolved in suitable excipients.

 For nasal or inhalation administration, the compound may be formulated as an aerosol from where it is conveniently released with the use of suitable propellants.

 The dosage and frequency of the doses will vary depending on the nature and severity of the disease to be treated, the age, the general condition and the weight of the patient, as well as the particular compound administered and the route of administration, among other factors. . By way of example, an adequate dosage range ranges from about 0.01 mg / kg to about 100 mg / kg per day, which can be administered as a single dose or in several doses.

Brief description of the figures

Figure 1: Anti-proliferative and cytotoxic activity of the compounds of examples 2, 7 and 1 1 in breast cancer MCF-7 cells (3 independent experiments). The invention is illustrated below by the following examples.

Examples

The following abbreviations have been used in the examples:

TLC: thin layer chromatography

CDCI ₃ : Deuterated Chloroform

EtOAc: ethyl acetate

MeOD: deuterated methanol

MEOH: methanol

HPLC: high performance liquid chromatography Example 1

a, p- (5S and 5 / ?, 6S, 7S, 8?, 8afí) -5-octylamino-6,7,8-trihydroxy-2-oxa-3- oxoindolizidine A solution of 5-hydroxy-2-oxa -3-derived oxoindolizidine (152 mg, 0.74 mmol) and n-octylamine (124 μΙ_, 0.74 mmol) in methanol (1 mL) are stirred at 65 ^e C for 2 h (control by TLC). The solvent is removed under reduced pressure to give glycosylamine (68% yield) as a mixture of the corresponding α and β anomers; α: β 6: 1 ratio (integration of H-5).

Example 2

 a- (5S, 6S, 7S, 8fí, 8a ^) - 5-OctHamino-6,7,8-trihydroxy-2-oxa-3-oxoindollzidine

The cc-anomer was obtained by purification of the α: β mixture of example 1 by chromatographic column (from 20: 1 to 10: 1 dichloromethane-methanol). Yield: 142 mg (60%). _f 0.45 (9: 1 dichloromethane-methanol). [garlic +69.2 (c 1 .0 in methanol). ¹ H NMR (500 MHz, MeOD) δ 4.64 (d, 1 H, J _5, e = 5.0 Hz, H-5), 4.50 (t, 1 H, J _{1 a} .sa = Jia .ib = 8.5 Hz, H-1 a), 4.29 (dd, 1 H, J _{1 bi8a} = 5.0 Hz, H-1 b), 3.85 (ddd, 1 H, J _8a , ₈ = 9.5 Hz, H-8a), 3.63 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 9.5 Hz, H-7), 3.49 (dd, 1 H, H-6), 3.28 (t, 1 H, H-8), 2.60 (m, 2 H, CH ₂ NH), 1.53 (m, 2 H, CH ₂ CH ₂ NH), 1 , 35 (m, 10 H, CH ₂ ), 0.92 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 160.5 (CO), 76.9 (C-8), 75.8 (C-7), 73.6 (C-6), 70.8 ( C-5), 69.2 (C-1), 55.9 (C-8a), 48.8 (CH ₂ NH), 34.3-25.0 (CH ₂ ), 15.7 (CH ₃ ). ESIMS: m / z 339.2 [M + Na] ⁺ . Anal. Caled for Ci ₅ H ₂₈ N ₂ O ₅ : C, 56.94; H, 8.92; N, 8.85. Found: C, 56.76; H, 8.83; N, 8.71.

Example 3

 (5 / ?, 6?, 7S, 8?, 8a?) - 5-Fluoro-6,7,8-tri-Oacetyl-2-oxa-3-oxolndollzldine

On the compound (5fi, 6 ^/:, 7S, 8 ^/:, 8a /???) - 5,6,7,8-tetra-0-acetyl-2-oxa-3- oxoindolizídína (560 mg, 1 .50 mmol) cooled to -40 ^S C, hydrofluoric acid / pyridine (70% hydrofluoric acid; 2.8 mL) is added. The reaction mixture is Stir at this temperature for 80 min (control by TLC), dilute with diethyl ether (30 mL), wash with a saturated solution of potassium fluoride (15 mL) and extract with diethyl ether (3 x 30 mL). The organic phase is washed with a saturated solution of sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified by chromatographic column (1: 2 EtOAc-petroleum ether) to give the title compound (300 mg, 60% yield). Starting product {Sfí ^ ñJS ^^ ea ^ -S.ej ^ -tetra-Oacetyl ^ -oxa-S-oxoindolizidine (1 50 mg, 27%) was recovered. Title compound: R / 0.77 (2: 1 EtOAc-petroleum ether). [a] _D +21.6 (c 0.9 in CHCI ₃ ). H NMR (500 MHz, CDCI ₃ ) δ 6.17 (dd, 1 H, J ₅ , F = 52.5 Hz, J ₅ , 6 = 3.5 Hz, H-5), 5.60 (t, 1 H, J ₆ , ₇ = J ?, ₈ = 10.0 Hz, H-7), 5.00 (ddd, 1 H, J _{6, F} = 14.0 Hz, H-6), 4.99 (t, 1 H, J ₈ , _8a = 10.0 Hz, H-8), 4.51 (dd, 1 H, J _{1 a, 1 b} = 9.0 Hz, J _{1 a, 8a} = 8, 0 Hz, H-1 a), 4.32 (t, 1 H, J _{1 b, 8a} = 9.0 Hz, H-1 b), 4.17-4.09 (m, 1 H, H- 8a), 2.15-2.09 (3 s, 9 H, eCO). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.0-169.5 (MeCO), 154.2 (CO), 87.5 (C-5, d, J _C5 , F = 21 1, 6 Hz), 72.0 (C-8), 69.8 (C-6, d, Jce.F = 24.8 Hz), 68.6 (C-7), 67.2 (C-1), 52.0 (C-8a), 20.4 (MeCO). ESIMS: m / z 356.1 [M + Na] ⁺ . Anal. Caled for Ci ₃ Hi ₆ NO ₈ F: C 46.85, H 4.84, N 4.20. Found: C 46.77, H 4.71, N 4.02.

Example 4

 α, β- (5 /? and 5S, 6 / ?, 7S, 8 / ?, 8a?) - 5-Octylthio-6,7,8-trihydroxy-2-oxa-3- oxoindolizidine

On a solution of (5f?, 6f?, 7S, 8f?, 8af?) -, 6,7,8-tetra-0-acetyl-2-oxa-3- oxoindolizidine (59 mg, 0.16 mmol) in Anhydrous dichloromethane (3 mL) at 0 ^e C, BF ₃ .Et ₂ O (70 ML, 0.57 mmol) and 1-octanotyl (58 pL, 0.33 mmol) are added under N ₂ atmosphere. The reaction mixture is stirred for 15 min (control by TLC), diluted with dichloromethane (25 mL), washed with water (5 mL), sodium bicarbonate (5 mL) and water (5 mL), dried with sulfate sodium anhydrous and concentrated to give the corresponding octylthioglycoside (α: β 20: 1 ratio; H-5 integration). Example 5

 a- (5H, 6? 7S, 8R a / ¾-5-Octylthio-6,7,8-tri-0-acetii-2-oxa-3-oxoindolizidine

The α-anomer was obtained by purification of the mixture: β of example 4 by chromatographic column (2: 3 EtOAc-petroleum ether). Yield: 24 mg (73%). R _f 0.75 (1: 1 EtOAc-petroleum ether). [a] _D +70.8 (c 0.7 in CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.69 (d, 1 H, J ₅ ¿= 6.0 Hz, H-5), 5.44 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 10.0 Hz, H-7), 4.97 (dd, 1 H, H-6), 4.94 (t, 1 H, J _8a , ₈ = 9.5 Hz, H-8) , 4.47 (dd, 1 H, J _{1a, 1 b} = 9.5 Hz, J _{1 a, 8a} = 8.5 Hz, H-1 a), 4.30 (dd, 1 H, J _{1b; 8a} = 6.5 Hz, H- 1 b), 4.18 (ddd, 1 H, H-8a), 2.63 (ddd, 1 H, ² J _H , _H = 12.5 Hz, ³ J _H , H = 8.5 Hz, ³ J _H , _H = 7.0 Hz, SCH ₂ ), 2.49 (ddd, 1 H, SCH ₂ ), 2.1 1 -2.05 (3 s, 9 H , MeCO), 1, 68-1, 50 (m, 2 H, SCH ₂ CH ₂ ), 1, 42-1, 24 (m, 10 H, CH ₂ ), 0.89 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). 3C NMR (125.7 MHz, CDCI ₃ ) δ 170.0-169.5 (MeCO), 155.3 (CO), 72.6 (C-8), 70.2 (C-6), 69, 9 (C-7), 66.2 (C-1), 57.7 (C-5), 51, 2 (C-8a), 31, 8-22.6 (CH ₂ ), 20.6- 20.5 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 481 .8 [M + Na] ⁺ . Anal. Caled for C21 H33NO8S: C 54.88, H 7.24, N 3.05, S 6.98. Found: C 54.75, H 7.12, N 2.89, S 6.67.

Example 6

 p- (5S, 6? 7S, 8f a ^ -5-Octylthio-6,7,8-tri-0-acetyl-2-oxa-3-oxoindolizidine

The β-anomer was obtained by purification of the α: β mixture of example 4 by chromatographic column (2: 3 EtOAc-petroleum ether). Yield: 4 mg (12%). R _f 0.53 (1: 1 EtOAc-petroleum ether). [] _D -9.0 (c 0.3 in CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.29 (dd, 1 H, J _8a , ₈ = 10.5 Hz, J ₇ , ₈ = 7.0 Hz, H-8), 5.23 (t , 1 H, J ₅ , e = Je = 4.0 Hz, H-6), 5.12 (dd, 1 H, H-7), 4.72 (d, 1 H, H-5), 4 , 42 (t, 1 H, Ji _a , ib = Jia, _8a = 8.0 Hz, H-1 a), 4.17 (t, 1 H, J _{1 b} , _8a = 9.0 Hz, H- 1 b), 4.00 (ddd, 1 H, H-8a), 2.96-2.84 (m, 2 H, SCH ₂ ), 2.15-2.10 (3 s, 9 H, MeCO ), 1, 70-1, 20 (m, 12 H, CH ₂ ), 0.90 (t, 3 H, ³ J _{H, H} = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 169.9-168.7 (MeCO), 156.1 (CO), 73.6 (C-7), 73.3 (C-6), 72 , 7 (C-8), 67.2 (C-1), 59.1 (C-5), 53.9 (C-8a), 34.3-22.6 (CH ₂ ), 20.9 -20.6 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 482.2 [M + Naj ⁺ . HRFABMS Caled for C ₂₁ H ₃₃ NO ₈ SNa [M + Na] 482.1825, found 482.1830.

Example 7

 - (5?, 6? S, 8?, 8afí) -5-Octylthio-6, 8 rihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of example 5 (54 mg, 0.12 mmol) with sodium methoxide in methanol and purified by chromatographic column (EtOAc). Yield: 36 mg (92%). R _f 0.33 (EtOAc). [a] _D +104.2 (c 0.8 in methanol). ¹ H NMR (500 MHz, MeOD) δ 5.28 (d, 1 H, J _5.6 = 5.5 Hz, H-5), 4.58 (t, 1 H, J _{1 a, 8a} = J _{1 a, 1 b} = 8.5 Hz, H-1 a), 4.30 (dd, 1 H, Chi b, 8a = 5.5 Hz, H-1 b), 3.95 (td, 1 H , J _8a = 8.5 Hz, H-8a), 3.68 (dd, 1 H, J _6i7 = 9.5 Hz, H-6), 3.55 (t, 1 H, J ₇ , ₈ = 9.5 Hz, H-7), 3.37-3.31 (m, 1 H, H-8), 2.60 (ddd, 1 H, ² J _H , H = 13.0 Hz, ³ J _H , H = 8.0 Hz, ³ J _H , _H = 6.0 Hz, SCH ₂ ), 2.53 (ddd, 1 H, SCH ₂ ), 1, 72-1, 56 (m, 2 H, SCH ₂ CH ₂ ), 1, 48-1, 28 (m, 10 H, CH ₂ ), 0.92 (t, 3 H, ³ JH, H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 157.0 (CO), 74.3 (C-8), 73.8 (C-7), 71, 1 (C-6), 66.9 (C- 1), 61, 0 (C-5), 53.1 (C-8a), 31, 6-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 355.8 [M + Na] ⁺ . Anal. Caled for C ₁₅ H ₂₇ NO ₅ S: C 54.03, H 8.16, N 4.20, S 9.62. Found: C 53.72, H 7.90, N 4.13, S 9.37.

Example 8

a, p- (5ff and 5S, 6 / ?, 7S, 8? ₅ 8a?) - 5-octyl-6,7,8-trihydroxl-2-oxa-3-oxolndollzidine

A solution of example 3 (300 mg, 0.90 mmol, 1.0 equiv.) In anhydrous toluene (10 mL) under nitrogen atmosphere is cooled to 0 ^S C. Then trioctylaluminum (3.8 mL, 1 is added) , 80 mmol, 2.0 equiv.) And the reaction is stirred for 3 h (control by TLC). It is processed with a saturated solution of ammonium chloride (10 mL) and extracted with EtOAc (3 x 30 mL). The organic phase is dried with anhydrous sodium sulfate and concentrated. The resulting residue is purified by chromatographic column (from 1: 5 to 1: 3.5 Petroleum EtOAc ether) to give the title compound (260 mg, 68% yield) as a mixture of the corresponding α and β anomers (ratio α: β 4: 1; integration of H-7).

Middle 9

 a - (5f, 6SJ?, 8f a ^ -5-OctH-6,7,8-tri- acetyl-2-oxa-3-oxoindoHzidine

The title compound was obtained from the compound of Example 8 by separation by HPLC (mobile phase EtOAc-hexane, 33:67). Colorless oil HPLC retention time: 23.6 min. R _f 0.51 (1: 1 EtOAc-petroleum ether). [a] _D +36.1 (c 1.0 in CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.34 (t, 1 H, J _6.7 = J ₇ , ₈ = 9.5 Hz, H-7), 5.04 (dd, 1 H, J _{5; 6} = 6.0 Hz, H-6), 4.96 (t, 1 H, J ₈ , _8a = 9.5 Hz, H-8), 4.41 (dd, 1 H, J _{1 a , 1b} = 9.0 Hz, J _{1 a, 8a} = 8.0 Hz, H-1 a), 4.27 (dd, 1 H, J _{1 bs8a} = 4.5 Hz, H-1 b), 4 , 31 -4.24 (m, 1 H, H-5), 3.82 (ddd, 1 H, H-8a), 2.08-2.04 (3 s, 9 H, MeCO), 1, 76-1, 53 (m, 2 H, CH ₂ ), 1, 43-1, 22 (m, 12 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H , _H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.0-169.1 (MeCO), 156.3 (CO), 72.5 (C-8), 69.9 (C-7), 69.7 (C-6), 65.5 (C-1), 52.1 (C-8a), 51, 0 (C-5), 31, 8-22.6 (CH ₂ ), 20.7-20 , 6 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 450.3 [M + Na] ⁺ . Anal. Caled for C ₂₁ H ₃₃ NO ₈ : C 59.00, H 7.78, N 3.28. Found: C 59.1 1, H 7.81, N 3.21. Example 10

 -ISS ^ SJ ^ S ^ Sa ^ -S-Octii-ej ^ -tri- ^ acetyl ^ -oxa-S-oxolndoliziclina

The title compound was obtained from the compound of Example 8 by separation by HPLC (mobile phase EtOAc-hexane, 33:67). Solid white. HPLC retention time: 26.2 min. R _/ 0.50 (1: 1 EtOAc-petroleum ether). [a] _D -14.7 (c 1.0 in chloroform). H NMR (500 MHz, CDCI ₃ ) δ 5.16 (t, 1 H, J ₆ , ₇ = J ₇ = 9.5 Hz, H-7), 5.08 (t, 1 H, J _8.8a = 9.5 Hz, H-8), 5.04 (t, 1 H, J ₅ , ₆ = 9.5 Hz, H-6), 4.33 (dd, 1 H, J _1a , _{1 b} = 9.0 Hz, J _{1 a, 8a} = 7.0 Hz, H-1 a), 4.12 (dd, 1 H, J _{1b, 8a} = 4.0 Hz, H- 1 b), 3.70 (ddd, 1 H, H-8a), 3.31 (td, 1 H, ³ J _H , H = 4.5 Hz, H-5), 2.40-2.30 (m, 1 H, CH ₂ ), 2.08-2.04 (3 s, 9 H, MeCO), 1, 80-1, 50 (m, 2 H, CH ₂ ), 1, 40-1, 20 (m, 1 1 H , CH ₂ ), 0.90 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.0- 169.2 (MeCO), 155.0 (CO), 74.1 (C-7), 71, 1 -70.9 (C-6, C-8), 69.4 (C-1), 57.7 (C-8a), 57.4 (C-5), 31, 8-22.6 (CH ₂ ), 20.6 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 450.2 [M + Naj ⁺ . Anal. Caled for C ₂ H ₃₃ N0 ₈ : C 59.00, H 7.78, N 3.28. Found: C 59.08, H 7.69, N 3.20. Example 11

 a- (5 / ?, 6S, 7fí, 8?, 8a?) - 5-OctH-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 9 (91 mg, 0.21 mmol) with sodium methoxide in methanol. Yield: 61 mg (95%). R _f 0.75 (9: 1 EtOAc-methanol). [cc] _D +42.3 (c 1.0 in methanol). ¹ H NMR (500 MHz, MeOD) δ 4.47 (dd, 1 H, J _{1 a, 1 b} = 9.0 Hz, J _{1 a, 8a} = 8.5 Hz, H-1 a), 4, 31 (dd, 1 H, J _{1 BI8A} = 4.0 Hz, H-1 b), 3.92 (ddd, 1 H, ³ J _H , H = 8.5 Hz, ³ JH, H = 3.0 Hz, J ₅ , 6 = 5.5 Hz, H-5), 3.64 (ddd, 1 H, J _8J8A = 9.5 Hz, H-8a), 3.52- 3.44 (m, 2 H, H-6, H-7), 3.25 (bt, 1 H, J _7, s = 9.5 Hz, H-8), 1, 94-1, 85 (m, 1 H, CH ₂ ), 1, 51 -1, 24 (m, 13 H, CH ₂ ), 0.92 (t, 3 H, ³ J _{H, H} = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 158.3 (CO), 74.1 (C-8), 73.3 (C-7), 70.9 (C-6), 66.1 (C- 1), 54.2 (C-5), 53.9 (C-8a), 31, 6-22.3 (CH ₂ ), 13.1 (CH ₃ ). ESIMS: m / z 324.2 [M + Na] ⁺ . Anal. Caled for Ci5H ₂₇ NO ₅ : C 59.78, H 9.03, N 4.65. Found: C 59.70, H 8.95, N 4.49.

Example 12

 (5S, 6S, 7S, 8 / ?, 8a /?) - 5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxolndolízidine

To a solution of (5S, 6S, 7S, 8fí, 8af?) - 5,6,7,8-tetrahydroxy-2-oxa-3- oxoindolizidine (151 mg, 0.74 mmol) in methanol (1 mL) was added n -butylamine (0.74 mmol) and the mixture was stirred under Ar atmosphere at 65 ^S C for 24 h. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography. Proportion α: β12: 1 (integration of H-5). Purification by column chromatography (CH ₂ CI ₂ -MeOH 20: 1 → 10: 1). Yield: 133 mg (67%). R, 0.38 (CH ₂ CI ₂ -MeOH 9: 1). [a] _D +84.1 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 4.65 (d, 1 H, J ₅ , ₆ = 5.0 Hz, H-5), 4.50 (t, 1 H, J _1a , _{1 b} = J _{1 a} , _8a = 8.5 Hz, H-1 a), 4.29 (dd, 1 H, J _{1b; 8a} = 5.0 Hz, H-1 b), 3.85 (ddd, 1 H, J _{8a, 8} = 9.5 Hz, H-8a), 3.63 (t, 1 H, J ₆ , ₇ = J _7.8 = 9.5 Hz, H-7), 3.49 (dd, 1 H, H-6), 3.28 (t, 1 H , H-8), 2.62 (ddd, 1 H, J _H , _H = 14.5 Hz, ³ J _H , H = 1 1.5 Hz, ³ J _H , H = 7.0 Hz, HHCH ₂ ), 2.58 (ddd, 1 H, NHCH ₂ ), 1 .51 (m, 2 H, NHCH ₂ CH ₂ ), 1 .45-1 .35 (m, 2 H, CH ^ CHs), 0.96 (t, 3 H, ³ J _{H ,} H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 160.5 (CO), 76.9 (C-8), 75.8 (C-7), 73.6 (C-6), 70.8 (C-5), 69.2 (C-1), 55.9 (C- 8a), 48.5 (H CH ₂ ), 34.0 (CH ₂ ), 22.7 (CH ₂ ), 15.5 (CH ₃ ). ESIMS: m / z 283.1 [M + Na] ⁺ . Analysis calculated for Ci and H ₂₀ N ₂ O ₅ : C 50.76, Η 7.74, Ν 10.76. Found: C 50.39, Η 7.58, Ν 10.54. Example 13

 (5S, 6S, 7S, 8?, 8af?) - 5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine

Following a procedure analogous to that described in the procedure of Example 14 but using hydroxyethylamine instead of n-butylamine, the title compound was obtained. Proportion α: β 7: 1 (integration of H-5). Purification by column chromatography (CH ₂ CI ₂ -MeOH 5: 1) and GPC (Sephadex G-10, MeOH-H ₂ 0 1: 1). Yield: 90 mg (76%). R, 0.41 (40: 10: 1 CH ₂ CI ₂ -MeOH-H ₂ 0). [oc] _D -3.3 (c 0.5, H ₂ 0). ¹ H NMR (500 MHz, D ₂ 0) δ 4.65 (d, 1 H, J ₅ , ₆ = 4.5 Hz, H-5), 4.54 (t, 1 H, J _{1 a} , ib = J a, _8a = 9.0 Hz, H-1 a), 4.31 (dd, 1 H, J _{1 b} , _8a = 5.0 Hz, H-1 b), 3.85 (ddd, 1 H, J _8A , ₈ = 9.5 Hz, H-8a) , 3.67 (ddd, 1 H, ² J _H = 1 1 .0 Hz, ³ JH = 6.5 Hz, ³ JH, H = 4.5 Hz, CH5OH), 3.64-3.61 (m, 2 H, H-6, H- 7), 3.60 (ddd, 1 H, CH ₂ OH), 3.44 (bt, 1 H, J ₇ , 8 = 9.5 Hz, H-8), 2.73 (ddd, 1 H, HCH ₂ ), 2.65 (ddd, 1 H, NHCH ₂ ). ¹³ C NMR (125.7 MHz, D ₂ 0) δ 158.8 (CO), 73.5 (C-8), 72.4 (C-7), 70.2 (C-6), 67.4 (C-5), 67.1 (C-1 ), 59.9 (CH≤OH), 52.9 (C-8a), 47.2 (NHCH ₂ ). ESIMS: m / z 271 .0 [M + Na] ⁺ . Analysis calculated for C ₉ H ₁₆ N ₂ O ₆ : C 43.55, H 6.50, N 1 1 .29. Found: C 43.15, H 6.33, N 1 1 .02.

Example 14

(5S, 6S, 7S, 8?, 8af -5- (4-Hydroxybutyl) -6,7,8-trlhydroxy-2-oxa-3- oxoindolizidine Following a procedure analogous to that described in the procedure of Example 14 but using 4-hydroxybutylamine instead of n-butylamine, the title compound was obtained. Proportion: β 10: 1 (integration of H-5). Purification by column chromatography (ΟΗ ₂ ΟΙ ₂ -ΜβΟΗ 5: 1). Yield: 24 mg (80%). R, 0.45 (40: 10: 1 CH ₂ CI ₂ -MeOH-H ₂ 0). [cc] _D -5.3 (c 1 .0, H ₂ 0). ¹ H NMR (500 MHz, D ₂ 0) δ 4.63 (d, 1 H, J ₅ , 6 = 4.5 Hz, H-5), 4.53 (t, 1 H, J _1a , _{1 b} = J ^ _8a = 9.0 Hz, H-1 a), 4.31 (dd, 1 H, J _{1b, 8a} = 5.0 Hz, H-1 b), 3.82 (ddd, 1 H, J _{8a, 8} = 9.5 Hz, H-8a), 3.65 -3.56 (m, 2 H, H-6, H-7), 3.54 (ta, 2 H, ³ J _H , H = 6.0 Hz, CH ₂ OH), 3.43 (ta, 1 H, J ₇ , ₈ = 9.5 Hz, H-8), 2.64-2.48 (m, 2 H, NHCH ₂ ), 1 .57-1 .44 (m, 4 H, CH ₂ CH ₂ ). ¹³ C NMR (125.7 MHz, D ₂ 0) δ 158.7 (CO), 73.5 (C-8), 72.4 (C-7), 70.1 (C-6), 67.3 (C-5), 67.0 (C-1 ), 61 .5 (OfeOH), 53.0 (C-8a), 45.5 (NHCH ₂ ), 29.2 (CH ₂ ), 24.7 (CH ₂ ). ESIMS: m / z 299.1 [M + Naj ⁺ . Analysis calculated for CnH ₂₀ N ₂ O ₆ : C 47.82, H 7.30, N 10.14. Found: C 47.49, H 7.05, N 9.85. Example 15

 (SSjeS.TSjSff.Sa/^-S-ÍPent-S-í--aminoí-e .e-trihydroxy ^ -oxa-S- oxoindolizidine

Following a procedure analogous to that described in the procedure of example 14 but using 3-pentylamine instead of n-butylamine, the title compound was obtained. Purification by column chromatography (CH ₂ CI ₂ -MeOH 5: 1). Yield: 24 mg (70%). R; 0.81 (CH ₂ CI ₂ -MeOH / H ₂ 0 40: 10: 1). [] _D +81 .7 (c 0.75, MeOH). ¹ H NMR (500 MHz, MeOD) δ 4.75 (d, 1 H, J _5, e = 5.0 Hz, H-5), 4.48 (t, 1 H, J _{1 a, 1 b} = J _{1a, 8a} = 9.0 Hz, H-1 a), 4.29 (dd, 1 H, J _{1 5a} = 5.0 Hz, H-1 b), 3.91 (ddd, 1 H, J _{8a, 8} = 9.5 Hz, H-8a), 3.65 ( t, 1 H, J _6.7 = J _7.8 = 9.5 Hz, H-7), 3.49 (dd, 1 H, H-6), 3.28 (t, 1 H, H-8), 2.42-2.35 (m, 1 H, H-3 ^' ), 1 .58-1.43 (m, 2 H, H- 2 ^' ), 1 .39-1 .28 (m, 2 H, H-4 ^' ), 0.95 ( t, 3 H, ³ J _HJ H = 7.0 Hz, CH ₃ ), 0.94 (t, 3 H, ³ J _HJ H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 157.7 (CO), 74.3 (C-8), 73.2 (C-7), 71 .1 (C-6), 66.5 (C-1), 66.4 (C-5 ), 57.1 (C-3 ^' ), 53.3 (C-8a), 26.7 (CH ₂ ), 24.9 (CH ₂ ), 9.5 (CH ₃ ), 8.4 (CH ₃ ). ESIMS: m / z 275.2 [M + Hj ⁺ . Calculated analysis for C12H22N2O5: C 52.54, H 8.08, N 10.21. Found: C 52.35, H 7.76, N 10.04.

Example 16

 (5S, 6? S, 8ff at ^ -5-ButHamino-6,7,8-tnhydroxy-2-oxa-3-oxoindolizidine

To a solution of (5S, 6f, 7S, 8f?, 8afi) -5,6,7,8-tetrahydroxy-2-oxa-3- oxoindolizidine (151 mg, 0.74 mmol) in MeOH (1 mL) was added n -butylamine {0.74 mmol) and the mixture was stirred under an atmosphere of Ar at 50 ^S C for 24 h. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography. Eluent CH ₂ Cl ₂ -MeOH-H ₂ O 70: 10: 1. Yield: 72 mg (38%). R, 0.41 (CH ₂ Cl ₂ -MeOH-H ₂ O 40: 10: 1). [] _D =. 18.3 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 4.60 (d, 1 H, J _5S = 2.5 Hz, H-1), 4.51 (t, 1 H, J _{1 a} , _1b = Jsaja = 9.0 Hz, H-1 a ), 4.31 (dd, 1 H, J _8a , _1b = 4.5 Hz, H-1 b), 3.97 (ta, 1 H, J ₆ , ₇ = 2.5 Hz, H-6), 3.75 (m, 1 H, H-8a), 3.70 (m, 2 H, H-7, H-8), 2.60 (m, 2 H, CH ₂ N), 1.48 (m, 2 H, CH ₂ CH ₂ N), 1 .38 (m, 2 H, CH ₂ ), 0.95 (t, 3 H, ³ J _H , _H = 7.5 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 158.9 (CO), 71 .7 (C-2), 71 .0 (C-4), 70.7 (C-1) 70.6 (C-3), 66.5 (C- 6), 54.3 (C-5), 45.4 (CH ₂ N), 31 .2 (CH ₂ CH ₂ N), 20.1 (CH ₂ ), 12.9 (CH ₃ ). MS (FAB): m / z 283 (50%, [M + Na] ⁺ ), 261 (20%, [M + H] ⁺ ). Analysis calculated for C11 H20N2O5: C, 50.76; H, 7.74; N, 10.76. Found: C, 50.39; H, 7.42; N, 10.44.

Example 17

(5S, 6?, 7S, 8?, 8a /?) - 5-Oct «lamlno-6,7,8-trlh» droxi-2-oxa-3-oxoindoliz »dlna

Following a procedure analogous to that described in example 16 procedure but using octylamine instead of n-butylamine, ^and 65 C for 24 h and the title compound was obtained. Eluent ΟΗ ₂ ΟΙ ₂ -ΜΘΟΗ 20: 1 → 10: 1. Yield: 144 mg (60%). R 0.15 (CH ₂ CI ₂ -MeOH 10: 1). [oc] _D = 20.6 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD, 313 K) δ 4.61 (d, 1 H, J _5.6 = 2.0 Hz, H-5), 4.50 (t, 1 H, J _1a , _{1 b} = J _a = 9.0 Hz, H-1 a), 4.46 (dd, 1 H, J _8a , _1b = 4.5 Hz, H-1 b), 3.97 (dd, 1 H, J _6.7 = 2.5 Hz, H-6), 3.75 (m, 1 H, H-8a), 3.70 (m, 2 H, H-7, H-8), 2.60 ( m, 2 H, CH ₂ N), 1 .53 (m, 2 H, CH ₂ CH ₂ N), 1 .33 (m, 10 H, CH ₂ ), 0.92 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR {125.7 MHz, MeOD, 313 K) δ 158.9 (CO), 71 .8 (C-6), 71 .2 (C-7), 70.7 (C-5, C-8), 66.5 (C -1), 54.3 (C-8a), 45.8 (CH ₂ N), 31 .6 (CH ₂ CH ₂ N), 29.1, 28.9, 27.0, 22.4 (CH ₂ ), 12.9 (CH ₃ ). MS (FAB): / z 339 (40%, [M + Na] ⁺ ), 315 (15%, [M + H] ⁺ ). Analysis calculated for Ci ₅ H ₂ gN ₂ 05: C, 56.94; H, 8.92; N, 8.85. Found: C, 56.61; H, 8.73; N, 8.50.

Example 18

 (SS ^ fí ^ S.S ^ ea ^ -S ^ -Hydroxyethylaminoi-e ^ .S-trihydroxy ^ -oxa-a- oxoindoiizidine

Following a procedure analogous to that described in example 16 but procedure using 2-hydroxyethylamine instead of n-butylamine, and 65 ^Q C for 24 h the title compound was obtained. Eluent: 100: 10: 1 → 30: 10: 1 CH ₂ CI ₂ -MeOH-H ₂ 0. Yield: 122 mg (67%). [ocj _D. 6.7 (c 1 .0, H ₂ 0). ñ _f 0.17 (40: 10: 1 CH ₂ CI ₂ -MeOH-H ₂ 0). ¹ H NMR (300 MHz, MeOD) δ 4.64 (d, 1 H, J ₅ , e =

2.1 Hz, H-5), 4.54 (t, 1 H, J _{1 a} , _1b = Jfe _a , _1a = 8.7 Hz, H-1 a), 4.33 (dd, 1 H, J _8a , i _b =

4.2 Hz, H-1 b), 4.00 (t, 1 H, J ₆ = 2.1 Hz, H-6), 3.80 (m, 1 H, H-7), 3.67 (m, 4 H, H-3, H-4, CH ₂ OH), 2.76 (m, 2 H, CH ₂ NH ₂ ). ¹³ C NMR (75.5 MHz, MeOD) δ 158.3

(CO), 73.2 (C-6), 72.5 (C-7), 72.0 (C-8, C-5), 68.0 (C-1), 61 .8 (CH ₂ OH), 54.6 (C-8a ), 48.9 (CH ₂ NH ₂ ), 31 .6 (CH ₂ CH ₂ N). FABMS: m / z 271 (90%, [M + Na] ⁺ ), 249 (12%, [M + H] ⁺ ).

Example 19

(5S, 6fí, 7S, 8 / ?, 8a?) - 5- (3-Pentylamino) -6,7,8-trihydroxy-2-oxa-3- oxoindoiizidine Following a procedure analogous to that described in the procedure of Example 16 but using 3-pentylamino instead of n-butylamine, at 65 ^S C and for 30 h the title compound was obtained. Eluent: 100: 10: 1 CH ₂ CI ₂ -MeOH- H ₂ 0. Yield: 133 mg (63%). [<x] _D. 38.8 (c 1 .0, MeOH). R, 0.5 (40: 10: 1 CH ₂ CI ₂ - MeOH-H ₂ 0). ¹ H NMR (300 MHz, CD ₃ OD) δ 4.70 (d, 1 H, J _{5: 6} = 2.1 Hz, H-5), 4.47 (t, 1 H, J _1a , _{1 b} = J _8a , i _a = 9.0 Hz, H-1 a), 4.28 (dd, 1 H, J _8a , _1b = 4.5 Hz, H-1 b), 3.93 (t, 1 H, J ₆ = 2.1 Hz, H-6), 3.77 (td, 1 H, J _8.8a = 9.0 Hz, H-8a), 3.72 (dd, 1 H, J _7i8 = 9.0 Hz, H-7), 3.67 (t, 1 H, H-8), 2.38 (m, 1 H, CHNH), 1 .50 (m, 2 H, CH ₂ ), 1 .32 (m, 2 H, CH ₂ ), 0.93 (t, 3 H, ³ J _H , _H = 7.2 Hz , CH ₃ ), 0.89 (t, 3 H, ³ J _H , H = 7.2 Hz, CH ₃ ). ¹³ C NMR (75.5 MHz, CD ₃ OD) δ 160.2 (CO), 73.5 (C-6), 72.6 (C- 7), 72.1 (C-8), 70.1 (C-5), 67.9 (C-1 ), 57.9 (CHN), 55.8 (C-8a), 27.6, 26.4 (CH ₂ ), 1 1 .0, 9.9 (CH ₃ ). FABMS: m / z 297 (75%, [M + Na] ⁺ ), 275 (12%, [M + H] ⁺ ). Analysis calculated for d ₂ H ₂₂ N ₂ 0 ₅ : C, 52.54; H, 8.08; N, 10.21. Found: C, 52.18; H, 7.71; N, 9.93.

Example 20

 (5S, 6S, 7S, 8 ^, 8a?) - 5-lothiocyanate-6,7,8-tri-0-acetyl-2-oxa-3-oxoindolizidine

To a solution of (5R, 6R, 7S, 8R, 8aR) -3-oxohexahydro-1 H-oxazolo [3,4- a] pyridine-5,6,7,8-tetrayl tetraacetate (60 mg, 0.16 mmol) and SnCI ₄ (160 μ [_, 1 M in CH ₂ CI ₂ ) in CH CI ₂ (2 mL), stirred under Ar atmosphere for 5 min, TMSNCS (25 μ [_, 0.18 mmol) was added and the mixture The reaction was stirred at room temperature for 15 min. It was washed with a saturated aqueous solution of NaHC0 ₃ (2 x 15 mL) and the aqueous phase was extracted with CH ₂ CI ₂ (3 x 15 mL). The organic extracts were washed with H ₂ 0 (10 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated under reduced pressure. The crude was purified by column chromatography (1: 1 AcOEt-petroleum ether). Yield: 41 mg (69%). R _f O.67 (1: 1 AcOEt / petroleum ether). [<x] _D +79.6 (c 1 .0, CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.09 (d, 1 H, J ₅ , ₆ = 4.5 Hz, H-5), 5.51 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 10.0 Hz , H-7), 5.02 (dd, 1 H, H-6), 4.95 (t, 1 H, J ₈ , _8a = 10.0 Hz, H-8), 4.49 (dd, 1 H, J _{1 a, 1 b} = 9.5 Hz, J _{1 a, 8a} = 8.0 Hz, H-1 a), 4.30 (dd, 1 H, J _{1 b; 8a} = 8.0 Hz, H-1), 4.03 (dt, 1 H, H-8a), 2.17-2.09 (3 s, 9 H, MeCO). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.0-169.5 (MeCO), 154.4 (CO), 145.2 (CS), 71 .8 (C-8), 70.2 (C-6), 69.0 (C- 7) , 66.8 (C-1), 63.3 (C-5), 52.3 (C-8a), 20.5-20.3 (MeCO). ESIMS: m / z 394.9 [M + Naj ⁺ . Analysis calculated for C ₄ H ₁₆ N ₂ 0 ₈ S: C 45.16, H 4.33, N 7.52, S 8.61. Found: C 45.15, H 4.22, N 7.26, S 8.33.

Example 21

 (5S, 6S, 7S, 8f?, 8afí) -5- (Octiltioureido) -6,7,8-tri-0-acetii-2-oxa-3- oxoindolizidine

To a solution of the compound obtained in example 19 (67 mg, 0.18 mmol) and octylamine hydrochloride (30 mg, 0.18 mmol, 1.0 equiv.) In DMF (2 mL) was added Et ₃ N (25 μί, 0.18 mmol) in DMF (10 mL). The reaction mixture was stirred for 45 min, the solvent was removed under reduced pressure and the crude was purified by column chromatography (3: 2 AcOEt-petroleum ether). Yield: 86 mg (95%). R, 0.65 (2: 1 AcOEt-petroleum ether). [a] _D +64.0 (c 1 .0, CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.46 (sa, 1 H, NH), 6.43 (d, 1 H, J _NH , ₅ = 5.0 Hz, NH), 5.69 (t, 1 H, J ₅ , e = 5.0 Hz, H-5), 5.45 (dd, 1 H, J ₆ , ₇ = 10.0 Hz, J _7i8 = 9.0 Hz, H-7), 5.07 (dd, 1 H, H-6), 4.96 (t , 1 H, J ₈ , _8a = 9.0 Hz, H-8), 4.54 (t, 1 H, J _{1 a} , _1b = J _1a , _8a = 9.0 Hz, H-1 a), 4.39 (dd, 1 H , J _{1b, 8a} = 7.5 Hz, H-1 b), 4.06 (m, 1 H, H-8a), 3.61 - 3.55 (m, 2 H, H CH ₂ ), 2.16-2.09 (3 s, 9 H , MeCO), 1 .75-1 .60 (m, 2 H, NHCH ₂ CH ₂ ), 1 .40-1 .22 (m, 10 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ³ C NMR (125.7 MHz, CDCI ₃ ) δ 181 .9 (CS), 170.0-169.4 (MeCO), 157.1 (CO), 72.4 (C-8), 68.4 (C-7), 68.2 (C-6) , 67.5 (C-1), 58.4 (C-5), 51 .8 (C-8a), 46.9 (NHCH ₂ ), 31 .8-22.6 (CH ₂ ), 20.6-20.4 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 524.0 [M + Na] ⁺ . Analysis calculated for C ₂₂ H ₃₅ N ₃ O ₈ S: C 52.68, H 7.03, N 8.38, S 6.39. Found: C 52.49, H 6.80, N 8.12, S 6.09.

Example 22

(5S, 6S, 7S, 8fí, 8a?) - 5- (Octiltioureido) -6 ₅ 7,8-trihydroxy-2-oxa-3- oxoindolizidine The title compound was obtained by deacetylation of the compound obtained in Example 21. Yield: 19 mg (95%). R _/ 0.40 (10: 1 CH ₂ CI ₂ -MeOH). [cc] _D -12.4 (c 0.8, DMSO). ¹ H NMR (500 MHz, MeOD, 313 K) δ 5.83 (d, 1 H, J _{5 <6} = 5.0 Hz, H-5), 4.50 (t, 1 H, J _{1 a} , _{1 b} = J _{1 a} , _8a = 9.0 Hz, H-1 a), 4.31 (dd, 1 H, J _{1 b} , _8a = 5.0 Hz, H-1 b), 3.70-3.65 (m, 2 H, H-6, H-8a ), 3.59-3.52 (m, 3 H, H-7, H CH ₂ ), 3.37-3.30 (m, 1 H, H-8), 1 .65-1 .55 (m, 2 H, NHCH ₂ CH ₂ ), 1 .45-1 .25 (m, 10 H, CH ₂ ), 0.92 (t, 3 H, ³ J _{H. H} = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD, 313 K) δ 183.5 (CS), 157.1 (CO), 73.5 (C-8), 73.3 (C-7), 69.7 (C-6), 66.4 (C-1) , 62.5 (C-5), 53.6 (C-8a), 44.7 (N CH ₂ ), 31 .6-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 398.0 [M + Na] ⁺ . Analysis calculated for C ₁₆ H ₂₉ N ₃ O ₅ S: C 51 .18, H 7.78, N 1 1 .19, S 8.54. Found: C 50.84, H 7.48, N 10.82, S 8.20.

Example 23

 (5S, 6R S ^ H, 8a / ¾-5-isothiocyanate-6,7,8-tri-0-acetyl-2-oxa-3-oxoindolizidine

To a solution of (5S, 6R, 7S, 8fí, 8afí) -5,6,7,8-tetra-0-acetyl-2-oxa-3- oxoindolizidine (179 mg, 0.48 mmol; prepared according to the method described by P. Díaz-Pérez et al. in Eur. J. Org. Chem., 2005, 2903-2913) and SnCI ₄ (477 μΙ_, 0.48 mmol, 1 M in CH ₂ CI ₂ ), stirred under Ar atmosphere for 5 min, TMSNCS (75 μΙ_, 0.53 mmol) was added and the reaction mixture was stirred for 3 h. CH ₂ CI ₂ (15 mL) was added and washed with saturated aqueous NaHCO ₃ solution (10 mL). The aqueous phase was extracted with CH ₂ CI ₂ (3 x 15 mL) and the organic extracts dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (1: 1 AcOEt-petroleum ether). Yield: 146 mg (78%). [a] _D. 39.1 (c 1 .0, CH ₂ CI ₂ ). R _f 0.76 (2: 1 AcOEt-petroleum ether). ¹ H NMR (300 MHz, CDCI ₃ ) δ 5.70 (d, 1 H, J ₅ , ₆ = 2.4 Hz, H-5), 5.36 (m, 2 H, H-6, H-7), 5.21 (t , 1 H, J ₇ , ₈ = J _8.8a = 9.6 Hz, H-8), 4.48 (dd, 1 H, J _{1 ab} = 9.3 Hz, J _{8a, 1 a} = 8.1 Hz, H-1 a) , 4.36 (dd, 1 H, J _8a , _b = 5.7 Hz, H-1 b), 4.00 (ddd, 1 H, H-8a), 2.14, 2.09, 2.01 (3 s, 9 H, MeCO). ¹³ C NMR (75.5 MHz, CDCI ₃ ) δ 170.3, 169.6, 169.5 (MeCO), 155.4 (CO carbamate), 144.9 (NCS), 69.6 (C-6), 68.9 (C-8), 68.1 (C-7 ), 66.6 (C-1), 64.4 (C-5), 53.4 (C-8a), 20.7 (MeCO). FABMS: m / z 395 (20%, [M + Na] ⁺ ), 314 (35%, [M ^~ NCS] ⁺ ). Analysis calculated for C ₁₄ H ₁₆ N ₂ O ₈ S: C, 45.16; H, 4.33; N, 7.52; S, 8.61. Found: C, 45.01; H, 4.25; N, 7.35; S, 8.37.

Example 24

 (5S, 6? S, 8 / ?, 8aff) -5-Thioureido-6,7,8-tn-0-acetyl-2-oxa-3-oxoindoliziclina

To a solution of the compound obtained in example 20 (159 mg, 0.43 mmol) and Et ₃ N (59 μΙ_, 0.43 mmol) in DMF (1.7 mL) was added, under Ar atmosphere and dropwise, a solution of 9-fluorenylmethylcarbamate (1 12 mg, 0.47 mmol) in DMF (10 mL). The reaction mixture was stirred for 24 h at 40 ⁹ C. The solvent was removed under reduced pressure and the residue was purified by 2: 1 column chromatography AcOEt-petroleum ether → 45: 5: 3 AcOEt-EtOH-H ₂ 0 Yield: 132 mg (79%). [a] _D. 9.3 (c 1 .0, CH ₂ CI ₂ ). Rf 0.08 (2: 1 AcOEt-petroleum ether). ¹ H NMR (500 MHz, CDCI ₃ , 313 K) δ 7.67 (sa, 1 H, NH), 7.83 (sa, 2 H, NH), 5.47 (t, 1 H, J ₅ , ₆ = J _{1 jNH} = 2.0 Hz, H-5), 5.44 (dd, 1 H, J _7.8 = 9-3 Hz, J ₆ , ₇ = 5.0 Hz, H-7), 5.18 (t, 1 H, J ₈ , _8a = 9.3 Hz, H-8), 4.53 (t, 1 H, J _{1 a} , _{1 b} = J _{8a, 1 a} = 9.3 Hz, H-1 a), 4.37 (dd, 1 H, J _8a , _{1 b} = 5.5 Hz, H-1 b), 4.12 (m, 1 H, H-8a), 2.13, 2.04, 2.02 (3 s, 9 H, MeCO). ¹³ C NMR (100.6 MHz, CDCI ₃ , 313K) δ 183.3 (CS), 170.4, 170.1, 170.0 (MeCO), 157.4 (CO), 69.8 (C-6), 69.3 (C-8), 68.9 (C- 7), 67.3 (C-1), 62.9 (C-5), 60.5 (C-8a), 31 .8, 29.2, 20.8, 20.7 (MeCO). FABMS: m / z 412 (100%, [M + Na] ⁺ ), 390 (30%, [M. H] ⁺ ). Anal. Caled for C ₄ H ₁₉ N ₃ O ₈ S: C, 43.18; H, 4.92; N, 10.79; S, 8.23. Found: 0.43.35; H, 5.20; N, 10.55; S, 7.94. Example 25

 (5S, 6?, 7S, 8?, 8aff) -5-thioureido-6, 8-trihydroxy-2-oxa-3-oxolndoHzidine

The title compound was obtained by deacetylation of 1 - ((5S, 6R, 7S, 8R, 8aR) - 6,7,8-trihydroxy-3-oxohexahydro-1 H-oxazolo [3,4-a] pyridin-5- and l) thiourea (92 mg, 0.24 mmol) in MeOH (4.5 mL) with NaMeO (1 M in MeOH, 0.1 eq per mole of acetate) for 30 min, followed by neutralization with solid CO ₂ , and purification by column chromatography ( 10: 1: 1 CH ₃ CN-H ₂ 0-NH ₄ OH). Yield: 44 mg (71%). [ocj _D. 4.44 (c 1 .0, H ₂ 0). R, 0.21 (10: 1: 1 CH ₃ CN-H ₂ 0-NH ₄ OH). ¹ H NMR (500 MHz, MeOD, 313 K) δ 5.82 (sa, 1 H, H-5), 4.52 (dd, 1 H, J _{1 a, 1b} = sa = 9-0 Hz, H-1 a) , 4.31 (dd, 1 H, J _8a , _{1 b} = 4.5 Hz, H-1 b), 4.13 (t, 1 H, J ₅ , ₆ = J ₆ , ₇ = 2.5 Hz, H-6), 3.74 ( t, 1 H, J _7.8 = J ^ a = 9.0 Hz, H-8), 3.71 (m, 1 H, H-8a), 3.64 (dd, 1 H, H-7). ¹³ C NMR (125.7 MHz, MeOD, 313 K) δ 184.9 (CS), 159.4 (CO), 72.4 (C-7), 72.1 (C-8), 71 .4 (C-6), 68.2 (C- 1), 67.2 (C-5), 56.6 (C-8a). Analysis calculated for C ₈ H ₁₃ N ₃ O ₅ SH ₂ O: C, 34.16; H, 5.37; N, 14.94; S, 1 1 .40. Found: C, 34.10; H, 5,402; N, 14.81; S, 1 1 .23. Example 26

 (5S, 6?, 7S, 8?, 8afí) -5- (OctHtioureido) -6,7,8-tri-0-acetyl-2-oxa-3- oxoindolizidine

To a solution of the compound obtained in example 19 (137 mg, 0.37 mmol) and Et ₃ N (51 μΙ_, 0.37 mmol) in DMF (10 mL) was added, under Ar atmosphere and dropwise, a solution of octylamine (67 μΙ_, 0.41 mmol) in DMF (14 mL). The reaction mixture was stirred for 45 min at 40 ^S C. The solvent was removed under reduced pressure and the residue was purified by column chromatography (3: 2 AcOEt-petroleum ether). Yield: 145 mg (79%). [a] _D. 16.9 (c 1 .0, CH ₂ CI ₂ ). ñf 0.56 (2: 1 AcOEt-petroleum ether). ). ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.20, 7.09 (2 s, 2 H, NH), 5.42 (m, 2 H, H-5, H-6), 5.38 (dd, 1 H, J /, 8 = 9.0 Hz, J ₆ = 2.1 Hz, H-7), 5.15 (t, 1 H, _8a = 9.0 Hz, H-8), 4.51 (t, 1 H, J _1a , _{1 b} = J _{8a, 1a} = 9.0 Hz, H-1 a), 4.40 (dd, 1 H, J _8a , _{1 b} = 6.0 Hz, H-1 b), 4.06 (m, 1 H, H-8a), 3.55 (m, 2 H , CH ₂ N), 2.15, 2.09, 2.03 (3 s, 9 H, MeCO), 1 .61 (m, 2 H, CH ₂ ), 1 .26 (m, 10 H, CH ₂ ), 0.86 (t , 3 H, ³ J _H , H = 6.9 Hz, CH ₃ ). ³ C NMR (75.5 MHz, CDCI ₃ ) δ 181 .2 (CS), 170.2, 169.8, 169.6 (MeCO), 157.5 (CO), 70.0 (C-6), 68.9 (C-8), 68.4 (C- 7), 67.4 (C-1), 61 .4 (C-5), 53.1 (C-8a), 46.6 (CH ₂ N), 31.8, 29.2, 29.1, 28.5, 26.9, 22.6 (CH ₂ ), 20.7 , 20.6, 20.5 (MeCO), 14.0 (CH ₃ ). FABMS: m / z 524 (70%, [M + Na] ⁺ ), 502 (50%, [MH] ⁺ ). Analysis calculated for C ₂₂ H ₃₅ N ₃ O ₈ S: C, 52.68; H, 7.03; N, 8.38; S, 6.39. Found: C, 52.60; H, 6.94; N, 8.19; S, 6.25.

Example 27 (SS ^ fixes ^ ffjea ^ -S-tOctiltioureidoí-e ^ .S-trihydroxy ^ -oxa-a- oxoindoiizidine

The title compound was obtained by deacetylation of example 26 (92 mg, 0.18 mmol) in MeOH (4 mL) with NaMeO (1 M in MeOH, 0.1 eq per mole of acetate) for 30 min, followed by neutralization with solid C0 ₂ , and purification by column chromatography (45: 5: 3 AcOEt-EtOH-H ₂ 0). Yield: 60 mg (89%). [aj _D 59.2 (c 1 .0, MeOH). R _f 0.45 (45: 5: 3 AcOEt-EtOH-H ₂ O). H NMR (300 MHz, MeOD, 313 K) δ 5.89 (sa, 1 H, H-5), 4.52 (dd, 1 H, J _{1a, 1 b} = 9.0 Hz, J _8a = 8.1 Hz, H-1 a ), 4.31 (dd, 1 H, J _{8a b} = 4.5 Hz, H-1 b), 4.12 (m, 1 H, H-6), 3.74 (t, 1 H, J7.8 = s.sa = 9.3 Hz, H-8), 3.72 (m, 1 H, H-8a), 3.62 (dd, 1 H, J ₆ , ₇ = 2.7 Hz, H-7), 3.51 (ta, 2 H, ³ J _H , _H = 7.0 Hz, CH ₂ NH), 1.56 (m, 2 H, CH ₂ ), 1.31 (m, 10 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H , H = 7.2 Hz, CH ₃ ). ¹³ C NMR (75.5 MHz, MeOD, 313 K) δ 183.7 (CS), 159.5 (CO), 72.4 (C-7), 72.2 (C-8), 71 .4 (C-6), 68.2 (C- 1), 66.6 (C-5), 56.6 (C-8a), 45.9 (CH ₂ N), 33.0, 30.4, 30.3, 30.0, 28.0, 23.7 (CH ₂ ), 14.5 (CH ₃ ). FABMS: m / z 398 (100%, [M + Na] ⁺ ), 376 (10%, [MH] ⁺ ). Analysis calculated for CieHsgNgOsS: C, 51 .18; H, 7.78; N, 1 1 .19; S, 8.54. Found: C, 50.92; H, 7.52; N, 1 1 .1 1; S, 8.32.

Example 28

(5S, 6S, 7S, 8 / ?, 8a /?) - 5- (W ^' -OctHcarbodimide) -6 ₅ 7,8-trí-0-acetyl-2-oxa-3- oxoindolizidine

To a solution of the compound obtained in example 26 (97 mg, 0.19 mmol) in CH ₂ CI ₂ -H ₂ O (1: 1, 4 mL) was added HgO (126 mg, 0.58 mmol, 3.0 equiv.) And the The reaction mixture was stirred at room temperature for 1 h, CH ₂ CI ₂ was added and the organic phase was separated. The organic extracts were dried (Na ₂ SO ₄ ), filtered over Celite, concentrated and the crude was purified by column chromatography (2: 1 AcOEt-petroleum ether). Yield: 76 mg (84%). R _f 0.73 (2: 1 AcOEt-petroleum ether). [oc] _D +41 .7 (c 1 .0, CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.72 (d, 1 H, J _5j6 = 4.5 Hz, H-5), 5.53 (t, 1 H, J _6j7 = J ₇ , ₈ = 9.5 Hz, H-7 ), 4.97 (dd, 1 H, H-6), 4.92 (t, 1 H, Jfe _i8a = 9.5 Hz, H-8), 4.43 (t, 1 H, J _{1a, 1 b} = J _{1 a} , _8a = 8.5 Hz, H-1 a), 4.25 (t, 1 H, Ji _b , _8a = 8.5 Hz, H-1 b), 4.07 (m, 1 H, H-8a), 3.33 ( dd, 1 H, ² J _H , H = 13.0 Hz, ³ J _H , H = 7.0 Hz, CH ₂ ), 3.28 (dd, 1 H, NCH ₂ ), 2.12-2.06 (3 s, 9 H, MeCO) , 1 .65-1 .58 (m, 2 H, NChfeCH *), 1 .41 -1 .24 (m, 10 H, CH ₂ ), 0.90 (t, 3 H, ³ J _{H. H} = 7.0 Hz , CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.1 - 169.5 (MeCO), 155.1 (CO), 137.0 (NCN), 72.4 (C-8), 70.9 (C-6), 69.3 (C-7), 66.7 (C-1), 63.0 (C-5), 52.0 (C-8a), 46.4 (NCH ₂ ), 31 .8-22.6 (CH ₂ ), 20.6-20.5 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 490.0 [M + Na] ⁺ . Analysis calculated for C ₂₂ H ₃₃ N ₃ 0 ₈ : C 56.52, H 7.1 1, N 8.99. Found: C 56.58, H 7.03, N 8.76. Example 29

Hydrochloride (5S, 6S, 7S, 8fl, 8a /?) - 5 - (/ V -Octil- / V ^' -octylguanidino) -6,7,8-tri-

0-acetiI-2-oxa-3-oxoindoIizidina

To a solution of the compound obtained in example 28 (23 mg, 0.049 mmol) in DMF (2 mL), octylamine hydrochloride (46 mg, 0.28 mmol, 5.7 equiv.) Was added. The reaction mixture was stirred at 100 ^S C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH ₂ CI ₂ (20 mL) and washed with water (5 mL). The organic extracts were dried (Na ₂ S0 ₄ ) and concentrated. The crude was purified by column chromatography (AcOEt-MeOH 6: 1). Yield: 18 mg (68%); R _f 0.57 (AcOEt-MeOH 3: 1). [oc] _D +60.7 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.83 (d, 1 H, J ₅ , e = 6.0 Hz, H-5), 5.83 (t, 1 H, J ₆ , 7 = J ₇ , ₈ = 9.5 Hz, H-7), 5.30 (dd, 1 H, H-6), 5.16 (t, 1 H, J ₈ , _8a = 9.5 Hz, H-8), 4.63 (t, 1 H, J _{1 a, 1 b} = J _{1a, 8a} = 9.0 Hz, H-1 a), 4.41 (dd, 1 H, J _{1 bs8a} = 7.5 Hz, H-1 b), 4.23-4.13 (m, 1 H, H-8a), 3.40 -3.25 (m, 4 H, NHCH ₂ ), 2.12-2.07 (3 s, 9 H, MeCO), 1.75-1 .60 (m, 4 H, CH ₂ ), 1 .50-1 .25 ( m, 20 H, CH ₂ ), 0.93 (t, 6 H, ³ J _H, H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 170.2-169.4 (MeCO), 158.0 (CN), 155.4 (CO), 72.0 (C-8), 68.9 (C-7), 68.6 (C-6), 68.0 ( C-1), 58.5 (C-5), 52.2 (C-8a), 42.4 (NHCH ₂ ), 31 .6-22.3 (CH ₂ ), 19.2-19.0 (MeCO), 13.0 (CH ₃ ). ESIMS: m / z 597.2 [M - Cl] ⁺ . Analysis calculated for C ₃₀ H ₅₃ CIN ₄ O ₈ : C 56.90, H 8.44, N 8.85. Found: C 56.53, H 8.12, N 8.51.

Example 30 (5S, 6S, 7S, 8?, 8a?) - 5 - (/ V -Octyl-W ^" -octylguanidine) -6,7,8- trihydroxy-2-oxa-3-oxoindoIizidine hydrochloride

To a solution of the compound obtained in example 29 (17 mg, 0.027 mmol) in MeOH (2 mL), NaOMe (1 M in MeOH, 0.1 equiv per mole of acetate) was added. The reaction mixture was stirred at room temperature for 1 h, neutralized with solid CO ₂ , concentrated and purified by column chromatography (CH ₂ Cl ₂ -MeOH 4: 1). The product was lyophilized at room temperature of a 0.1 M HCI solution. Yield: 5.5 mg (74%). R, 0.44 (CH ₂ CI ₂ -MeOH 5: 1). [] _D +31 .7 (c 0.4, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.39 (d, 1 H, J ₅ , 6 = 6.0 Hz, H-5), 4.63 (t, 1 H, J _1a , _{1 b} = J _{1 a} , _8a = 8.5 Hz, H-1 a), 4.31 (ta, 1 H, J _1b , _8a = 8.5 Hz, H-1 b), 3.86 (m, 1 H, J ₈ , _8a = 8.5 Hz, H-8a), 3.82 (dd, 1 H, J ₆ , ₇ = 9.0 Hz, H-6), 3.74 (t, 1 H, J _7.8 = 9.0 Hz, H-7), 3.42 (t, 1 H, H-8) , 3.38-3.25 (m, 4 H, NHCH ₂ ), 1 .71 -1.63 (m, 4 H, CH ₂ ), 1 .45-1 .27 (m, 20 H, CH ₂ ), 0.93 (t, 6 H, ³ J _{H, H} = 7.0 Hz, CH ₃ ). ³ C NMR (125.7 MHz, MeOD) δ 158.3 (CN), 155.8 (CO), 73.8 (C-8), 72.7 (C-7), 69.6 (C-6), 68.2 (C-1), 61. 6 (C-5), 53.8 (C-8a), 42.1 (NHCH ₂ ), 31 .6-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 471 .1 [M - Cl] ⁺ . HRFABMS Caled for C ₂₄ H ₄₇ N ₄ O ₅ [M-Cl] ⁺ 471 .3546, Found 471 .3528.

Example 31

(5S, 6?, 7S, 8?, 8af?) - 5- (W ^' -Octiicarbodiimido) -6,7,8-tri-0-acetyl-2-oxa-3- oxoindoiizidine

To a solution of the compound obtained in example 21 (206 mg, 0.41 mmol) in CH ₂ CI ₂ -H ₂ O (1: 1, 9 mL) was added HgO (254 mg, 1.23 mmol, 3 eq) and The reaction mixture was stirred at room temperature for 45 min, CH ₂ CI ₂ (9 mL) was added and the organic phase was separated. The organic extracts were dried (Na ₂ SO ₄ ), filtered over Celite, concentrated and the crude was purified by column chromatography (AcOEt-petroleum ether 1: 2 → 2: 1). Yield: 154 mg (80%). [cc] _D. 18.3 (c 1 .0, CH ₂ CI ₂ ). _{f f} 0.72 (AcOEt-petroleum ether 2: 1). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.43 (d, 1 H, J _5.6 = 3.0 Hz, H-5), 5.40 (dd, 1 H, J _7.8 = 10.0 Hz, J ₆ = 3.0 Hz, H-7), 5.21 (t, 1 H, H-6), 5.18 (t, 1 H, J ₈ , _8a = 10.0 Hz, H-8), 4.39 (dd, 1 H, J _{1 ¾1b} = 9.5 Hz, J ₅ , 6a = 8.0 Hz, H-1 a), 4.30 (dd, 1 H, J _{8a, 1 b} = 6.0 Hz, H-1 b), 3.99 (ddd, 1 H, H-8a), 3.30 (t, 2 H, ³ J _H , H = 7.0 Hz, CH ₂ N), 2.12, 2.07, 2.01 (3 s, 9 H, MeCO), 1. 58 (m, 2 H, CH ₂ ), 1.29 (m, 10 H, CH ₂ ), 0.87 (t, 3 H, ³ JH, H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.4, 169.8, 169.7 (MeCO), 156.1 (CO), 136.0 (NCN), 70.9 (C-6), 69.4 (C-8), 68.4 (C-7) , 66.4 (C-1), 65.1 (C-5), 53.2 (C-8a), 46.4 (CH ₂ N), 31 .9, 31 .1, 29.2, 29.1, 26.8, 22.7 (CH ₂ ), 20.8 , 20.7 (MeCO), 14.2 (CH ₃ ). FABMS: m / z 598 (60%, [M + Na + thioglycerol] ⁺ ), 576 (50%, [M. H + thioglycerol] ⁺ ). Analysis calculated for C ₂₂ H ₃₃ N ₃ 0 ₈ : C, 56.52; H, 7.1 1; N, 8.99. Found: C, 56.28; H, 6.88; N, 8.73.

Example 32

Hydrochloride (5S, 6fí, 7S, 8 / ?, 8a /?) - 5- (W ^' -octilguanldino) -6,7,8-tri-0-acetll-

2-oxa-3-oxoindoiizidine To a solution of the compound obtained in example 31 (130 mg, 0.28 mmol) in DMF (7 mL), octylamine hydrochloride (182 mg, 3.41 mmol, 12 eq) was added. The reaction mixture was stirred at 100 ^Q C for 20 h. The solvent was removed under reduced pressure. The residue was dissolved in CH ₂ CI ₂ (10 mL) and washed with water (2 x 10 mL). The organic extracts were dried (Na ₂ S0 ₄ ) and concentrated. The crude was purified by column chromatography (AcOEt-MeOH 20: 1 → 5: 1). Yield: 103 mg (76%). [α] _α 7.7 (c 1 .0, CH ₂ CI ₂ ). Rf O.50 (5: 1 AcOEt-MeOH). H NMR (500 MHz, CDCI ₃ ) δ 7.35 (bs, 2 H, NH), 5.64 (dd, 1 H, J ₇ , ₈ = 9.0 Hz, J ₆ = 3.0 Hz, H-7), 5.40 (sa, 1 H, H-6), 5.33 (bs, 1 H, H-5), 5.14 (t, 1 H, J _7.8 = 9.0 Hz, H-8), 4.55 (t, 1 H, J _{1 a , 1 b} = J _{8a, 1 a} = 8.5 Hz, H-1 a), 4.43 (m, 1 H, H- 8a), 4.37 (dd, 1 H, J _8a , i _b = 6.0 Hz, H-1 b), 3.32 (m, 2 H, CH ₂ NH), 2.13, 2.07, 2.00 (3 s, 9 H, MeCO), 1.64 (m, 2 H, CH ₂ ), 1.34 (m, 2 H, CH ₂ ), 1 .26 (m, 8 H, CH ₂ ), 0.86 (t, 3 H, ³ J _H, H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.7, 170.3, 169.5 (MeCO), 157.8 (CO), 156.0 (CN), 69.6 (C-6, C-8), 68.6 (C-7), 67.8 ( C-1), 60.4 (C-5), 53.2 (C-8a), 43.0 (CH ₂ NH), 31 .9, 29.3, 29.2, 28.5, 26.8, 22.7 (CH ₂ ), 20.9, 20.8, 20.7 ( MeCO), 14.2 (CH ₃ ). FABMS: m / z 507 (5%, [M + Na] ⁺ ), 485 (100%, [M. H] ⁺ ). Analysis calculated for C ₂₂ H ₃₇ CIN ₄ O ₈ : C, 50.72; H, 7.16; N, 10.75. Found: C, 50.60; H, 7.003; N, 10.58. Example 33

Hydrochloride (5S _s 6 / ?, 7S, 8fí, 8a /?) - 5- (A / ^' -octilluanidine) -6,7,8-Trichroxy-2- oxa-3-oxoindolizidine

To a solution of the compound obtained in example 32 (50 mg, 0.10 mmol) in MeOH (2.5 mL), NaOMe (1 M in MeOH, 0.1 equiv. Per mole of acetate) was added. The reaction mixture was stirred at room temperature for 30 min, neutralized with solid CO2, concentrated and purified by column chromatography (MeCN-H ₂ 0-NH ₄ OH 10: 1: 1). The product was lyophilized at room temperature of a 0.1 M HCI solution. Yield: 27 mg (75%). [a] o. 1 1 .79 (c 0.36, H ₂ 0). R _f 0.66 (6: 3: 1 CH ₃ CN-H ₂ 0-NH ₄ OH). H NMR (500 MHz, D ₂ 0) δ 5.36 (d, 1 H, ₂ = 1.9 Hz, H-5), 4.70 (t, 1 H, J _{1 a> 1b} = J _8a , ia = 9.0 Hz, H -1 a), 4.46 (dd, 1 H, J _{8a, 1b} = 6.0 Hz, H-1 b), 4.25 (sa, 1 H, H-6), 3.91 (m, 1 H, H-8a), 3.86 (m, 2 H, H-7, H-8), 3.27 (t, 2 H, ³ J _H , H = 6.8 Hz, CH ₂ NH), 1.63 (m, 2 H, CH ₂ ), 1.33 (m, 10 H, CH ₂ ), 0.89 (t, 3 H, ³ J _H , H = 7.1 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, D ₂ 0) δ 159.4 (CO), 155.4 (CN), 70.1 (C-7), 69.9 (C-6, C-8), 68.2 (C-1), 62.9 (C - 5), 54.1 (C-8a), 41 .9 (CH ₂ NH), 31 .1, 28.4, 28.3, 27.6, 25.8, 22.1 (CH ₂ ), 13.5 (CH ₃ ). FABMS: m / z 381 (10%, [M + Na] ⁺ ), 359 (70%, [M. H] ⁺ ). Analysis calculated for Ci ₆ H ₃ iCIN ₄ 0 ₅ : C, 48.66; H, 7.91; N, 14.19. Found: C, 48.32; H, 7.725; N, 13.84.

Example 34

(5S, 6S, 7S, 8?, 8afí) -5- (Acetamldo) -6 _s 7,8-tri-Oacetjl-2-oxa-3-oxolndolízidjna

To a solution of (5R, 6R, 7S, 8R, 8aR) -3-oxohexahydro-1 H-oxazolo [3,4- a] pyridin-5,6,7,8-tetrayl tetraacetate (75 mg, 0.20 mmol) in acetonitrile / TfOH (4: 1, 0.75 mL) it was stirred at room temperature for 30 min, put on ice and the mixture was extracted with CH ₂ CI ₂ (25 mL x 3). The organic phase was washed with a saturated solution of NaHC0 ₃ (15 mL x 2), dried (Na ₂ S0 ₄ ) and concentrated to dryness. The residue was acetylated by treatment with Ac ₂ 0-pyridine (1: 1, 1 mL) for 1 h and the reaction crude was purified by chromatography on column (AcOEt). Yield: 38 mg (51%). R / 0.51 (9: 1 AcOEt-MeOH). [aj _D +25.0 (c 0.5, MeOH). H NMR (500 MHz, MeOD) δ 6.18 (d, 1 H, J ₅ , ₆ = 5.5 Hz, H-5), 5.56 (t, 1 H, J _6i7 = J ₇ , ₈ = 10.0 Hz, H-7 ), 5.14 (t, 1 H, J ₈ , 8a = 0.0 Hz, H-8), 5.11 (dd, 1 H, H-6), 4.48 (dd, 1 H, J _1a , _1b = 9.0 Hz, J _1a , _8a = 8.0 Hz, H-1a), 4.31 (dd, 1 H, J _1b sa = 5.5 Hz, H-1b), 4.14 (ddd, 1 H, H-8a), 2.07-2.02 (4 s, 12 H, eCO). ¹³ C NMR (125.7 MHz, MeOD) δ 172.0 (NHCOMe), 170.2-169.7 (MeCO), 155.9 (CO), 71.7 (C-8), 69.2 (C-7), 68.8 (C-6), 66.3 ( C-1), 55.4 (C-5), 52.5 (C-8a), 21.0 (NHCOMe), 19.1-19.0 (MeCO). ESIMS: m / z 394.8 [M + Na] ⁺ . Analysis calculated for Ο ₁₅ Η ₂ οΝ ₂ Ο ₉ : C 48.39, H 5.41, N 7.52. Found: C 48.11, H 5.10, N 7.19.

Example 35

 (5S, 6S, 7S, 8?, 8a?) - 5- (Butanamido) -6,7,8-tri-Oacetyl-2-oxa-3- oxoindoiizidine

Following a procedure analogous to that described in example 34 but using butyronitrile / TfOH (4: 1, 2.0 mL) instead of acetonitrile / TfOH, the title compound was obtained. It was purified by column chromatography (AcOEt-petroleum ether 2: 1). Yield: 130 mg (61%). R _f 0.28 (3: 1 AcOEt-petroleum ether). [] _D +29.8 (c 1.0, CH ₂ CI). ¹ H NMR (500 MHz, CDCI ₃ -MeOD 7: 1) δ 6.03 (d, 1 H, J ₅ , ₆ = 6.0 Hz, H-5), 5.39 (t, 1 H, J ₆ = J ₇ , s = 9.5 Hz, H-7), 4.98 (m, 1 H, H-6), 4.92 (t, 1 H, J _8s8a = 9.5 Hz, H-8), 4.34 (t, 1 H, J _{1a b} = J _{1a> 8a} = 9.0 Hz, H-1a), 4.25 (dd, 1 H, J _{1b, 8a} = 5.5Hz, H-1b), 4.02 (m, 1 H, H-8a), 2.15 (t, 2 H, NHCOCH ₂ ), 2.00-1.94 (3 s, 9 H, MeCO), 1.58 (m, 2 H, CH ₂ ), 0.88 (t, 3 H, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCVMeOD 7: 1) δ 174.5 (NHCO), 170.4-169.5 (MeCO), 155.4 (CO), 71.9 (C- 8), 69.5 (C-7), 68.7 (C-6) , 66.0 (C-1), 55.6 (C-5), 52.4 (C-8a), 37.6 (NHCOCH ₂ ), 20.3-20.1 (MeCO), 18.9 (CH ₂ ), 13.3 (CH ₃ ). ESIMS: m / z 423.2 [M + Na] ⁺ . Analysis calculated for C ₁₇ H ₂₄ N ₂ O ₉ : C 51.00, H 6.04, N 7.00.

Example 36

(5S, 6S, 7S, 8ff, 8a /?) - 5- (Octanamido) -6,7,8-trí-0-acetjl-2-oxa-3- oxoindolizidine Following a procedure analogous to that described in example 34 but using octanamide / TfOH (4: 1, 2.0 mL) instead of acetonitrile / TfOH, the title compound was obtained. Purification by column chromatography (AcOEt-ether petroleum 1: 1 → 2: 1). Yield: 40 mg (67%). R _f 0.31 (AcOEt-petroleum ether 2: 1). [ocj _D +14.5 (c 1 .0, CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ , 313 K) δ 6.31 (sa, 1 H, NH), 5.97 (t, 1 H, J ₅ , e = _> , NH = 6.0 Hz, H-5), 5.53 ( t, 1 H, J ₆ = J7, s = 9.5 Hz, H-7), 5.12 (dd, 1 H, H-6), 5.01 (t, 1 H, J _{8> 8a} = 9-5 Hz, H -8), 4.42 (t, 1 H, i ¾ib = Jia, _8a = 8.5 Hz, H-1 a), 4.25 (dd, 1 H, J _1b , _8a = 5.0 Hz, H-1 b), 4.13- 4.06 (m, 1 H, H-8a), 2.32-2.24 (m, 2 H, NHCOCH ₂ ), 2.08-2.06 (3 s, 9 H, MeCO), 1 .70-1 .61 (m, 2 H , CH ₂ ), 1 .38-1 .25 (m, 8 H, CH ₂ ), 0.91 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 173.9 (NH CO), 170.1 -169.1 (MeCO), 155.1 (CO), 72.2 (C-8), 69.9 (C-7), 68.7 (C-6), 66.0 (C-1), 56.6 (C-5), 52.5 (C-8a), 36.4 (NHCOCH ₂ ), 31 .7-22.6 (CH ₂ ), 20.6-20.5 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 478.9 [M + Na] ⁺ . Analysis calculated for C ₂ and H ₃₂ N ₂ O ₉ : C 55.25, H 7.07, N 6.14. Found: C 54.99, H 6.84, N 5.88.

Example 37

 (5S, 6S7S, 8 / ?, 8a?) - 5 Adamantane-1-carboxamido) -6,7,8-tri-D-acetii-2-oxa- 3-oxoindolizidine

Following a procedure analogous to that described in example 34 using adamantane-1-carbonyl (445 mg, 2.7 mmol) in CH ₂ CI ₂ (1.5 mL) and TfOH (0.4 mL), the title compound was obtained. Purification by column chromatography (AcOEt-petroleum ether 1: 2 1: 1). Yield: 190 mg (72%). R, 0.19 (AcOEt-petroleum ether 1: 1). [aj _D +33.4 (c 1 .0, CH ₂ CI ₂ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.24 (d, 1 H, NH), 5.87 (t, 1 H, J ₅ , ₆ = Η = 6.0 Hz, H-5), 5.57 (t, 1 H, J ₆ , ₇ = Jis = 9.0 Hz, H-7), 5.10 (dd, 1 H, H-6), 4.99 (t, 1 H, J ₈ , _8a = 9.0 Hz, H-8), 4.40 (t , 1 H, J _{1 a} , i _b = J _{1 a} , 8a = 8.5 Hz, H-1 a), 4.22 (dd, 1 H, J _{1b, 8a} = 5.5Hz, H-1 b), 4.12 (m , 1 H, H-8a), 2.07-2.01 (12 H, MeCO, CH), 1 .86-1 .67 (m, 12 H, CH ₂ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 178.6 (NHCO), 170.1 -169.2 (MeCO), 155.3 (CO), 72.4 (C-8), 70.3 (C- 7), 69.1 (C-6), 66.1 (C-1), 56.9 (C-5), 52.9 (C-8a), 41 .2 (C-1 adamantane), 39.3, 36.4 (CH ₂ ), 28.1 (CH) 20.8-20.6 (eCO). ESIMS: m / 515.2 [M + Na] ⁺ . Analysis calculated for C24H32N2O9: C 58.53, H 6.55, N 5.69.

Example 38

 (5S, 6S S, 8? Aff) -5- (Acetamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 34 (17 mg, 0.046 mmol). Yield: 1 1 mg (98%). R / 0.37 (CH ₂ CI ₂ - MeOH 4: 1). [oc] _D +31 .4 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.85 (d, 1 H, J ₅ , ₆ = 5.5 Hz, H-5), 5.51 (s, 1 H, NH), 4.46 (t, 1 H, J _{1 a} , _1b = J _{1 a} , _8a = 8.5 Hz, hil a), 4.29 (dd, 1 H, J _1b , _8a = 4.5 Hz, H-1 b), 3.71 (ddd, 1 H, J ₈ , _8a = 9.5 Hz, H-8a), 3.63 (t, 1 H, J ₆ , 7 = J ₇ , ₈ = 9.5 Hz, H-7), 3.59 (dd, 1 H, H-6), 3.32 (t, 1 H , H-8), 2.04 (s, 3 H, NHCOMe). ¹³ C NMR (125.7 MHz, MeOD) δ 172.6 (NHCOMe), 156.6 (CO), 73.5 (C-8), 73.0 (C-7), 69.9 (C-6), 66.1 (C-1), 58.6 ( C-5), 53.8 (C-8a), 21 .2 (NHCOMe). ESIMS: m / z 268.8 [M + Na] ⁺ . Analysis calculated for C ₉ H ₁₄ N ₂ O ₆ : C 43.90, H 5.73, N 1 1 .38. Found: C 43.56, H 5.39, N 1 1 .01.

Example 39

 (5S, 6S, 7S, 8fí, 8a /?) - 5- (Butanamido) -6,7,8-trihydroxy-2-oxa-3-oxolndollzidine

The title compound was obtained by conventional deacetylation of the compound of example 35 (82 mg, 0.20 mmol). Yield: 56 mg (99%). R _f 0.24 (CH ₂ CI ₂ - MeOH 5: 1). [a] _D +40.6 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.86 (d, 1 H, J ₅ , 6 = 5.5 Hz, H-5), 4.47 (t, 1 H, J _{1 a, 1 b} = J _1a , _8a = 8.5 Hz, H-1 a), 4.30 (dd, 1 H, Ji b.sa = 4.0 Hz, H-1 b), 3.71 (ddd, 1 H, H-8a), 3.65 (t, 1 H, J ₆ , ₇ = J7, ₈ = 10.0 Hz, H-7), 3.60 (dd, 1 H, H-6), 3.32 (t, 1 H, H-8), 2.30 (d, 2 H, NHCOCH ₂ ), 1.68 (m, 2 H, CH ₂ ), 0.99 (t, 3 H, CH ₃ ). ³ C NMR (125.7 MHz, MeOD) δ 175.6 (NHCO), 156.6 (CO), 73.5 (C-8), 73.0 (C-7), 69.8 (C-6), 66.0 (C-1), 58.6 ( C-5), 53.8 (C- 8a), 35.3 (NHCOCH ₂ ), 31 .5-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 297.1 [M + Na] ⁺ . Analysis calculated for CnH ^ N ^: C 48.17, H 6.61, N 10.20.

Example 40 (5S, 6S S, 8?, 8a / ¾-5- (Octanamide) -6,7,8-trihydroxy-2-oxa-3-oxoindophizidine

The title compound was obtained by conventional deacetylation of the compound of example 36 (20 mg, 0.04 mmol). Yield: 13 mg (90%). R _/ 0.27 (7: 1 CH ₂ CI ₂ - MeOH). [cc] _D +22.1 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.84 (d, 1 H, J _5.6 = 5.5 Hz, H-5), 4.47 (t, 1 H, J _{1 a, 1b} = J _{1 a, 8a} = 8.5 Hz, H-1 a), 4.29 (dd, 1 H, J b, 8a = 4.5 Hz, H-1 b), 3.68 (ddd, 1 H, J ₈ = 9.5 Hz, H-8a), 3.63 (t , 1 H, J ₆ , ₇ = J ₇ , ₈ = 9.5 Hz, H-7), 3.59 (dd, 1 H, H-6), 3.32 (t, 1 H, H-8), 2.30 (dt, 2 H, ³ J _H , H = 7.5 Hz, ⁴ J _H , H = 2.0 Hz, NHCOCH ₂ ), 1 .69-1 .60 (m, 2 H, CH ₂ ), 1 .40-1 .28 ( m, 8 H, CH ₂ ), 0.92 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 175.6 (NHCO), 156.6 (CO), 73.5 (C-8), 73.0 (C-7), 69.8 (C-6), 66.0 (C-1), 58.6 ( C-5), 53.8 (C-8a), 35.3 (NHCOCH ₂ ), 31 .5-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 352.9 [M + Na] ⁺ . Analysis calculated for Ci ₅ H ₂₆ N ₂ O ₆ : C 54.53, H 7.93, N 8.48. Found: C 54.16, H 7.60, N 8.10.

Example 41

(5S, 6S, 7S, 8 / ?, 8a?) - 5- (Adamantane-1-carboxamido) -6,7,8-trihydroxy-2-oxa-3- oxoindoiizidine The title compound was obtained by conventional deacetylation of the compound from example 37 (58 mg, 0.12 mmol). Yield: 43 mg (99%). R 0.71 (30: 10: 1 CH ₂ CI ₂ -MeOH-H ₂ O). [aj _D -1 .02 (c 0.5 in MeOH). ¹ H NMR (500 MHz, Me ₂ SO-d ₆ ) δ 7.13 (d, 1 H, NH), 5.69 (t, 1 H, J ₅ , e = Js, = 6.5 Hz, H-5), 4.36 ( t, 1 H, J _{1 a} , _1b = Jia, sa = 9.0 Hz, H-1 a), 4.14 (dd, 1 H, J _{1 b, 8a} = 3.5 Hz, H-1 b), 3.71 (ddd, 1 H, H- 8a), 3.64 (t, 1 H, J ₆ = J ₇ , ₈ = 9.0 Hz, H-7), 3.35 (dd, 1 H, H-6), 3.12 (t, 1 H, H-8), 2.00 (sa, 3 H, CH), 1 .84, 1 .70 (2 s, 12 H, CH ₂ ). ¹³ C NMR (125.7 MHz, Me ₂ SO-d ₆ ) δ 178.2 (NHCO), 156.2 (CO), 74.3 (C-8), 73.0 (C-7), 70.9 (C-6), 66.3 (C- 1), 59.3 (C-5), 54.2 (C-8a), 41.2 (C-1 adamantane), 39.3, 37.0 (CH ₂ ), 28.6 (CH). FABMS: m / z 389 [M + Na] ⁺ . Analysis calculated for C ₁₈ H ₂₆ N ₂ O ₆ : C 59.00, H 7.15, N 7.65.

Example 42 (SS.eS SS ^ eafíJ-S-í / V ^' -OctHureidoJ-e .S-tri-O-acetyl ^ -oxa-S- oxoindoiizidine

To a solution of the compound obtained in example 28 (129 mg, 0.28 mmol) in acetone-water (2: 1, 6.5 ml_), TFA (50 μΙ_) was added and the reaction mixture was stirred at room temperature for 8 h . The solvent was removed under reduced pressure and the residue was purified by column chromatography (2: 1 Petroleum EtOAther). Yield: 93 mg (70%). Yield: 16 mg (23%). R, 0.79 (AcOEt-MeOH 6: 1). [oc] _D +39.1 (c 0.6 in CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ , 313 K) δ 5.68 (d, 1 H, J ₅ , 6 = 6.0 Hz, H-5), 5.50 (t, 1 H, J ₆ , ₇ = J ₇ , 8 = 9.5 Hz, H-7), 5.07 (dd, 1 H, H-6), 4.96 (t, 1 H, J _8.8a = 9.5 Hz, H-8), 4.50 (t, 1 H, J _{1 a, 1 b} = J _{1 a} , _8a = 9.0 Hz, H-1 a), 4.34 (dd, 1 H, J _{1 b} , ₈ a = 7.0 Hz, H-1), 4.12 (bq, 1 H, H -8a), 3.21 (t, 2 H, ³ J _H , H = 7.0 Hz, NHCH ₂ ), 2.12-2.07 (3 s, 9 H, MeCO), 1 .60-1 .50 (m, 2 H, NHCH ₂ CH ₂ ), 1 .40-1 .22 (m, 10 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.0-169.3 (MeCO), 157.3 (CO), 156.8 (CO), 72.5 (C-8), 68.8-68.7 (C-6, C- 7), 67.2 ( C-1), 58.1 (C-5), 51 .8 (C-8a), 40.8 (HCH ₂ ), 31 .8-22.6 (CH ₂ ), 20.6-20.5 (MeCO), 14.1 (CH ₃ ). ESIMS: m / z 508.0 [M + Na] ⁺ . Analysis calculated for C ₂₂ H ₃₅ N ₃ O ₉ : C 54.42, H 7.27, N 8.65. Found: C 54.23, H 7.12, N 8.43.

Example 43

 (5S, 6S, 7S, 8f, 8a ^) - 5- (W-Octylureido) -6,7,8-trihydroxy-2-oxa-3- oxoindolizidine

C 53.47, H 8.13, N 1 1 .69. Encontrado: C 53.14, H 7.91 , N 1 1 .33. Ejemplo 44 The title compound was obtained by conventional deacetylation of the compound of example 42 (15 mg, 0.03 mmol). Yield: 9 mg (81%). R / 0.17 (AcOEt-MeOH 6: 1). [a] _D +18.5 (c 0.7 in MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.58 (d, 1 H, J ₅ , ₆ = 5.5 Hz, H-5), 4.46 (t, 1 H, J _{1 a, 1b} = J _{1a, 8a} = 8.5 Hz , H-1 a), 4.29 (dd, 1 H, J _{1 b, 8a} = 4.0 Hz, H-1 b), 3.67 (ddd, 1 H, J ₈ , _8a = 9.5 Hz, H-8a), 3.59 (dd, 1 H, J _B = 9.5 Hz, H-6), 3.51 (t, 1 H, J _7i8 = 9.5 Hz, H-7), 3.31 (t, 1 H, H-8), 3.15 (dd , 1 H, ² J _H = 10.5 Hz, ³ J _H , H = 6.5 Hz, NHCH ₂ ), 3.12 (dd, 1 H, NHCH ₂ ), 1 .53-1 .46 (m, 2 H, NHCH ₂ CH ₂ ), 1 .39-1 .28 (m, 10 H, CH ₂ ), 0.92 (t, 3 H, ³ J _{H, H} = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 159.1 (CO), 156.7 (CO), 73.6 (C-8), 73.3 (C-7), 69.8 (C-6), 66.0 (C-1), 60.3 (C-5), 53.4 (C-8a), 39.5 (HCH ₂ ), 31 .6-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 382.0 [M + Na] ⁺ . Analysis calculated for

C 53.47, H 8.13, N 1 1 .69. Found: C 53.14, H 7.91, N 1 1 .33. Example 44

 (5S, 6? JS, 8? Affi) -5- (OctHureido) -67.8 ri-0-acetii-2-oxa-3-oxoindoiizidine

C, 54.42; H, 7.27; N, 8.65. Encontrado: C, 54.40; H, 7.41 ; N, 8.47. Ejemplo 45 To a solution of the compound obtained in example 33 (129 mg, 0.28 mmol) in acetone-water (2: 1, 6.5 ml_), TFA (50 μΙ_) was added and the reaction mixture was stirred at room temperature for 8 h . The solvent was removed under reduced pressure and the residue was purified by column chromatography (2: 1 Petroleum EtOAther). Yield: 1 10 mg (82%). [cc] _D +4.3 (c 1 .0, CH ₂ CI ₂ ). R / 0.25 (AcOEt- petroleum ether 2: 1). H NMR (500 MHz, CDCI ₃ ) δ 6.91 (sa, 1 H, J _sm = 7.0 Hz, NH), 5.77 (sa, 1 H, NH ^' ), 5.43 (dd, 1 H, J ₆ , ₇ = 3.0 Hz, J _7j8 = 9.5 Hz, H-7), 5.36 (dd, 1 H, H-6), 5.31 (dd, 1 H, H-5), 4.46 (t, 1 H, J _{8a, 1 a} = J _{1 ¾1b} = 9.0 Hz, H-1 a), 4.35 (dd, 1 H, J _8aAb = 5.5 Hz, H-1 b), 4.10 (ddd, 1 H, H-8a), 3.16 (m, 2H, CH ₂ NH), 2.14, 2.07, 2.02 (MeCO), 1.49 (m, 2 H, CH ₂ ), 1.28 (m, 4 H, CH ₂ ), 0.86 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.4, 170.0, 169.9 (MeCO), 157.6 (CO carbamate), 157.3 (CO), 69.8 (C-6, C-8), 68.7 (C-7), 66.9 (C-1), 60.8 (C-5), 53.0 (C-8a), 40.8 (CH ₂ NH), 31 .9, 29.8, 29.4, 29.3, 27.0, 22.8 (CH ₂ ), 20.9, 20.8, 20.7 (MeCO), 14.2 (CH ₃ ). FABMS: m / z 508 (100%, [M + Na] ⁺ ), 486 (20%, [M + H] ⁺ ). Analysis calculated for

C, 54.42; H, 7.27; N, 8.65. Found: C, 54.40; H, 7.41; N, 8.47. Example 45

 (5S, 6?, 7S, 8?, 8a?) - 5- (Octylureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 45 (92 mg, 0.19 mmol) with NaMeO (1 M, 0.1 equiv per mole of acetate) in MeOH (4.5 ml_) for 30 min, followed by neutralization with solid CO ₂ . Purification by column chromatography (AcOEt-EtOH-H ₂ O 45: 5: 3). Yield: 58 mg (86%). [a] _D +6.76 (c 0.42, MeOH). R ^ 0.34 (AcOEt-EtOH-H ₂ O 45: 5: 3). ¹ H NMR (500 MHz, MeOD) δ 5.54 (d, 1 H, J ₅₃ = 2.0 Hz, H-5), 4.49 (t, 1 H, Ji _a , ib = 4 »a.ia = 9.0 Hz, H -1 a), 4.31 (dd, 1 H, J _8a , _1b = 4.0 Hz, H-1 b), 3.98 (t, 1 H, J ₆ j = 9.5 Hz, H-6), 3.73 (t, 1 H, J _{7> 8} = 9.5 Hz, H-7), 3.68 (td, 1 H, H-8a), 3.63 (dd, 1 H, H-8), 3.14 (m, 2 H, CH ₂ NH) , 1 .50 (m, 2 H, CH ₂ CH ₂ NH), 1 .34 (sa, 10 H, CH ₂ ), 0.93 (t, 3H, ³ J _H, H = 6.5 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 159.4 (CO; carbamate), 159.3 (CO), 72.8 (C-6), 72.3 (C-7), 71 .3 (C-8), 67.8 (C-1 ), 64.0 (C-5), 56.3 (C-8a), 40.9 (CH ₂ NH), 33.0, 31 .2, 30.4, 30.4, 28.0, 23.7 (CH ₂ ), 14.4 (CH ₃ ). FABMS: m / z 382 (100%, [M + Na] ⁺ ). Analysis calculated for Ci ₆ H ₂₉ N30 ₆ : C, 53.47; H, 8.13; N, 1 1.69. Found: C, 53.22; H, 7,991; N, 1 1 .75.

Example 46

(5S, 6 / ?, 7S, 8?, 8a?) - 5-Octylamino-6.7 ₅ 8-trihydroxy-2-oxa-3-thioxoindoiizidine A solution of (5S, 6R, 7S, 8fí, 8afí) -5,6,7,8-tetrahydroxy-2-oxa-3- thioxoindolizidine (93 mg, 0.42 mmol; prepared according to the method described by P. Díaz-Pérez et al. In Eur. J. Org. Chem. , 2005, 2903-2913) in MeOH (2 mL) was added octylamine (69 μΙ_, 0.42 mmol) and the mixture stirred under Ar at 40 ^Q C for 24 h. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (CH ₂ CI ₂ -MeOH-H ₂ O 100: 10: 1). Yield: 104 mg (75%). [cc] _D -7.4 (c 1 .0, MeOH). R _f 0.1 1 (CH ₂ CI ₂ -MeOH-H ₂ O 70: 10: 1). UV (CH ₂ CI ₂ ) 284 nm {£ _mU 15.4). ¹ H NMR (500 MHz, MeOD) δ 5.23 (d, 1 H, J ₅ = 2.1 Hz, H-5), 4.71 (t, 1 H, J _{1 a} , _1b = J _8a , _{1 a} = 9.3 Hz, H-1 a), 4.46 (dd, 1 H, J _{8a, 1 b} = 6.3 Hz, H-1 b), 4.00 (m, 2 H, H-2, H-8a), 3.72 (dd, 1 H , J _7.8 = 9.4 Hz, J _6.7 = 2.8 Hz, H-7), 3.68 (t, 1 H, J _8.8a = 9.4 Hz, H-8), 2.61 (m, 2 H, CH ₂ N), 1 .57, 1.47 (2 m, 2 H, CH ₂ CH ₂ N), 1 .31 (m, 10 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 189.8 (CS), 75.2 (C-5), 73.3 (C-6), 72.4 (C-7, C-8), 70.1 (C-1), 59.0 (C -8a), 47.2 (CH ₂ N), 33.0, 30.7, 30.6, 30.4, 28.4 (CH ₂ ), 14.4 (CH ₃ ). ESIMS: m / z 355 [M + Na] ⁺ , 333 [M + H] ⁺ . Analysis calculated for Ci ₅ H ₂₈ N ₂ O ₄ S: C, 54.19; H, 8.49; N, 8.46; S, 9.54. Found: C, 53.90; H, 8.34; N, 8.23; S, 9.40. Example 47

 (5S, 6?, 7S, 8?, 8af?) - 5-OctiUio-6,7,8-tri-0-acetyl-2-oxa-3-thioxoindoHzidine

To a solution of (5S, 6R, 7S, 8fí, 8afí) -5,6,7,8-tetra-O-acetyl-2-oxa-3- thioxoindolizidine (93 mg, 0.42 mmol; prepared according to the method described by P. Díaz-Pérez et al. in Eur. J. Org. Chem., 2005, 2903-2913) in CH2CI2 (7.5 mL) at 0 ^Q C and under Ar atmosphere was added octanethiol (86 μΙ_, 0.50 mmol) and BF ₃ -Et ₂ O (104 μΙ_, 0.86 mmol). The reaction mixture was stirred for 2 h, CH ₂ CI ₂ (25 mL) was diluted, washed with saturated aqueous NaHC0 ₃ solution (15 mL) and water (15 mL), dried (MgSO ₄ ), and concentrated. The resulting residue was purified by column chromatography (AcOEt-petroleum ether 1: 2 → 1: 1). Yield: 53 mg (46%). [aj _D -33.0 (c 1 .0, CH ₂ CI ₂ ). Rf 0.62 (AcOEt-petroleum ether 1: 1). UV (CH ₂ CI ₂ ) 256 nm (e _mM 18.3). H NMR (500 MHz, CDCI ₃ ) δ 5.90 (d, 1 H, J ₅ , e = 2.2 Hz, H-5), 5.38 (dd, 1 H, J ₆ = 2.9 Hz, H- 6), 5.36 ( dd, 1 H, J _7.8 = 9.5 Hz, H-7), 5.28 (t, 1 H, J ₈ , _8a = 9.5 Hz, H-8), 4.67 (dd, 1 H, J _{1 at} jb = Jsa = 9.5 Hz, H-1 a), 4.58 (dd, 1 H, J _8a , i _b = 6.0 Hz, H-1 b), 4.41 (td, 1 H, H-8a), 2.81, 2.67 (2 m, 2 H, CH ₂ S), 2.14, 2.10, 2.04 (3 s, 9 H, MeCO), 1.68 (m, 2 H, CH ₂ ), 1.38 (m, 2 H, CH ₂ ) , 1.29 (m, 8 H, CH ₂ ), 0.90 (t, 3 H, ³ J _H , H = 6.9 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 187.7 (CS), 170.1, 169.9, 169.5 (CO), 70.9 (C-6), 70.4 (C-1), 69.6 (C-8), 68.7 (C- 7), 61 .0 (C-5), 56.0 (C-8a), 32.0 (CH ₂ S), 31 .8, 29.7, 29.1, 29.0, 28.7 22.6 (CH ₂ ), 20.8, 20.6 (MeCO), 14.1 (CH ₃ ). FABMS: m / z 498 (67%, [M + Naf), 476 (18%, [M + H] ⁺ ). Analysis calculated for C ₂ H ₃₃ NO ₇ S ₂ : C, 53.03; H, 6.99; N, 2.94; S, 13.48. Found: C, 52.94; H, 6.86; N, 2.69; S, 13.20.

Example 48

 (5S, 6fí S, 8fí a /?) - 5-Octiithio-6,7,8-trihydroxy-2-oxa-3-thioxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 47 (50 mg, 0.1 1 mmol) in MeOH (2.5 mL) with NaMeO (1 M, 0.1 equiv per mole of acetate) for 30 min. It was neutralized with solid CO ₂ , concentrated and the resulting residue was purified by column chromatography. {CH ₂ CI ₂ -MeOH-H ₂ 0 70: 10: 1). Yield: 35 mg (90%). [a] _D -32.0 (c 1 .0, MeOH). R, 0.38 (CH ₂ CI ₂ -MeOH-H ₂ 0 70: 10: 1). UV (CH ₂ CI ₂ ) 213 nm (e _mM 7.57). ¹ H NMR (500 MHz, MeOD) δ 5.79 (d, 1 H, J ₅ , ₆ = 2.2 Hz, H-5), 4.78 (t, 1 H, J _{1 a} , _1b = J _8a , _{1 a} = 9.5 Hz, H-1 a), 4.46 (dd, 1 H, J _8a , _{1 b} = 7.0 Hz, H-1 b), 4.16 (td, 1 H, J ₈ , _8a = 9.5 Hz, H-8a), 4.07 (dd, 1 H, J ₆ = 2.9 Hz, H-6), 3.72 (t, 1 H, J ₇ , ₈ = 9.5 Hz, H-8), 3.64 (dd, 1 H, H-7), 2.80, 2.62 (2 m, 2 H, CH ₂ S), 1 .68 (m, 2 H, CH ₂ CH ₂ S), 1.37 (m, 10 H, CH ₂ ), 0.90 (t, 3 H , ³ J _H , H = 7.2 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 189.3 (CS), 73.6 (C-6), 72.6 (C-3, C-8), 72.4 (C-1), 65.3 (C-5), 58.9 (C -8a), 32.8 (CH ₂ ), 32.1 (CH ₂ S), 31 .2 (CH ₂ CH ₂ S), 30.2, 30.1, 29.7, 23.6 (CH ₂ ), 14.3 (CH ₃ ). ESIMS: m / z 372 [M + Na] ⁺ . Analysis calculated for C ₁₅ H ₂₇ N0 ₄ S ₂ : C, 51 .55; H, 7.79; N, 4.01; S, 18.35. Found: C, 51.33; H, 7.62; N, 3.75; S, 18.01.

Example 49

 (5fí, 6?, 7S, 8fí, 8afí) -7,8-Dihydroxy-5,6-OisopropHidén-2-oxa-3- oxoindolizidina

A mixture of (5R, 6R, 7S, 8R, 8aR) -5,6,7,8-tetrahydroxytetrahydro-1 H- oxazolo [3,4-a] pyridin-3 (5H) -one (50 mg, 0.24 mmol ), acetone (10 mL) and p-tolunesulfonic acid (53 mg, 0.28 mmol) was stirred at 50 ° C for 4 h 30 min. The reaction mixture was diluted with AcOEt (75 mL) and washed with saturated aqueous NaHCOs solution (10 mL). The aqueous phase was extracted with AcOEt (3 x 30 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by column chromatography (CH ₂ CI ₂ -MeOH 10: 1). Yield: 30 mg (51%). 0.73 (CH ₂ CI ₂ -MeOH 5: 1). [cc] _D +34.3 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.72 (d, 1 H, J ₅ , 6 = 5.5 Hz, H-5), 4.59 (t, 1 H, J _{1 a} , _{1 b} = Ji a, 8a = 9.0 Hz, H-1 a), 4.31 (dd, 1 H, J _{1 bi8a} = 6.5 Hz, H-1 b), 4.07 (dd, 1 H, J ₆ = 7.0 Hz, H-6), 3.85 (td, 1 H, J ₈ , 8a = 9.0 Hz, H-8a), 3.63 (dd, 1 H, J ₇ , ₈ = 9.0 Hz, H- 7), 3.35 (t, 1 H, H-8), 1. 54, 1 .43 (2 s, 6 H, CMe ₂ ). ¹³ C NMR (125.7 MHz, MeOD) δ 157.2 (CO), 108.9 (CMe ₂ ), 79.8 (C-5), 77.0 (C-6), 75.2 (C-7), 72.4 (C-8), 66.9 (C-1), 53.6 (C-8a), 26.9, 25.5 (CMe ₂ ). ESIMS: m / z 267.9 [M + Na] ⁺ . Analysis calculated for C ₁₀ H ₁₅ NO ₆ : C, 48.98; H, 6.17 ;, N, 5.71. Found: C, 48.82; H, 6.04; N, 5.66. Example 50

(5?, 6 / ?, 7S, 8?, 8a?) - 7,8-Di-0-acetyl-5 _s 6-0-isopropiiiden-2-oxa-3- oxoindolizidine

The title compound was obtained by conventional acetylation of the compound of example 49 (200 mg, 0.82 mmol) with Ac ₂ 0-pyridine (1: 1, 4 mL) at room temperature for 2 h and purification by column chromatography (AcOEt-ether of 1: 1 oil). Yield: 215 mg (80%). R, 0.62 (AcOEt-petroleum ether 2: 1).

[ocj _D +1 .8 (c 1 .0, CHCI ₃ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.82 (d, 1 H, J ₅ , ₆ = 5.5 Hz, H-5), 5.30 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 5.5 Hz , H-7), 4.74 (dd, 1 H, J ₈ , _8a = 8.0 Hz, H- 8), 4.55 (dd, 1 H, J _{1 a} , ib = 9-5 Hz, J _1a , _8a = 8.0 Hz, H-1 a), 4.34 (t, 1 H, H-6), 4.32 (dd, 1 H, J _1bi8a = 6.0 Hz, H-1 b), 4.01 (td, 1 H, H-8a) , 2.12-2.1 1 (2 s, 6 H, MeCO), 1 .58, 1 .43 (2 s, 6 H, CMe ₂ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 170.2-169.4 (MeCO), 155.9 (CO), 1 10.3 (CMe ₂ ), 79.0 (C-5), 72.8 (C-6), 72.4 (C-8) , 71 .1 (C- 7), 67.6 (C-1), 52.1 (C-8a), 27.1 -25.8 (CMe ₂ ), 20.7-20.6 (MeCO). ESIMS: m / z 351 .9 [M + Na] ⁺ . Analysis calculated for C ₁₄ H ₁₉ NO ₈ : C, 51 .06; H, 5.82; N, 4.25. Found: C, 50.78; H, 5.74; N, 4.17. Example 51

 (Sff.efí fíje ^ SafíJ-y.S-Di-O-acetyl-S.e-dihydroxy ^ -oxa-S-oxoindolizjdlna

The title compound was obtained by treating the compound obtained in example 50 (96 mg, 0.29 mmol) with TFA-H ₂ O (90%, 3.2 mL) at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was purified by column chromatography (CH ₂ Cl ₂ -MeOH 7: 1). Yield: 82 mg (97%). R, 0.56 (CH ₂ CI ₂ -MeOH 9: 1). [cc] _D +47.3 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.38 (d, 1 H, J _5, e = 5.5 Hz, H-5), 5.37 (t, 1 H, J _6.7 = J _7.8 = 9.5 Hz, H-7), 4.96 (t, 1 H, J _8.8a = 9.0 Hz, H-8), 4.48 (t, 1 H, J _{1 a, 1 b} = J _{1a, 8a} = 9.0 Hz, H-1 a), 4.25 (dd, 1 H, J _1bj8a = 7.5 Hz, H-1 b), 4.14 (dt, 1 H, H-8a), 3.72 (dd, 1 H, H-6), 2.08-2.05 ( 2 s, 6 H, MeCO). ¹³ C NMR (125.7 MHz, MeOD) δ 170.8- 170.6 (MeCO), 156.4 (CO), 74.7 (C-5), 72.6 (C-8), 72.0 (C-7), 70.0 (C-6), 66.7 (C-1), 51 .8 (C-8a), 19.4-19.2 {MeCO). ESIMS: m / z 31 1 .9 [M + Na] ⁺ . Analysis calculated for CH ₁₅ N0 ₈ : C, 45.68; H, 5.23; N, 4.84. Found: C, 45.44; H, 5.00; N, 4.51.

To a solution of the compound obtained in example 51 (1 18 mg, 0.41 mmol, 1.0 equiv.) And acetonitrile (213 μΙ, 4.1 mmol, 10 equiv.) In CH ₂ CI ₂ (4 ml_) at -40 ^e C and under Ar's atmosphere, TfOH (53 μΙ_, 0.61 mmol, 1.5 equiv.) Was added. The reaction mixture was stirred at -40 C for 30 min ^and. Et ₃ N was added, the solvents were removed under reduced pressure and the residue was purified by column chromatography (AcOEt). Yield: 106 mg (83%). R, 0.59 (AcOEt-MeOH 16: 1). [a] _D -17.8 (c 1.0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 6.00 (d, 1 H, J ₅ , e = 9-0 Hz, H-5), 5.24 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 5.5 Hz, H-7), 4.91 (t, 1 H, J ₈ , 8a = 5.5 Hz, H-8), 4.82 (dd, 1 H, H-6), 4.61 (t, 1 H, J _{1 a} , ib = Jia.sa = 9.0 Hz, H-1 a), 4.36 (dd, 1 H, J _{1 b} , 8a = 5.5 Hz, H-1 b), 3.93 (td, 1 H, H-8a), 2.10 (2 s, 9 H, 2 MeCO, CH ₃ ). ³ C NMR (125.7 MHz, MeOD) δ 170.3 (CN), 169.5-169.4 (MeCO), 156.9 (CO), 75.1 (C-6), 73.2 (C-5), 70.5 (C-8), 69.7 ( C-7), 67.4 (C-1), 52.5 (C-8a), 19.2 (MeCO), 12.6 (CH ₃ ). ESIMS: m / z 334.9 [M + Na] ⁺ . Analysis calculated for C ₁₃ H ₁₆ N ₂ O7: C, 50.00; H, 5.16; N, 8.97. Found: C, 50.12; H, 5.05; N, 8.75.

El compuesto titular se obtuvo a partir del compuesto obtenido en el ejemplo 51 (57 mg, 0.20 mmol) y una disolución de octanonitrilo (300 μΐ_, 2.0 mmol) en CH2CI2 (2 mL) y TfOH (26 μΙ_, 0.30 mmol). Purificación por cromatografía en columna (AcOEt-éter de petróleo 2:3). Rend.: 51 mg (65%).¹ H NMR (500 MHz, CDCI3) δ 6.02 (d, 1 H, J₅,₆ = 9.0 Hz, H-5), 5.19 (t, 1 H, J₆ = J₇,₈ = 5.5 Hz, H-7), 4.76 (t, 1 H, Jasa = 6.0 Hz, H-8), 4.58 (dd, 1 H, H-6), 4.52 (t, 1 H, J_{1 a},_{1 b} = Ji_a,8a = 9.0 Hz, H-1 a), 4.28 (dd, 1 H, Ji_b,_8a = 4.5 Hz, H-1 b), 3.77 (ddd, 1 H, H-8a), 2.34 (t, 2 H, ³J_H,H = 8.0 Hz, CH₂), 2.1 1 -2.08 (2 s, 6 H, MeCO), 1.73-1 .60 (m, 2 H, CH₂), 1 .42-1 .23 (m, 8 H, CH₂), 0.89 (t, 3 H, ³J H = 6.5 Hz, CH₃). ¹³C NMR (125.7 MHz, CDCI₃) δ 171 .1 -169.2 (MeCO), 155.8 (CO), 74.4 (C-6), 73.7 (C-5), 71 .0 (C-8), 70.0 (C-7), 67.0 (C-1 ), 52.6 (C-8a), 31.6-22.6 (CH₂), 20.7-20.5 (MeCO), 14.0 (Me). ESIMS: m/z 419.0 [M + Na]⁺.

The title compound was obtained from the compound obtained in example 51 (57 mg, 0.20 mmol) and a solution of octanonitrile (300 μΐ_, 2.0 mmol) in CH2CI2 (2 mL) and TfOH (26 μΙ_, 0.30 mmol). Purification by column chromatography (AcOEt-petroleum ether 2: 3). Yield: 51 mg (65%). ¹ H NMR (500 MHz, CDCI3) δ 6.02 (d, 1 H, J ₅ , ₆ = 9.0 Hz, H-5), 5.19 (t, 1 H, J ₆ = J ₇ , ₈ = 5.5 Hz, H- 7), 4.76 (t, 1 H, Jasa = 6.0 Hz, H-8), 4.58 (dd, 1 H, H-6), 4.52 (t, 1 H, J _{1 a} , _{1 b} = Ji _a , 8a = 9.0 Hz, H-1 a), 4.28 (dd, 1 H, Chi _b , _8a = 4.5 Hz, H-1 b), 3.77 (ddd, 1 H, H-8a), 2.34 (t, 2 H, ³ J _H , H = 8.0 Hz, CH ₂ ), 2.1 1 -2.08 (2 s, 6 H, MeCO), 1.73-1 .60 (m, 2 H, CH ₂ ), 1 .42-1 .23 ( m, 8 H, CH ₂ ), 0.89 (t, 3 H, ³ JH = 6.5 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, CDCI ₃ ) δ 171 .1 -169.2 (MeCO), 155.8 (CO), 74.4 (C-6), 73.7 (C-5), 71 .0 (C-8), 70.0 ( C-7), 67.0 (C-1), 52.6 (C-8a), 31.6-22.6 (CH ₂ ), 20.7-20.5 (MeCO), 14.0 (Me). ESIMS: m / z 419.0 [M + Na] ⁺ .

 1 -Adamantane

The title compound was obtained from the compound obtained in example 51 (85 mg, 0.29 mmol) and a solution of adamantane-1-carbonitrile (472 mg, 2.9 mmol) in CH ₂ CI ₂ (5 mL) and TfOH (39 pl, 0.44 mmol). Purification by column chromatography (CH ₂ CI ₂ -MeOH 20: 1). Yield: 1 18 mg (93%). ñ _f 0.32 (CH ₂ CI ₂ -MeOH 20: 1). [a] _D -26.8 (c 1 .0, CH ₂ CI ₂ ). ¹ H NMR (500 MHz, CDCI ₃ ) δ 5.92 (d, 1 H, J ₅ , 6 = 5.5 Hz, H-5), 5.10 (t, 1 H, J ₆ , ₇ = J ₇ , ₈ = 5.5 Hz , H-7), 4.66 (t, 1 H, J _8.8a = 5.5 Hz, H-8), 4.47 (dd, 1 H, H-6), 4.43 (t, 1 H, J _1¾1b = J _{1 a, 8a} = 9.0 Hz, H-1 a), 4.23 (dd, 1 H, J _{1 b, 8a} = 4.0 Hz, H-1 b), 3.65 (m, 1 H, H-8a), 2.04, 2.00 (2 s, 9 H, 2 MeCO), 1.97 (m, 3 H, CH), 1.84, 1.66 (2 m, 12 H, CH ₂ ). ³ C NMR (125.7 MHz, CDC) δ 176.4 (CN), 170.0, 169.3 (MeCO), 155.7 (CO), 74.3 (C-6), 73.5 (C-5), 71 .2 (C-8), 70.3 (C-7 ), 67.0 (C-1), 52.5 (C-8a), 39.2 (CH ₂ ), 36.4 (CH), 27.7 (CH ₂ ), 20.7, 20.6 (MeCO). Analysis calculated for C22H28N2O7: C, 61.10; H, 6.53; N, 6.48.

The title compound was obtained by conventional deacetylation of the compound obtained in example 52 (58 mg, 0.18 mmol). Purification by column chromatography (CH ₂ CI ₂ -MeOH 5: 1). Yield: 30 mg (71%). R, 0.60 (CH ₂ CI ₂ -MeOH 4: 1). [CC] D -2.0 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.88 (dd, 1 H, J ₅ , e = 8.5 Hz, ⁵ J ₅ , Me = 1 .0 Hz, H-5), 4.56 (t, 1 H, J _{1a > 1 b} = Chi a, 8a = 9.0 Hz, H-1 a), 4.55 (dd, 1 H, J _6.7 = 7.0 Hz, H-6), 4.36 (dd, 1 H, J _{1 b, 8a} = 5.5 Hz, H-1 b), 3.66 (td, 1 H, J _8.8a = 9.0 Hz, H-8a), 3.47 (dd, 1 H, J _7.8 = 9.0 Hz, H-7), 3.40-3.30 (m, 1 H, H-8), 2.07 (d, 3 H, Me). ³ C NMR (125.7 MHz, MeOD) δ 169.1 (CN), 157.4 (CO), 80.6 (C-6), 75.3 (C-7), 74.0 (C-5), 70.8 (C-8), 66.0 ( C-1), 53.9 (C-8a), 12.9 (CH ₃ ). ESIMS: m / z 250.8 [M + Na] ⁺ . Analysis calculated for 0 _{9 12} Ν ₂ 0 ₅ : C, 47.37; H, 5.30; N, 12.28. Found: C, 47.19; H, 5.12; N, 1 1 .98.

 ep

The title compound was obtained by conventional deacetylation of the compound obtained in example 53 (24 mg, 0.06 mmol. Purification by column chromatography (CH ₂ CI ₂ -MeOH 8: 1). Yield: 11 mg (59%). R ^ O.58 (CH ₂ CI ₂ -MeOH 6: 1). [a] _D -1 -6 (c 0.7, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.88 (d, 1 H, J ₅ , ₆ = 8.5 Hz, H-5), 4.56 (t, 1 H, J _{1 a, 1 b} = J _{1 a, 8a} = 9.0 Hz, H-1 a), 4.54 (dd, 1 H, J ₆ = 7.0, H- 6), 4.37 (dd, 1 H, J _{1 b} , _8a = 5.0 Hz, H-1 b), 3.64 ( td, 1 H, J ₈ , _8a = 9.0 Hz, H-8a), 3.43 (dd, 1 H, J ₇ , 8 = 9.5 Hz, H-7), 3.36-3.30 (m, 1 H, H-8 ), 2.37 (t, 2 H, ³ J _H , H = 7.5 Hz, CH ₂ ), 1 .74-1 .63 (m, 2 H, CH ₂ ), 1 .44-1 .27 (m, 8 H, CH ₂ ), 0.93 (t, 3 H, ³ J _H , H = 7.0 Hz, CH ₃ ). ¹³ C NMR (125.7 MHz, MeOD) δ 171 .9 (CN), 157.4 (CO), 80.4 (C-6), 75.5 (C-7), 73.9 (C-5), 70.9 (C-8), 66.0 (C-1), 53.9 (C-8a), 31 .4-22.3 (CH ₂ ), 13.0 (CH ₃ ). ESIMS: m / z 334.9 [M + Na] ⁺ . Analysis calculated for Ci5H ₂₄ N20 ₅ : C, 57.68; H, 7.74; N, 8.97. Found: C, 57.40; H, 7.62; N, 8.73.

The title compound was obtained by conventional deacetylation of the compound obtained in example 54 (84 mg, 0.19 mmol). Purification by column chromatography (CH ₂ CI ₂ -MeOH 20: 1). Yield: 43 mg (65%). R _f 0.32 (CH ₂ CI ₂ -MeOH 20: 1). [oc] _D -7.2 (c 1 .0, MeOH). ¹ H NMR (500 MHz, MeOD) δ 5.90 (d, 1 H, J ₅ , ₆ = 9.0), 4.60 (t, 1 H, J _{1 a} , _{1 b} = J _{1 a: 8a} = 9.0 Hz, H- 1 a), 4.55 (dd, 1 H, J ₆ = 7.0 Hz, H- 6), 4.42 (dd, 1 H, J _{1 b, 8a} = 5.5 Hz, H-1 b), 3.67 (dt, 1 H , J _8.8a = 9.0 Hz, H-8a), 3.38 (m, 2 H, H-7, H-8), 2.10 (m, 3 H, CH), 2.01, 1.85 (2 m, 12 H, CH ₂ ).

Example 58

 Biological test 1: Inhibition of glycosidases

Table 1 summarizes the inhibitory activity of synthesized castanospermine analog glycosides (examples 2, 7 and 1 1) against selected glycosidases. Table 1: Values of K¡ (μΜ) for examples 2, 7, 1 1 and castanospermine. ³ enzyme ¹³ 2 7 11 castanospermine -glucosidase II Neutral (RE, yeast) 0.54 3.4 0.87> 1500

 α-glucosidasa Acid

 neither. neither. neither. 0.1

(lysosomial, human)

 Trehalasa

 185 n.i. neither. neither.

 (pig kidney)

 Amyloglucosidasa

 138 328 n.i. fifteen

{Aspergilius niger)

 Neutral β-Glucosidase

 21 60 253 40

(cytosol, ox liver)

 β-G! ucosidase

 236 149 682 1, 5

(almonds)

competitive inhibition in all cases. ^b No inhibition at 1 mM concentration is observed for any of the new compounds against α-mannosidase (from Jack bean beans and of human lysosomal origin), β-mannosidase {Helix pomatia), ce-galactosidase (green coffee beans and of human lysosomal origin) and β-galactosidase {£. coli and of human lysosomal origin), ni = No inhibition is observed at 1 mM concentration.

The compounds of examples 2, 7 and 1 1 showed total configurational selectivity for glucosidases (no inhibition was observed for ce- and β-mannosidases or a- and β-galactosidases) and a high affinity towards the oc-glucosidasa li neutral enzyme ( RE). The oc-selectivity against ia β-giucosidase was considerably higher for the S- and C-glycosides neutral (examples 7 and 1 1) than for the basic A / -glycoside (example 2). None of the sp ² -imino-sugar analogs of castanospermine was active against human lysosomial acid ct-glucosidase, an enzyme that belongs to the same GH31 family as the neutral α-glucosidase II. In comparison, castanospermine is a very poor inhibitor of yeast cc-glucosidase II, but it has been shown to inhibit human liver α-glucosidase II RE, with 100 times lower potency compared to lysosomial enzyme (K _t 10 fente at 0.1 μΜ). It also behaves as a potent inhibitor of β-glucosidases. Also, the compounds of examples 12, 13, 14, 15, 22, 30, 38, 39, 40, 41, 55, 56 and 57 showed values of K¡ (yeast α-glucosidase, μΜ) of 1 .20 , 23.0, 7.30, 7.90, 5.70, 70.00, 25.00, 16.00, 1 .60, 0.68, 34.00, 1 .20, and 1 .00 respectively and the compounds of examples 16, 17 and 18 showed values of K¡ (α -Ja beans bean, μΜ) of 27, 4.5 and 62 respectively.

EXAMPLE 59

 Biological test 2: Study of the cytostatic and cytotoxic activity against the human breast carcinoma MCF-7 cell line

The cytostatic and cytotoxic activity of Examples 2, 7 and 1 1 against the human breast carcinoma MCF-7 cell line is shown in Figures 1 AC (Antiproliferative and cytotoxic activity of the compounds of Examples 2, 7 and 1 1 in MCF-7 breast cancer cells (3 independent experiments) The N-oc \\\ derivative 2 decreased cell proliferation to 78.6 ± 5.7% (P <0.05), and 56.3 ± 6.6% (P <0.01) at 50 and 100 μΜ, respectively, with a very low cytotoxic profile Only 2% mortality at 100 μΜ was observed (Figure 1, example 2). Octyl 7 showed prolonged dose-dependent anti-proliferative activity between 0-50 μΜ (IC ₅₀ 29 μΜ; 34.2 ± 9.5% proliferation at 50 μΜ; P <0.01) with virtually no cell mortality observed in this range (Figure 1 example 7) C 1 glycoside 1 1 proved to be a more potent antiproliferative agent at low concentrations (IC ₅₀ 22 μΜ) At 50 μΜ cell proliferation was re it decreased to 16.7 ± 5.3% (P <0.01), but with 40% cell mortality (Figure 1, example 1 1). In comparison, the anti-cancer drug doxorubicin shows more than 50% mortality at concentrations necessary to inhibit 50% proliferation in this cell line.

Claims

1.- A compound of formula I:

 I or a salt thereof, where: X represents O, S or -NR ₅ ; Y represents O or S; Ri represents Ci-i2alkyl, C2-i2alkenyl, C2-i2alkynyl, -COR6, -CONR ₆ R6, -COCONR ₆ R ₆ , -SR ₆ , -SOR ₆ , -S0 ₂ R ₆ , -SO ₂ NR ₆ R6, - SOaNRgCORe, -NR ₆ R ₆ , -NR ₅ COR ₆ , -NR ₅ (C = O) NR ₆ R ₆ , -NR ₅ (C = S) NR ₆ R ₆ , -NR ₅ (C = NR ₅ ) NR ₆ R ₆ , -NR ₅ C02R6 or -NR5SO2R6, where Ci-i ₂ alkyl, C ₂ -i ₂ -alkenyl and C ₂ -i ₂ -alkynyl are independently optionally substituted by one or more R ₇ ; R2 represents hydrogen, C2-alkyl, C2-i2alkenyl, C2-i2alkyl, -COR6, -CONR ₆ R6, or Cy-ι, where Ci-i ₂ alkyl, C ₂ -i2alkenyl and C ₂ -i2alkynyl are independently optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re; or two groups R1 and R2 are optionally linked to form a monocyclic ring of 3 to 7 members which can be carbocyclic or heterocyclic in which case it can contain 1 to 4 heteroatoms selected from N, S and O, which can be saturated or partially saturated. unsaturated, and wherein one or more carbon atoms or S ring may be optionally oxidized forming CO groups, SO or SO2, and optionally substituted by one or more Rs R3 and _R4 independently represent hydrogen, Ci-i2alquilo, C- 2-i2alkenyl, C ₂ -i2alkyl, -COR6, -CONR ₆ R6, or Cyi, where Ci- 2alkyl, C-2-i2alkenyl and C2-i2alkynyl are independently optionally substituted by one or more R ₇ and Cy-i is optionally substituted by one or more R ₈ ; each R ₅ represents hydrogen or C1-2 alkyl; each R6 independently represents hydrogen, Ci-i2alkyl, haloCi-

or Cyi, where Cy-ι is optionally substituted by one or more R ₈ ; each R independently represents halogen, -CN, -N0 ₂ , -CORg, - CO2R9, -CONR9R9, -ORg, -OCORg, -OCONRgRg, -OC0 ₂ R ₉₎ -SR ₉ , -SOR ₉₎ - SO2R9, -SO2NR9R9 , -S02NR ₅ COR _9j -NR9R9, -NR5COR9 _, -NR5CONR9R9, - NR5CO2R9, -NR5SO2R9 or Cyi, where Cy is optionally substituted by one or more Re; Each Rg independently represents CM2alkyl,

haloC-i-i ₂ alkyl, Ci-i2alkoxyC- ₁₂ alkyl, halogen, -CN, -N0 ₂ , -COR ₉ , -C0 ₂ Rg, -CONR ₉ R ₉ , -ORg, -OCOR ₉ , -OCONR ₉ R ₉ , -OCO ₂ R ₉₎ -SR ₉ , -SORg, -SO ₂ R ₉ , -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9

each Rg independently represents hydrogen, Ci-i ₂ alkyl, haloCi- ₂ alkyl,

or cyanoCi-i ₂ alkyl; Y each Cyi independently represents a 3- to 7-membered monocyclic or 6 to 11-membered bicyclic ring which may be carbocyclic or heterocyclic in which case it may contain from 1 to 4 heteroatoms selected from N, S and O, where Cyi can be saturated or partially unsaturated, and may be attached to the rest of the molecule through any available C or N atom, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO2 groups, with the condition that the following compounds are excluded:

 2. - A compound according to claim 1 wherein X represents O.  3. - A compound according to any of claims 1 or 2 wherein Y represents O. 4. A compound according to claims 1 to 3 wherein Ri represents Ci-i ₂ alkyl, C ^ alkenyl, C ₂ -i2alkynyl, -SRe, -NR ₆ R6, -NR ₅ COR ₆ , -NR ₅ (C = 0 ) NR ₆ R _6, -NR ₅ (C = S) NR ₆ R ₆ or -NR ₅ (C = NR ₅₎ NR ₆ R _6, where d- i2alquilo, C2-i2alquenilo and C ₂ -i ₂ alkynyl are independently optionally substituted by one or more R7. 5. A compound according to claim 4 wherein R1 represents _Ci-i2 alkyl, -SR _6, -NR ₆ R _6, -NR ₅ COR _{5 6j} -NR (C = 0) NR ₆ R _6, -NR ₅ ( C = S) NR ₆ R ₆ or

is optionally substituted by one 6. A compound according to claim 5 wherein R ₁ represents C _1. ^ Alkyl, -SRe or -NR ₆ R6, wherein

is optionally substituted by one or more R ₇ . 7. A compound according to claim 6 wherein R1 represents Ci-i2alquílo or -NR ₆ R 6, where _Ci-i2 alkyl, is optionally substituted by one or more R _7. 8. - A compound according to any of claims 1 to 7 wherein R ₂ represents hydrogen, _Ci-i2 alkyl, -COR _6, -CONR ₆ R ₆ or Cyi, where Ci- i2alquilo is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more Re- 9. - A compound according to reinvindication 8 where R ₂ represents hydrogen, Ci-i ₂ alkyl or Cy-ι, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ and Cyi is optionally substituted by one or more R ₈ ; 10. - A compound according to reinvindication 9 where R ₂ represents hydrogen. 11. A compound according to any of claims 1 to 10 wherein R3 and R ₄ independently represent hydrogen or Ci-i ₂ alkyl, where Ci-i ₂ alkyl is optionally substituted by one or more R ₇ . 12. A compound according to claim 11 wherein R ₃ and R ₄ independently represent hydrogen. 13. A compound according to any of claims 1 to 12 selected from:  {5S, 6S, 7S, 8fí, 8afí) -5-Octylamino-6,7,8-tnhydroxy-2-oxa-3-oxoindolizidine; (5fí, 6fí, 7S, 8fí, 8afí) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; Y (5fí, 6S, 7fí, 8fí, 8afí) -5-Octyl-6,7,8-trídroxy-2-oxa-3-oxoindolizidine. 14. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 15. - Use of a compound of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases mediated by glycosidases. 16. - Use of a compound of formula I according to any of the claims 1 to 13 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of at least one disease selected from cancer, viral infections, tuberculosis, diabetes and glycosphingolipid storage disorders. 17. Use of a compound of formula I according to claim 16 wherein the disease is selected from cancer; preferably of lung, pancreas, colon, prostate, skin and breast cancer; and even more preferably breast cancer.  18. A process for preparing a compound of formula I according to claim 1, comprising:  (a) reacting a compound of formula il with a compound of formula lil:

 II III where A represents a halogen group; Z represents a nucleophile group; and where X, Y, Ri, F½, R3 and R4 have the meaning described above; or (b) reacting a compound of formula II with a compound of formula IV:

IV where R1 represents Ci-i2alkyl, C2-i2alkenyl or C ^ alkynyl, where each C1-i2alkyl, C2-i2alkenyl or C2-i2alkyl is independently optionally substituted by one or more R ₇ ; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R ₂ , R3 and R ₄ have the meaning described above; or (c) reacting a compound of formula V with a compound of formula

v VI where B represents hydrogen or -COFFI ₆ ; C represents -NH ₂ , -SH or -CN; Ri represents Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl or C ₂ -i ₂ alkynyl, where each Ci-i ₂ alkyl, C ₂ -i ₂ alkenyl or C ₂ -i ₂ alkynyl is independently optionally substituted by one or plus R ₇ ; and where X, Y, R ₂ , R ₃ and R ₄ have the meaning described above; or  (d) transform, in one or several stages, a compound of formula l into another compound of formula I.