ES2370852B1 - SP2 DERIVATIVES, IMNOAZÚCAR AS INHIBITORS OF ALPHA-GLYCOSIDASES. - Google Patents

Abstract

Sp {sup, 2} imnoazúcar derivatives as inhibitors of {al} -glycosidases. # Glycosylated derivatives of formula I, where the meanings for the different substituents are those indicated in the description. These compounds are useful as inhibitors of {al} -glycosidases.

Description

Sp2 imnoazúcar derivatives as inhibitors of α-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 inhibitors of glycosyl hydrolases in therapies directed to cancer, viral infections, tuberculosis, diabetes and storage disorders of glycosipolipids, has led to the discovery of many types of natural and synthetic structures that help unravel both the mechanism of action of glycosidases as to 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 the 1-deoxinojirimycin and castanospermine alkaloids, which are potent inhibitors of neutral α-glucosidases (α-glucosidases I and II) that participate in the processing of Nglicoproteins in the endoplasmic reticulum (ER). Since there is evidence that abnormal glycosidation of glycoproteins and glycolipids plays a crucial role in several pathophysiological processes involved in tumor progression, both 1-deoxinojirimycin and castanospermine would be promising as anti-cancer agents if the above-mentioned problems were resolved.

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

The attempt to develop more selective inhibitors of the neutral α-glucosidases of the ER by chemically modifying the natural alkaloids has proved unsuccessful. Alternatively, sp2iminoazúcar 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 (such as carbamate groups , thiocarbamate, urea, thiourea or guanidine) with an accused sp2 character. 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 CO bond, translates into a significant increase in the orbitical contribution to the anomeric effect, setting the orientation axial in aqueous solution. Consequently, these compounds have stereochemical complementarity with α-glycosides, which translates into a very high α-anomeric selectivity in their inhibition of glycosidases. It should be noted that the "reducing" bicyclic sp2-iminoazúres with a 5-hydroxy-2-oxacastanospermine structure show a remarkable selectivity between different α-glucosidases, preferably by 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 the 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 α-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.

One aspect of the invention refers to the compounds of formula I

where:

X represents O, So-NR5;

And represents OOS;

R1 represents C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, -COCONR6R6, -SR6, -SOR6, -SO2 R6, -SO2NR6R6, -SO2NR5COR6, -NR6R6, -NR5COR O) NR6R6, -NR5 (C = S) NR6R6, -NR5 (C = NR5) NR6R6, -NR5CO2R6 or -NR5SO2R6, where C1-12alkyl, C2-12alkenyl and C2-12alkyl are independently optionally substituted by one or more R7;

R2 represents hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkyl are independently optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8;

or two R1 and R2 groups are optionally linked to form a 3- to 7-membered monocyclic ring that may be carbocyclic or heterocyclic in which case it may contain from 1-4 heteroatoms selected from N, S and O, which may be saturated or partially unsaturated, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO2 groups, and which is optionally substituted by one or more R8

R3 and R4 independently represent hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CON R6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8;

each R5 represents hydrogen or C1-12 alkyl;

each R6 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl, cyanoC1-12alkyl or Cy1, where Cy1 is optionally substituted by one or more R8;

Each R7 independently represents halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9, -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5ROR9, -NN , -NR5COR9, -NR5CONR9R9, -NR5CO2R9, -NR5SO2R9 oCy1, where Cy1 is optionally substituted by one or more R8;

Each R8 independently represents C1-12 alkyl, hydroxy C1-12 alkyl, halo C1-12 alkyl, C1-12 alkylC1-12 alkyl, halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9 , -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9 or -NR5SO2R9;

each R9 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl or cyanoC1-12alkyl; Y

each Cy1 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 Cy1 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 can be optionally oxidized to form CO, SO or SO2 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 glycosidases mediated diseases.

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

or a salt thereof, where:

X represents O, So-NR5;

And represents OOS;

R1 represents C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, -COCONR6R6, -SR6, -SOR6, -SO2R6, -SO2NR6R6, -SO2NR5COR6, -NR6R6, -NR5COR (-NR5COR5) ) NR6R6, -NR5 (C = S) NR6R6, -NR5 (C = NR5) NR6R6, -NR5CO2R6 or -NR5SO2R6, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7;

R2 represents hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkyl are independently optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8;

or two R1 and R2 groups are optionally linked to form a 3- to 7-membered monocyclic ring that may be carbocyclic or heterocyclic in which case it may contain from 1-4 heteroatoms selected from N, S and O, which may be saturated or partially unsaturated, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO2 groups, and which is optionally substituted by one or more R8.

R3 and R4 independently represent hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CON R6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8;

each R5 represents hydrogen or C1-12 alkyl;

each R6 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl, cyanoC1-12alkyl or Cy1, where Cy1 is optionally substituted by one or more R8;

Each R7 independently represents halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9, -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5ROR9, -NN , -NR5COR9, -NR5CONR9R9, -NR5CO2R9, -NR5SO2R9 oCy1, where Cy1 is optionally substituted by one or more R8;

Each R8 independently represents C1-12 alkyl, hydroxy C1-12 alkyl, halo C1-12 alkyl, C1-12 alkylC1-12 alkyl, halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9 , -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9 or -NR5SO2R9;

each R9 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl or cyanoC1-12alkyl; Y

each Cy1 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 Cy1 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 can be optionally oxidized to form CO, SO or SO2 groups,

with the proviso 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 αglycosidases.

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 disease selected from cancer, viral infections, tuberculosis, diabetes and storage disorders of glycosipolipids. 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, which comprises:

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

where A represents a halogen group; Z represents a nucleophilic group; and where X, Y, R1, R2, R3 and R4 have the meaning described above; or

(b) reacting a compound of formula II with a compound of formula IV:

where R1 represents C1-12alkyl, C2-12alkenyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R2, R3 and R4 have the meaning described above; or

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

where B represents hydrogen or -COR6; C represents -NH2, -SH or -CN; R1 represents C1-12alkyl, C2-12alkyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; and where X, Y, R2, 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.

In the above definitions, the term C1-12alkyl, as a group or part of a group, means a straight or branched chain alkyl group containing 1 to 12 C atoms. Examples include methyl, ethyl, propyl, isopropyl groups. butyl, isobutyl, sec-butyl, tert-butyl, ventyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

A C2-12 alkenyl group means a linear or branched alkyl chain containing from 2 to 12 atoms of C, and also containing 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, 1nonenyl, 1-decenyl, 1-undecenyl and 1-dodecenyl.

A C2-12alkynyl group means a linear or branched alkyl chain containing from 2 to 12 C atoms, and also containing 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-hexinyl, 1-heptinyl, 1-octinyl, 1-noninyl groups, 1-decinyl, 1-undecinyl and 1-dodecinyl.

A C1-12alkoxy group, as a group or part of a group, means a -OC1-12alkyl group, where the C1-12alkyl part has the same meaning described above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, octoxy and nonoxy.

A halogen radical or its abbreviation halo means fluorine, chlorine, bromine or iodine.

A C1-12alkoxyC1-12alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-12 alkyl group by one or more C1-12alkoxy groups as defined above, which may be the same or different. Examples include, among others, the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-diethoxyethyl, 1 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 2-sec-butoxyethyl, 3-tert-butoxypropyl and 4-methoxybutyl.

A haloC1-12 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-12 alkyl group with one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which may be the same

or different. Examples include, among others, the tri-fluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-tri-fluoroethyl, pentafluoroethyl, 3-fl uoropropyl groups 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nona fluorobutyl.

A hydroxyC 1-12 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-12 alkyl group by one or more hydroxy groups. Examples include, but are not limited to, 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 cyanoC1-12 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1-12 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 Cy1 group refers to a 3- to 7-membered monocyclic or 6 to 11-membered bicyclic heterocycle with the proviso that the ring is saturated or partially unsaturated. When Cy1 is bicyclic, the second ring can be saturated, partially unsaturated or aromatic. Cy1 contains a total of 1-4 heteroatoms selected from N, O and S. Cy1 can be attached to the rest of the molecule through any available C or N atom. When Cy1 is a bicyclic ring, it can be formed by two rings fused through two adjacent C or N atoms,

or through two non-adjacent atoms of C or N forming a bridge ring, or it may be formed by two rings joined through a single atom of C forming a ring of the Spieran type. In Cy1 one or more C or S atoms of any saturated or partially unsaturated ring may optionally be oxidized forming CO, SO or SO2 groups. The group Cy1 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 Cy1 groups include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, aziridinyl, azetidinyl, 1,4-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-oxoazetidinyl, 2-oxo-1,4-diazepanyl, 2-oxo-pyrid, 2-oxo-2-oxyl -oxo-piperazinyl, 2-oxo-piperidinyl, 3-oxo-piperidinyl, 4oxo-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] heptan ilo, 6-aza-bicyclo [3.2.1] octanyl, octahydro-pyrrolo [1,2-a] pyrazinyl, 2Hespiro [benzofuran-3,4'-piperidinyl], 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 Cy1, when the speci fi ed 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 speci fi ed examples refer to a radical of a ring in general terms, for example tetrahydrofuran, all possible binding positions are included, except that in the de fi nition of the group corresponding, indicate any limitation in this regard, in which case such limitation applies. Thus, for example, in the definition of Cy1, which does not include any limitation with respect to the binding position, the term tetrahydrofuran includes 2-tetrahydrofuran and 3-tetrahydrofuran.

The term "nucleophilic group" refers to a species that reacts by giving 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 in 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 nucleophils such as hydrogen sulphides, thiols, thiolates and sulfides. Examples of nucleophilic groups include, among others, water, methanol, ethanethiol, sodium propionate, 1-propanylamine, 1-octylamine, 1,1-diethylamine, 1-octanotiol, dimethyl sulphide, 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, bonds between metal atoms (or metalloids) and carbon atoms, M + δ -C − δ, 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, trioctylaluminium, ethyl mercury chloride, methyl magnesium iodide, diethyl 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 expression "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 in a definition of a substituent two or more groups appear with the same numbering (for example-CONR6R6, -NR9R9, -CONR9R9, 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 that 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 refers to the compounds of formula I as defined above.

In another embodiment, the invention relates to the compounds of formula I 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 -NR5.

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 I wherein R 1 represents C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 ( C = S) NR6R6 or -NR5 (C = NR5) NR6R6, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I wherein R 1 represents C 1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5) NR6R6, where C1-12 alkyl, is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I wherein R 1 represents C 1-12 alkyl, -SR 6 or -NR 6 R 6, where C 1-12 alkyl, is optionally substituted by one or more R 7.

In another embodiment, the invention relates to the compounds of formula I where R 1 represents C 1-12 alkyl or -NR 6 R 6, where C 1-12 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 R1 represents C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5)

NR6R6, where C1-12 alkyl, is optionally substituted by one or more R7.

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

X represents O; Y

R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

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

X represents O; Y

R1 represents C1-12 alkyl or -NR6R6, where C1-12 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 C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5)

NR6R6, where C1-12 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 C1-12 alkyl, -SR6 or -NR6R6, where C1-12 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 C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; Y R1 represents C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5)

NR6R6, where C1-12 alkyl, is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; Y R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; Y R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R1 represents C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5)

NR6R6, where C1-12 alkyl, is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; Y R1 represents C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5)

NR6R6, where C1-12 alkyl, is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; Y R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

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

X represents O;

Y represents S; Y

R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7.

In another embodiment, the invention relates to the compounds of formula I where R2 represents hydrogen, C1-12 alkyl, -COR6, -CONR6R6 oCy1, where C1-12 alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8.

In another embodiment, the invention relates to the compounds of formula I wherein R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8;

In another embodiment, the invention relates to the compounds of formula I wherein R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12 alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

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

Y represents S;

R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment, the invention relates to compounds of formula I wherein R 3 and R 4 independently represent hydrogen or C 1-12 alkyl, where C 1-12 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; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; Y R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; Y R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to compounds of formula I where: R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1 −12 alkyl, where C1−12 alkyl is optionally substituted

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; and R3 and R4 independently represent hydrogen or C1-12 alkyl, where C1-12 alkyl is optionally substituted.

Do for one or more R7, preferably R3 and R4 independently represent hydrogen.

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

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents O; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

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

R1 represents R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; R1 represents R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or

plus R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents O; R1 represents R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or

plus R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: Y represents S; R1 represents R1 represents C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or

plus R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

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

X represents O;

Y represents O;

R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 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 C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or

plus R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment, the invention relates to the compounds of formula I where: X represents O; Y represents S; R1 represents C1-12 alkyl, -SR6 or -NR6R6, where C1-12 alkyl is optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and

Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 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 C1-12 alkyl or -NR6R6, where C1-12 alkyl is optionally substituted by one or

plus R7;

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 independently represent hydrogen.

In another embodiment the invention refers to the compounds of formula I selected from Ia-Ii: In another embodiment the invention refers to the compounds of formula I selected from Ia-Ii:

where:

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen.

In another embodiment the invention refers to the compounds of formula I selected from Ia-Ii:

where:

R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8, preferably R2 represents hydrogen; Y

R3 and R4 independently represent hydrogen or C1-12alkyl, where C1-12alkyl is optionally substituted by one or more R7, preferably R3 and R4 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 the activity of neutral α-glycosidase at 100 µM, more preferably at 10 µM, even more preferably at 1 µM and still more preferably at 0.1 µM in a glycosidase inhibition assay such as that described in example 58.

In another embodiment, the invention relates to a compound of formula I 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, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5R, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5R, 6S, 7R, 8R, 8aR) -5-Octyl-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (4-Hydroxybutylamino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Pent-3-yl-amino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6R, 7S, 8R, 8aR) -5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6R, 7S, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6R, 7S, 8R, 8aR) -5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Octylthioureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Acetamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Butanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Octanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5S, 6S, 7S, 8R, 8aR) -5- (Adamantane-1-carboxamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine;

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

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

(5R, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; Y

(5R, 6S, 7R, 8R, 8aR) -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, tri-fluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic 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, N-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. Pharmaceutically acceptable salts 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 I can in turn be transformed 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 those that are precipitated or crystallized. These complexes are known as solvates. As used herein, the term "solvate" refers to a complex of variable stoichiometry 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 their salts), 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 diffractograms, melting points or solubility. All physical forms of the compounds of formula I, 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 performed on synthesis intermediates that are chiral 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. Also, in some of the procedures detailed below, it may be necessary or convenient to protect reactive or labile groups by conventional protecting 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, 3rd 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 various 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-oxa3-oxocastanospermine derivative, obtained from commercial D-glucurono-3-lactone in five stages, 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, the content of which is incorporated herein by reference). It is based on the hypothesis that the gauche-trans orientation of the oxygen atom equivalent to O-6 in glucopyranosides (O-2 in the nomenclature of indolizidines) could confer selectivity to the inhibitory activity of these compounds, in comparison with the Free spin scenario found in 1-deoxinojirimycin or of the gauche-gauche orientation in castanospermina. The incorporation of axially oriented pseudoanomeric substituents guarantees αanomeric 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:

Scheme 1

where A represents a halogen group; Z represents a nucleophilic group; and where X, Y, R1, R2, R3 and R4 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 reaction with a nucleophile of formula III are the conditions of a conventional nucleophilic substitution (SN).

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

Scheme 2

where R1 represents C1-12alkyl, C2-12alkenyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R2, R3 and R4 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 stages by the method described in scheme 3:

Scheme 3

where B represents hydrogen or -COR6; C represents -NH2, -SH or -CN; R1 represents C1-12alkyl, C2-12alkyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; and where X, Y, R2, R3 and R4 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 11, 5-hydroxy-2-oxa-3-oxocastanospermine (scheme 4), easily obtained from commercial D-glucurono-3-lactone in five steps, was chosen as the basic skeleton .

Scheme 4

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

The per-O-acetylated thioglycoside analog of castanospermine (example 7) was obtained as a mixture of the corresponding α and β anomers in a 20: 1 ratio by reacting the corresponding sp2-imino sugar with tetra-O-acetate with octanotiol after selective activation of the Hemiaminal center with BF3.OEt2. 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 8C5 chair conformation as a major diastereoisomer. The minor β-anomer adopts the 5.8B boat conformation, placing the octylthio group in axial arrangement, thus fulfilling the anomeric effect. 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 derivative of scheme 4, obtained from the corresponding per-O-acetylated by treatment with poly (hydrogen fluoride) pyridine (HF / pyridine). The reaction of the aforementioned fluoroderivative with tri-n-octylaluminum in anhydrous toluene proceeded gently at 0 ° C to give a mixture of the triacetates α 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, R1 R2, R3 or R4 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 NiCl2, or SnCl2;

the replacement 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 LiAlH4;

the oxidation of a thioether to sulfoxide or sulfone under standard conditions;

the transformation of an alcohol into a halogen by treatment with SOCl2, PBr3, tetrabutylammonium bromide in the presence of P2O5, oPl3;

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 nucleic 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 RE neutral neutral α-glycosidases selectively. Therefore, these compounds could be useful for the treatment of those diseases in which the participation of the neutral α-glycosidases of the ER 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. Compain, 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 Mitrakou, A. et al. Diab. Med. 1998, 15, 657; Scott, LJ et al. Drugs, 2000, 59, 521) and storage disorders of glycosipolipids (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 α-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 antiproliferative activity assays against human breast carcinoma MCF-7 cell line (see for example the method described in El Hiani, Y. et al. Arch. Biochem. Biphys. 2009, 486, 58, the content of which is here incorporated by reference).

To select active compounds, the 100 µM 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 µM; even more preferably more than 50% inhibition at 1 μM; and still more preferably more than 50% inhibition at 0.1 µM.

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 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 may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate; binding agents such as starch, gelatin or polyvinylpyrrolidone; 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 pellets by using natural or synthetic film 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 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. . As an 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 fi gures

Figure 1: Antiproliferative and cytotoxic activity of the compounds of examples 2,7 and 11 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

CDCl3: Deuterated Chloroform

EtOAc: ethyl acetate

MeOD: deuterated methanol

MEOH: methanol

HPLC: high performance liquid chromatography.

Example 1

α, β- (5Sy5R, 6S, 7S, 8R, 8aR) -5-octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

A solution of the derived 5-hydroxy-2-oxa-3-oxoindolizidine (152 mg, 0.74 mmol) and n-octylamine (124 µL, 0.74 mmol) in methanol (1 mL) are stirred at 65 ° C for 2 h (control via CCF). 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

α- (5S, 6S, 7S, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The α-anomer was obtained by purifying the α: β mixture of example 1 by chromatographic column (from 20: 1 to 10: 1 dichloromethane-methanol). Yield: 142 mg (60%). Rf 0.45 (9: 1 dichloromethane-methanol). [α] D +69.2 (c 1.0 in methanol). 1H NMR (500 MHz, MeOD) δ 4.64 (d, 1 H, J5.6 = 5.0 Hz, H-5), 4.50 (t, 1 H, J1a, 8a = J1a, 1b = 8 , 5Hz, H-1a), 4.29 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.85 (ddd, 1 H, J8a, 8 = 9.5 Hz, H -8a), 3.63 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H7), 3.49 (dd, 1 H, H-6), 3.28 (t, 1 H, H-8), 2.60 (m, 2 H, CH2NH), 1.53 (m, 2 H, CH2CH2NH), 1.35 (m, 10 H, CH2), 0.92 (t, 3H , 3JH, H = 7.0 Hz, CH3). 13C 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 (CH2NH), 34.3-25.0 (CH2), 15.7 (CH3). ESIMS: m / z 339.2 [M + Na] +. Anal. Calcd for C15H28N2O5: C, 56.94; H, 8.92; N, 8.85. Found: C, 56.76; H, 8.83; N, 8.71.

Example 3

(5R, 6R, 7S, 8R, 8aR) -5-Fluoro-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

On the compound (5R, 6R, 7S, 8R, 8aR) -5,6,7,8-tetra-O-acetyl-2-oxa-3-oxoindolizidine (560 mg, 1.50 mmol) cooled to -40 ° C acid is added fl uorhydric / pyridine (70% fl uoric acid; 2.8 mL). The reaction mixture is stirred at this temperature for 80 min (control by TLC), diluted with diethyl ether (30 mL), washed with a saturated solution of potassium fl uoride (15 mL) and extracted 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 (5R, 6R, 7S, 8R, 8aR) -5,6,7,8-tetra-O-acetyl-2-oxa-3oxoindolizidine (150 mg, 27%) was recovered. Title compound: Rf 0.77 (2: 1 EtOAc-petroleum ether). [α] D +21.6 (c 0.9 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 6.17 (dd, 1 H, J5, F = 52.5 Hz, J5.6 = 3.5 Hz, H-5), 5.60 (t, 1 H, J6.7 = J7.8 = 10.0 Hz, H-7), 5.00 (ddd, 1 H, J6, F = 14.0 Hz, H-6), 4.99 (t, 1 H, J8.8a = 10.0 Hz, H-8), 4.51 (dd, 1 H, J1a, 1b = 9.0 Hz, J1a, 8a = 8.0 Hz, H-1a), 4.32 ( t, 1 H, J1b, 8a = 9.0 Hz, H-1b), 4.17-4.09 (m, 1 H, H-8a), 2.15-2.09 (3 s, 9 H , Dumb). 13C NMR (125.7 MHz, CDCl3) δ 170.0-169.5 (MeCO), 154.2 (CO), 87.5 (C-5, d, JC5, F = 211.6 Hz), 72 , 0 (C-8), 69.8 (C-6, d, JC6, 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. Calcd for C13H16NO8F: C 46.85, H 4.84, N 4.20. Found: C 46.77, H 4.71, N 4.02.

Example 4

α, β- (5Ry5S, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

On a solution of (5R, 6R, 7S, 8R, 8aR) -, 6,7,8-tetra-O-acetyl-2-oxa-3-oxoindolizidine (59 mg, 0.16 mmol) in anhydrous dichloromethane (3 mL) at 0 ° C, BF3.Et2O (70 µL, 0.57 mmol) and 1-octanotiol (58 µL, 0.33 mmol) are added under N2 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

α- (5R, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

The α-anomer was obtained by puri fi cation of the α: β mixture of example 4 by chromatographic column.

(2: 3 EtOAc-petroleum ether). Yield: 24 mg (73%). Rf 0.75 (1: 1 EtOAc-petroleum ether). [α] D +70.8 (c 0.7 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 5.69 (d, 1 H, J5.6 = 6.0 Hz, H-5), 5.44 (t, 1 H, J6.7 = J7.8 = 10 , 0 Hz, H-7), 4.97 (dd, 1 H, H-6), 4.94 (t, 1 H, J8a, 8 = 9.5 Hz, H-8), 4.47 ( dd, 1 H, J1a, 1b = 9.5Hz, J1a, 8a = 8.5 Hz, H-1a), 4.30 (dd, 1 H, J1b, 8a = 6.5 Hz, H-1b), 4.18 (ddd, 1 H, H-8a), 2.63 (ddd, 1 H, 2JH, H = 12.5 Hz, 3JH, H = 8.5Hz, 3JH, H = 7.0Hz, SCH2) , 2.49 (ddd, 1 H, SCH2), 2.11-2.05 (3 s, 9 H, MeCO), 1.68-1.50 (m, 2 H, SCH2CH2), 1.42- 1.24 (m, 10 H, CH2), 0.89 (t, 3H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2), 20.6-20, 5 (MeCO), 14.1 (CH3). ESIMS: m / z 481.8 [M + Na] +. Anal. Calcd for C21H33NO8S: 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

β- (5S, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

The β-anomer was obtained by puri fi cation of the α: β mixture of example 4 by chromatographic column

(2: 3 EtOAc-petroleum ether). Yield: 4 mg (12%). Rf 0.53 (1: 1 EtOAc-petroleum ether). [α] D -9.0 (c 0.3 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 5.29 (dd, 1 H, J8a, 8 = 10.5 Hz, J7.8 = 7.0 Hz, H-8), 5.23 (t, 1 H, J5.6 = J6.7 = 4.0 Hz, H-6), 5.12 (dd, 1 H, H-7), 4.72 (d, 1 H, H-5), 4.42 ( t, 1 H, J1a, 1b = J1a, 8a = 8.0 Hz, H-1a), 4.17 (t, 1 H, J1b, 8a = 9.0 Hz, H-1b), 4.00 ( ddd, 1 H, H-8a), 2.96-2.84 (m, 2 H, SCH2), 2.15-2.10 (3 s, 9 H, MeCO), 1.70-1.20 (m, 12 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2), 20.9-20, 6 (MeCO), 14.1 (CH3). ESIMS: m / z 482.2 [M + Na] +. HRFABMS Calcd for C21H33NO8SNa [M + Na] + 482.1825, found 482.1830.

Example 7

α- (5R, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-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%). Rf 0.33 (EtOAc). [α] D +104.2 (c 0.8 in methanol). 1H NMR (500 MHz, MeOD) δ 5.28 (d, 1 H, J5.6 = 5.5 Hz, H-5), 4.58 (t, 1 H, J1a, 8a = J1a, 1b = 8 , 5 Hz, H-1a), 4.30 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b), 3.95 (td, 1 H, J8a, 8 = 8.5 Hz, H-8a), 3.68 (dd, 1 H, J6.7 = 9.5 Hz, H-6), 3.55 (t, 1 H, J7.8 = 9.5 Hz, H-7) , 3.37-3.31 (m, 1 H, H-8), 2.60 (ddd, 1 H, 2JH, H = 13.0 Hz, 3JH, H = 8.0 Hz, 3JH, H = 6.0Hz, SCH2), 2.53 (ddd, 1 H, SCH2), 1.72-1.56 (m, 2 H, SCH2CH2), 1.48-1.28 (m, 10 H, CH2) , 0.92 (t, 3 H, 3 JH, H = 7.0 Hz, CH3). 13C 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 (CH2), 13.0 (CH3). ESIMS: m / z 355.8 [M + Na] +. Anal. Calcd for C15H27NO5S: 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

α, β- (5Ry5S, 6R, 7S, 8R, 8aR) -5-octyl-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

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 ° C. Trioctylaluminum (3.8 mL, 1.80 mmol, 2.0 equiv.) Is then added 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 EtOAc-petroleum ether) to give the title compound (260 mg, 68% yield) as a mixture of the corresponding α and β anomers (α ratio : β 4: 1; integration of H-7).

Example 9

α- (5R, 6S, 7R, 8R, 8aR) -5-Octyl-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

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. Rf 0.51 (1: 1 EtOAc-petroleum ether). [α] D +36.1 (c 1.0 in CHCl3). 1H NMR (500 MHz, CDCl3) δ 5.34 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7), 5.04 (dd, 1 H, J5.6 = 6 , 0 Hz, H-6), 4.96 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.41 (dd, 1 H, J1a, 1b = 9.0Hz, J1a , 8a = 8.0 Hz, H-1a), 4.27 (dd, 1H, J1b, 8a = 4.5 Hz, H-1b), 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, CH2), 1.43-1.22 (m, 12 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2), 20.7-20.6 (MeCO), 14.1 (CH3). ESIMS: m / z 450.3 [M + Na] +. Anal. Calcd for C21H33NO8: C 59.00, H 7.78, N 3.28. Found: C 59.11, H 7.81, N 3.21.

Example 10

β- (5S, 6S, 7R, 8R, 8aR) -5-Octyl-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

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. Rf 0.50 (1: 1 EtOAc-petroleum ether). [α] D -14.7 (c 1.0 in chloroform). 1H NMR (500 MHz, CDCl3) δ 5.16 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7), 5.08 (t, 1 H, J8.8a = 9 , 5 Hz, H-8), 5.04 (t, 1 H, J5.6 = 9.5 Hz, H-6), 4.33 (dd, 1 H, J1a, 1b = 9.0Hz, J1a , 8a = 7.0 Hz, H-1a), 4.12 (dd, 1 H, J1b, 8a = 4.0 Hz, H-1b), 3.70 (ddd, 1 H, H-8a), 3.31 (td, 1 H, 3 JH, H = 4.5 Hz, H-5), 2.40-2.30 (m, 1 H, CH2), 2.08-2.04 (3 s, 9 H, MeCO), 1.80-1.50 (m, 2 H, CH2), 1.40-1.20 (m, 11 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2), 20.6 (MeCO), 14, 1 (CH3). ESIMS: m / z 450.2 [M + Na] +. Anal. Calcd for C21H33NO8: C 59.00, H 7.78, N 3.28. Found: C 59.08, H 7.69, N 3.20.

Example 11

α- (5R, 6S, 7R, 8R, 8aR) -5-Octyl-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%). Rf 0.75 (9: 1 EtOAc-methanol). [α] D +42.3 (c 1.0 in methanol). 1H NMR (500 MHz, MeOD) δ 4.47 (dd, 1 H, J1a, 1b = 9.0Hz, J1a, 8a = 8.5 Hz, H-1a), 4.31 (dd, 1 H, J1b , 8a = 4.0 Hz, H-1b), 3.92 (ddd, 1 H, 3JH, H = 8.5Hz, 3JH, H = 3.0 Hz, J5.6 = 5.5 Hz, H- 5), 3.64 (ddd, 1 H, J8.8a = 9.5 Hz, H8a), 3.52-3.44 (m, 2 H, H-6, H-7), 3.25 ( bt, 1 H, J7.8 = 9.5 Hz, H-8), 1.94-1.85 (m, 1 H, CH2), 1.51-1.24 (m, 13 H, CH2) , 0.92 (t, 3 H, 3 JH, H = 7.0 Hz, CH3). 13C 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 (CH2), 13.1 (CH3). ESIMS: m / z 324.2 [M + Na] +. Anal. Calcd for C15H27NO5: C 59.78, H 9.03, N 4.65. Found: C 59.70, H 8.95, N 4.49.

Example 12

(5S, 6S, 7S, 8R, 8aR) -5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

To a solution of (5S, 6S, 7S, 8R, 8aR) -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 ° 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). Puri fi cation by column chromatography (CH2Cl2-MeOH 20: 1 → 10: 1). Yield: 133 mg (67%). Rf 0.38 (CH2Cl2-MeOH 9: 1). [α] D +84.1 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 4.65 (d, 1 H, J5.6 = 5.0 Hz, H-5), 4.50 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a) , 4.29 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.85 (ddd, 1 H, J8a, 8 = 9.5 Hz, H-8a), 3.63 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7), 3.49 (dd, 1 H, H-6), 3.28 (t, 1 H, H-8), 2.62 (ddd, 1 H, 2JH, H = 14.5 Hz, 3JH, H = 11.5 Hz, 3JH, H = 7.0 Hz, NHCH2), 2.58 (ddd, 1 H, NHCH2), 1.51 (m, 2 H, NHCH2CH2), 1.45-1.35 (m, 2H, CH2CH3), 0.96 ( t, 3 H, 3 JH, H = 7.0 Hz, CH3). 13C 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 (NHCH2), 34.0 (CH2), 22.7 (CH2), 15.5 (CH3). ESIMS: m / z 283.1 [M + Na] +. Analysis calculated for C11H20N2O5: C 50.76, H 7.74, N 10.76. Found: C 50.39, H 7.58, N

10.54.

Example 13

(5S, 6S, 7S, 8R, 8aR) -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). Puri fi cation by column chromatography (CH2Cl2-MeOH 5: 1) and GPC (Sephadex G-10, MeOH-H2O 1: 1). Yield: 90 mg (76%). Rf 0.41 (40: 10: 1 CH2Cl2-MeOH-H2O). [α] D -3.3 (c 0.5, H2O). 1H NMR (500 MHz, D2O) δ 4.65 (d, 1 H, J5.6 = 4.5 Hz, H-5), 4.54 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a) , 4.31 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.85 (ddd, 1 H, J8a, 8 = 9.5 Hz, H8a), 3.67 (ddd, 1 H, 2JH, H = 11.0 Hz , 3JH, H = 6.5Hz, 3JH, H = 4.5 Hz, CH2OH), 3.64-3.61 (m, 2 H, H-6, H-7), 3.60 (ddd, 1H, CH2OH), 3.44 (bt, 1 H, J7.8 = 9.5 Hz, H-8), 2.73 (ddd, 1 H, NHCH2), 2.65 (ddd, 1 H, NHCH2). 13C NMR (125.7 MHz, D2O) 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 (CH2OH), 52.9 (C-8a), 47.2 (NHCH2). ESIMS: m / z 271.0 [M + Na] +. Analysis calculated for C9H16N2O6: C 43.55, H 6.50, N 11.29. Found: C 43.15, H 6.33, N 11.02.

Example 14

(5S, 6S, 7S, 8R, 8aR) -5- (4-Hydroxybutylamino) -6,7,8-trihydroxy-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 α: β 10: 1 (integration of H-5). Puri fi cation by column chromatography (CH2Cl2-MeOH 5: 1). Yield: 24 mg (80%). Rf 0.45 (40: 10: 1 CH2Cl2-MeOH-H2O). [α] D -5.3 (c 1.0, H2O). 1H NMR (500 MHz, D2O) δ 4.63 (d, 1 H, J5.6 = 4.5 Hz, H-5), 4.53 (t, 1 H, J1a, 1b = J1a, 8a = 9.0Hz, H-1a) , 4.31 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.82 (ddd, 1 H, J8a, 8 = 9.5 Hz, H-8a), 3.65-3.56 (m, 2 H, H- 6, H-7), 3.54 (ta, 2H, 3JH, H = 6.0 Hz, CH2OH), 3.43 (ta, 1 H, J7.8 = 9.5 Hz, H-8), 2.64-2.48 (m, 2 H , NHCH2), 1.57-1.44 (m, 4 H, CH2CH2). 13C NMR (125.7 MHz, D2O) 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 (CH2OH), 53.0 (C-8a), 45.5 (NHCH2), 29.2 (CH2), 24.7 (CH2). ESIMS: m / z 299.1 [M + Na] +. Analysis calculated for C11H20N2O6: C 47.82, H 7.30, N 10.14. Found: C 47.49, H 7.05, N 9.85.

Example 15

(5S, 6S, 7S, 8R, 8aR) -5- (Pent-3-yl-amino) -6,7,8-trihydroxy-2-oxa-3-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. Puri fi cation by column chromatography (CH2Cl2-MeOH 5: 1). Yield: 24 mg (70%). Rf 0.81 (CH2Cl2-MeOH / H2O 40: 10: 1). [α] D +81.7 (c 0.75, MeOH). 1 H NMR (500 MHz, MeOD) δ 4.75 (d, 1 H, J5.6 = 5.0 Hz, H-5), 4.48 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a) , 4.29 (dd, 1 H, J1b, 8a = 5.0 Hz, H1b), 3.91 (ddd, 1 H, J8a, 8 = 9.5 Hz, H-8a), 3.65 (t, 1 H, J6.7 = J7, 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, 3JH, H = 7.0 Hz, CH3), 0.94 (t, 3H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, MeOD) δ 157.7 (CO), 74.3 (C-8), 73.2 (C-7), 71.1 (C-6), 66.5 (C1), 66.4 (C-5), 57.1 (C -3 '), 53.3 (C-8a), 26.7 (CH2), 24.9 (CH2), 9.5 (CH3), 8.4 (CH3). ESIMS: m / z 275.2 [M + H] +. Analysis calculated for C12H22N2O5: C 52.54, H 8.08, N 10.21. Found: C 52.35, H 7.76, N 10.04.

Example 16

(5S, 6R, 7S, 8R, 8aR) -5-Butylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

To a solution of (5S, 6R, 7S, 8R, 8aR) -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 stirred under Ar atmosphere at 50 ° C for 24

h. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography. Eluent CH2Cl2-MeOH-H2O 70: 10: 1. Yield: 72 mg (38%). Rf 0.41 (CH2Cl2-MeOH-H2O 40: 10: 1). [α] D = 18.3 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 4.60 (d, 1 H, J5.6 = 2.5 Hz, H-1), 4.51 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H-1a) , 4.31 (dd, 1 H, J8a, 1b = 4.5 Hz, H-1b), 3.97 (ta, 1 H, J6.7 = 2.5 Hz, H-6), 3.75 (m, 1 H, H-8a) , 3.70 (m, 2 H, H-7, H-8), 2.60 (m, 2H, CH2N), 1.48 (m, 2 H, CH2CH2N), 1.38 (m, 2 H, CH2), 0.95 (t, 3 H, 3 JH, H = 7.5 Hz, CH3) .13C 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 (CH2N), 31.2 (CH2CH2N), 20.1 (CH2), 12.9 (CH3). MS (FAB): m / z 283 (50%, [M + Na] +), 261 (20%, [M + H] +). Analysis calculated for C11H20N2O5: C, 50.76; H, 7.74; N, 10.76. Found: C, 50.39; H, 7.42; N, 10.44.

Example 17

(5S, 6R, 7S, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

Following a procedure analogous to that described in the procedure of example 16 but using octylamine instead of n-butylamine, at 65 ° C and for 24 h the title compound was obtained. Eluent CH2Cl2-MeOH 20: 1 → 10: 1. Yield: 144 mg (60%). Rf 0.15 (CH2Cl2-MeOH 10: 1). [α] D = 20.6 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD, 313 K) δ 4.61 (d, 1 H, J5.6 = 2.0 Hz, H-5), 4.50 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H -1a), 4.46 (dd, 1 H, J8a, 1b = 4.5 Hz, H-1b),

3.97 (dd, 1 H, J6.7 = 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, CH2N), 1.53 (m, 2 H, CH2CH2N), 1.33 (m, 10 H, CH2), 0.92 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C 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 (CH2N), 31.6 (CH2CH2N), 29.1, 28.9, 27.0, 22.4 (CH2), 12.9 (CH3). MS (FAB): m / z 339 (40%, [M + Na] +), 315 (15%, [M + H] +). Analysis calculated for C15H28N2O5: C, 56.94; H, 8.92; N, 8.85. Found: C, 56.61; H, 8.73; N, 8.50.

Example 18

(5S, 6R, 7S, 8R, 8aR) -5- (2-Hydroxyethylamino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

Following a procedure analogous to that described in the procedure of example 16 but using 2-hydroxyethylamine instead of n-butylamine, at 65 ° C and for 24 h the title compound was obtained. Eluent: 100: 10: 1 → 30: 10: 1 CH2Cl2-MeOH-H2O. Yield: 122 mg (67%). [α] D 6.7 (c 1.0, H2O). Rf 0.17 (40: 10: 1 CH2Cl2-MeOH-H2O). 1 H NMR (300 MHz, MeOD) δ 4.64 (d, 1 H, J5.6 = 2.1 Hz, H-5), 4.54 (t, 1 H, J1a, 1b = J8a, 1a = 8.7 Hz, H-1a) , 4.33 (dd, 1 H, J8a, 1b = 4.2 Hz, H-1b), 4.00 (t, 1 H, J6.7 = 2.1 Hz, H-6), 3.80 (m, 1 H, H-7) , 3.67 (m, 4 H, H-3, H-4, CH2OH), 2.76 (m, 2 H, CH2NH2). 13C 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 (CH2OH) , 54.6 (C-8a), 48.9 (CH2NH2), 31.6 (CH2CH2N). FABMS: m / z 271 (90%, [M + Na] +), 249 (12%, [M + H] +).

Example 19

(5S, 6R, 7S, 8R, 8aR) -5- (3-Pentylamino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

Following a procedure analogous to that described in the procedure of example 16 but using 3-pentylamino instead of n-butylamine, at 65 ° C and for 30 h the title compound was obtained. Eluent: 100: 10: 1 CH2Cl2-MeOH-H2O. Yield: 133 mg (63%). [α] D 38.8 (c 1.0, MeOH). Rf 0.5 (40: 10: 1 CH2Cl2-MeOH-H2O). 1H NMR (300 MHz, CD3OD) δ 4.70 (d, 1 H, J5.6 = 2.1 Hz, H-5), 4.47 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H-1a) , 4.28 (dd, 1 H, J8a, 1b = 4.5Hz, H-1b), 3.93 (t, 1 H, J6.7 = 2.1 Hz, H-6), 3.77 (td, 1 H, J8.8a = 9.0 Hz, H-8a), 3.72 (dd, 1 H, J7.8 = 9.0 Hz, H-7), 3.67 (t, 1 H, H-8), 2.38 (m, 1 H, CHNH), 1.50 (m, 2 H, CH2), 1.32 (m, 2 H, CH2), 0.93 (t, 3 H, 3JH, H = 7.2 Hz, CH3), 0.89 (t, 3H, JH, H = 7.2 Hz, CH3 ). 13C NMR (75.5 MHz, CD3OD) δ 160.2 (CO), 73.5 (C-6), 72.6 (C-7), 72.1 (C-8), 70.1 (C5), 67.9 (C-1), 57.9 (CHN ), 55.8 (C-8a), 27.6, 26.4 (CH2), 11.0, 9.9 (CH3). FABMS: m / z 297 (75%, [M + Na] +), 275 (12%, [M + H] +). Analysis calculated for C12H22N2O5: C, 52.54; H, 8.08; N, 10.21. Found: C, 52.18; H, 7.71; N,

9.93.

Example 20

(5S, 6S, 7S, 8R, 8aR) -5-Isothiocyanate-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of (5R, 6R, 7S, 8R, 8aR) -3-oxohexahydro-1H-oxazolo [3,4-a] pyridine-5,6,7,8-tetrayl tetraacetate (60 mg, 0.16 mmol) and SnCl4 (160 µL, 1 M in CH2Cl2) in CH2Cl2 (2 mL), stirred under Ar atmosphere for 5 min, TMSNCS (25 µL, 0.18 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. It was washed with a saturated aqueous solution of NaHCO3 (2 x 15 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The organic extracts were washed with H2O (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified by column chromatography (1: 1 AcOEt-petroleum ether). Yield: 41 mg (69%). Rf

0.67 (1: 1 AcOEt / petroleum ether). [α] D +79.6 (c 1.0, CHCl3). 1 H NMR (500 MHz, CDCl 3) δ 6.09 (d, 1 H, J5.6 = 4.5 Hz, H-5), 5.51 (t, 1 H, J6.7 = J7.8 = 10.0 Hz, H-7) , 5.02 (dd, 1 H, H-6), 4.95 (t, 1 H, J8.8a = 10.0 Hz, H-8), 4.49 (dd, 1 H, J1a, 1b = 9.5Hz, J1a, 8a = 8.0 Hz, H-1a), 4.30 (dd, 1 H, J1b, 8a = 8.0 Hz, H-1b), 4.03 (dt, 1 H, H-8a), 2.17-2.09 (3 s, 9 H, MeCO ). 13C NMR (125.7 MHz, CDCl3) 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 + Na] +. Analysis calculated for C14H16N2O8S: 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, 8R, 8aR) -5- (Octylthioureido) -6,7,8-tri-O-acetyl-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 Et3N (25 µL, 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%). Rf 0.65 (2: 1 AcOEt-petroleum ether). [α] D +64.0 (c 1.0, CHCl3). 1 H NMR (500 MHz, CDCl 3) δ 7.46 (sa, 1 H, NH), 6.43 (d, 1 H, JNH, 5 = 5.0 Hz, NH), 5.69 (t, 1 H, J5.6 =

5.0 Hz, H-5), 5.45 (dd, 1 H, J6.7 = 10.0 Hz, J7.8 = 9.0 Hz, H-7), 5.07 (dd, 1 H, H-6), 4.96 (t, 1 H, J8.8a = 9.0 Hz, H-8),

4.54 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.39 (dd, 1 H, J1b, 8a = 7.5 Hz, H-1b), 4.06 (m, 1 H, H -8a), 3.61-3.55 (m, 2 H, NHCH2), 2.16-2.09 (3 s, 9 H, MeCO), 1.75-1.60 (m, 2 H, NHCH2CH2), 1.40-1.22 (m, 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) δ 181.9 (CS), 170.0-169.4 (MeCO), 157.1 (CO), 72.4 (C-8), 68.4 (C7), 68.2 (C-6), 67.5 (C-1 ), 58.4 (C-5), 51.8 (C-8a), 46.9 (NHCH2), 31.8-22.6 (CH2), 20.6-20.4 (MeCO), 14.1 (CH3). ESIMS: m / z 524.0 [M + Na] +. Analysis calculated for C22H35N3O8S: 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, 8R, 8aR) -5- (Octylthioureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by deacetylation of the compound obtained in Example 21. Yield: 19 mg (95%). Rf 0.40 (10: 1 CH2Cl2-MeOH). [α] D -12.4 (c 0.8, DMSO). 1 H NMR (500 MHz, MeOD, 313 K) δ 5.83 (d, 1 H, J5.6 =

5.0 Hz, H-5), 4.50 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.31 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.70-3.65 (m, 2 H, H-6, H-8a), 3.59-3.52 (m, 3 H, H-7, NHCH2), 3.37-3.30 (m, 1 H, H-8), 1.65- 1.55 (m, 2 H, NHCH2CH2), 1.45-1.25 (m, 10 H, CH2), 0.92 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, MeOD, 313 K) δ 183.5 (CS), 157.1 (CO), 73.5 (C8), 73.3 (C-7), 69.7 (C-6), 66.4 (C-1), 62.5 ( C-5), 53.6 (C-8a), 44.7 (NHCH2), 31.6-22.3 (CH2), 13.0 (CH3). ESIMS: m / z 398.0 [M + Na] +. Analysis calculated for C16H29N3O5S: C 51.18, H 7.78, N 11.19, S 8.54. Found: C 50.84, H 7.48, N 10.82, S 8.20.

Example 23

(5S, 6R, 7S, 8R, 8aR) -5-Isothiocyanate-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of (5S, 6R, 7S, 8R, 8aR) -5,6,7,8-tetra-O-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 SnCl4 (477 μL, 0.48 mmol, 1 m in CH2Cl2), stirred under Ar atmosphere for 5 min, TMSNCS (75 μL, 0.53 mmol) was added and the reaction mixture was stirred for 3 h. CH2Cl2 (15 mL) was added and washed with saturated aqueous NaHCO3 solution (10 mL). The aqueous phase was extracted with CH2Cl2 (3 x 15 mL) and the organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (1: 1 AcOEt-petroleum ether). Yield: 146 mg (78%). [α] D 39.1 (c 1.0, CH2Cl2). Rf 0.76 (2: 1 AcOEt-petroleum ether). 1 H NMR (300 MHz, CDCl 3) δ 5.70 (d, 1 H, J5.6 = 2.4 Hz, H-5), 5.36 (m, 2 H, H-6, H-7), 5.21 (t, 1 H , J7.8 = J8.8a = 9.6Hz, H-8), 4.48 (dd, 1 H, J1a, 1b = 9.3 Hz, J8a, 1a = 8.1 Hz, H-1a), 4.36 (dd, 1 H, J8a, 1b = 5.7 Hz, H-1b), 4.00 (ddd, 1 H, H-8a), 2.14, 2.09, 2.01 (3 s, 9 H, MeCO). 13C NMR (75.5 MHz, CDCl3) 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 C14H16N2O8S: 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, 6R, 7S, 8R, 8aR) -5-Thioureido-6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of the compound obtained in example 20 (159 mg, 0.43 mmol) and Et3N (59 μL, 0.43 mmol) in DMF (17 mL) was added, under Ar and dropwise, a solution of 9-fl uorenylmethylcarbamate (112 mg,

0.47 mmol) in DMF (10 mL). The reaction mixture was stirred for 24 h at 40 ° 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-H2O. Yield: 132 mg (79%). [α] D 9.3 (c 1.0, CH2Cl2). Rf 0.08 (2: 1 AcOEt-petroleum ether). 1 H NMR (500 MHz, CDCl 3, 313 K) δ 7.67 (sa, 1 H, NH), 7.83 (sa, 2 H, NH), 5.47 (t, 1 H, J5.6 = J1, NH = 2.0 Hz, H-5), 5.44 (dd, 1 H, J7.8 = 9.3 Hz, J6.7 = 5.0 Hz, H-7), 5.18 (t, 1 H, J8.8a = 9.3 Hz, H-8), 4.53 (t, 1 H, J1a, 1b = J8a, 1a = 9.3 Hz, H-1a), 4.37 (dd, 1 H, J8a, 1b = 5.5 Hz, H-1b), 4.12 (m, 1 H, H -8a), 2.13, 2.04, 2.02 (3 s, 9 H, MeCO). 13C NMR (100.6 MHz, CDCl3, 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 (C1), 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. Calcd for C14H19N3O8S: C, 43.18; H, 4.92; N, 10.79; S, 8.23. Found: C, 43.35; H, 5.20; N, 10.55; S,

7.94.

Example 25

(5S, 6R, 7S, 8R, 8aR) -5-thioureido-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by deacetylation of 1 - ((5S, 6R, 7S, 8R, 8aR) -6,7,8-trihydroxy-3-oxohexahydro-1Hoxazolo [3,4-a] pyridin-5-yl) 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 CO2 and puri fi cation by column chromatography

(10: 1: 1 CH3CN-H2O-NH4OH). Yield: 44 mg (71%). [α] D 4.44 (c 1.0, H2O). Rf 0.21 (10: 1: 1 CH3CN-H2O-NH4OH) .1 H NMR (500 MHz, MeOD, 313 K) δ 5.82 (sa, 1 H, H-5), 4.52 (dd, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H-1a), 4.31 (dd, 1 H, J8a, 1b = 4.5 Hz, H-1b), 4.13 (t, 1 H, J5.6 = J6.7 = 2.5 Hz, H -6), 3.74 (t, 1 H, J7.8 = J8.8a = 9.0 Hz, H-8), 3.71 (m, 1 H, H8a), 3.64 (dd, 1 H, H-7). 13C 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 C8H13N3O5S · H2O: C, 34.16; H, 5.37; N, 14.94; S,

11.40 Found: C, 34.10; H, 5,402; N, 14.81; S, 11.23.

Example 26

(5S, 6R, 7S, 8R, 8aR) -5- (Octylthioureido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of the compound obtained in example 19 (137 mg, 0.37 mmol) and Et3N (51 μL, 0.37 mmol) in DMF (10 mL) was added, under Ar atmosphere and dropwise, a solution of octylamine (67 μL, 0.41 mmol) in DMF (14 mL). The reaction mixture was stirred for 45 min at 40 ° 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%). [α] D 16.9 (c 1.0, CH2Cl2). Rf 0.56 (2: 1 AcOEt-petroleum ether). 1H NMR (300 MHz, CDCl3) δ 7.20, 7.09 (2 s, 2 H, NH), 5.42 (m, 2 H, H-5, H-6), 5.38 (dd, 1 H, J7.8 = 9.0 Hz, J6.7 = 2.1 Hz, H-7), 5.15 (t, 1 H, J8.8a = 9.0 Hz, H-8), 4.51 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz , H-1a), 4.40 (dd, 1 H, J8a, 1b = 6.0 Hz, H-1b), 4.06 (m, 1 H, H-8a), 3.55 (m, 2 H, CH2N), 2.15, 2.09 ,

2.03 (3 s, 9 H, MeCO), 1.61 (m, 2 H, CH2), 1.26 (m, 10 H, CH2), 0.86 (t, 3 H, 3JH, H = 6.9 Hz, CH3). 13C NMR (75.5 MHz, CDCl3) 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 (CH2N), 31.8, 29.2, 29.1, 28.5, 26.9, 22.6 (CH2), 20.7, 20.6, 20.5 (MeCO), 14.0 (CH3). FABMS: m / z 524 (70%, [M + Na] +), 502 (50%, [M H] +). Analysis calculated for C22H35N3O8S: 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

(5S, 6R, 7S, 8R, 8aR) -5- (Octylthioureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

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 CO2 and purification. by column chromatography (45: 5: 3 AcOEt-EtOH-H2O). Yield: 60 mg (89%). [α] D 59.2 (c 1.0, MeOH). Rf 0.45 (45: 5: 3 AcOEt-EtOH-H2O). 1 H NMR (300 MHz, MeOD, 313 K) δ 5.89 (sa, 1 H, H-5), 4.52 (dd, 1 H, J1a, 1b = 9.0 Hz, J8a, 1a = 8.1 Hz, H-1a), 4.31 (dd, 1 H, J8a, 1b = 4.5 Hz, H-1b), 4.12 (m, 1 H, H-6), 3.74 (t, 1 H, J7.8 = J8.8a = 9.3 Hz, H -8), 3.72 (m, 1 H, H-8a), 3.62 (dd, 1 H, J6.7 = 2.7 Hz, H-7), 3.51 (ta, 2 H, 3JH, H = 7.0Hz, CH2NH ),

1.56 (m, 2 H, CH2), 1.31 (m, 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.2 Hz, CH3). 13C 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 (CH2N), 33.0, 30.4, 30.3, 30.0, 28.0, 23.7 (CH2), 14.5 (CH3). FABMS: m / z 398 (100%, [M + Na] +), 376 (10%, [M H] +). Analysis calculated for C16H29N3O5S: C, 51.18; H, 7.78; N, 11.19; S, 8.54. Found: C, 50.92; H, 7.52; N, 11.11; S,

8.32.

Example 28

(5S, 6S, 7S, 8R, 8aR) -5- (N’-Octylcarbodiimido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of the compound obtained in example 26 (97 mg, 0.19 mmol) in CH2Cl2-H2O (1: 1, 4 mL) was added HgO (126 mg, 0.58 mmol, 3.0 equiv.) And the reaction mixture was stirred at room temperature for 1 h, CH2Cl2 was added and the organic phase separated. The organic extracts were dried (Na2SO4), filtered over Celite, concentrated and the crude was purified by column chromatography (2: 1 AcOEt-petroleum ether). Yield: 76 mg (84%). Rf

0.73 (2: 1 AcOEt-petroleum ether). [α] D +41.7 (c 1.0, CHCl3). 1 H NMR (500 MHz, CDCl 3) δ 5.72 (d, 1 H, J5.6 = 4.5 Hz, H-5), 5.53 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7) , 4.97 (dd, 1 H, H-6), 4.92 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.43 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a), 4.25 (t, 1 H, J1b, 8a = 8.5 Hz, H-1b), 4.07 (m, 1 H, H-8a), 3.33 (dd, 1 H, 2JH, H = 13.0 Hz, 3JH, H = 7.0 Hz, NCH2), 3.28 (dd, 1 H, NCH2), 2.12-2.06 (3 s, 9 H, MeCO), 1.65-1.58 (m, 2 H, NCH2CH2), 1.41-1.24 (m , 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (NCH2 ), 31.8-22.6 (CH2), 20.6-20.5 (MeCO), 14.1 (CH3). ESIMS: m / z 490.0 [M + Na] +. Analysis calculated for C22H33N3O8: C 56.52, H 7.11, N 8.99. Found: C 56.58, H 7.03, N 8.76.

Example 29

(5S, 6S, 7S, 8R, 8aR) -5- (N’-Octyl-N ”-octylguanidino) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine hydrochloride

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 ° C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed with water (5 mL). The organic extracts were dried (Na2SO4) and concentrated. The crude was purified by column chromatography (AcOEt-MeOH 6: 1). Yield: 18 mg (68%); Rf 0.57 (AcOEt-MeOH 3: 1). [α] D +60.7 (c 0.7, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.83 (d, 1 H, J5.6 = 6.0 Hz, H-5), 5.83 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7) , 5.30 (dd, 1 H, H-6), 5.16 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.63 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.41 (dd, 1 H, J1b, 8a = 7.5 Hz, H-1b), 4.23-4.13 (m, 1 H, H-8a), 3.40-3.25 (m, 4 H, NHCH2), 2.12-2.07 (3 s, 9 H, MeCO), 1.75-1.60 (m, 4 H, CH2), 1.50-1.25 (m, 20 H, CH2), 0.93 (t, 6 H, 3JH, H = 7.0 Hz , CH3). 13C 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 (NHCH2), 31.6-22.3 (CH2), 19.2

19.0 (MeCO), 13.0 (CH3). ESIMS: m / z 597.2 [M -Cl] +. Analysis calculated for C30H53ClN4O8: C 56.90, H 8.44, N

8.85. Found: C 56.53, H 8.12, N 8.51.

Example 30

(5S, 6S, 7S, 8R, 8aR) -5- (N’-Octyl-N ”-octylguanidino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine 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 CO2, concentrated and purified by column chromatography (CH2Cl2-MeOH 4: 1). The product was lyophilized at room temperature of a 0.1 M HCl solution. Yield: 5.5 mg (74%). Rf 0.44 (CH2Cl2-MeOH 5: 1). [α] D +31.7 (c 0.4, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.39 (d, 1 H, J5.6 = 6.0 Hz, H-5), 4.63 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a) , 4.31 (ta, 1 H, J1b, 8a = 8.5 Hz, H-1b), 3.86 (m, 1 H, J8.8a = 8.5 Hz, H-8a), 3.82 (dd, 1H, J6.7 = 9.0 Hz, H-6), 3.74 (t, 1 H, J7.8 = 9.0 Hz, H-7), 3.42 (t, 1 H, H-8), 3.38-3.25 (m, 4 H, NHCH2), 1.71-1.63 (m, 4 H, CH2), 1.45-1.27 (m, 20 H, CH2), 0.93 (t, 6 H, 3JH, H = 7.0 Hz, CH3). 13C 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 (NHCH2), 31.6-22.3 (CH2), 13.0 (CH3). ESIMS: m / z 471.1 [M -Cl] +. HRFABMS Calcd for C24H47N4O5 [M-Cl] + 471.3546, Found 471.3528.

Example 31

(5S, 6R, 7S, 8R, 8aR) -5- (N’-Octylcarbodiimido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of the compound obtained in example 21 (206 mg, 0.41 mmol) in CH2Cl2-H2O (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, CH2Cl2 (9 mL) was added and the organic phase separated. The organic extracts were dried (Na2SO4), filtered over Celite, concentrated and the crude was purified by column chromatography (AcOEt-petroleum ether 1: 2 → 2: 1). Yield: 154 mg (80%). [α] D 18.3 (c 1.0, CH2Cl2). Rf 0.72 (AcOEt-petroleum ether 2: 1). 1H NMR (500 MHz, CDCl3) δ 5.43 (d, 1H, J5.6 = 3.0 Hz, H-5), 5.40 (dd, 1 H, J7.8 = 10.0 Hz, J6.7 = 3.0 Hz, H- 7), 5.21 (t, 1 H, H-6), 5.18 (t, 1 H, J8.8a =

10.0 Hz, H-8), 4.39 (dd, 1 H, J1a, 1b = 9.5Hz, J5.6a = 8.0 Hz, H-1a), 4.30 (dd, 1 H, J8a, 1b = 6.0 Hz, H- 1b), 3.99 (ddd, 1 H, H-8a), 3.30 (t, 2 H, 3JH, H = 7.0 Hz, CH2N), 2.12, 2.07, 2.01 (3 s, 9 H, MeCO), 1.58 (m , 2 H, CH2), 1.29 (m, 10 H, CH2), 0.87 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2N ), 31.9, 31.1, 29.2, 29.1, 26.8, 22.7 (CH2), 20.8, 20.7 (MeCO), 14.2 (CH3). FABMS: m / z 598 (60%, [M + Na + thioglycerol] +), 576 (50%, [M H + thioglycerol] +). Analysis calculated for C22H33N3O8: C, 56.52; H, 7.11; N, 8.99. Found: C, 56.28; H, 6.88; N, 8.73.

Example 32

(5S, 6R, 7S, 8R, 8aR) -5- (N’-octylguanidino) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine hydrochloride

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 ° C for 20 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and washed with water (2 x 10 mL). The organic extracts were dried (Na2SO4) and concentrated. The crude was purified by column chromatography (AcOEt-MeOH 20: 1 → 5: 1). Yield: 103 mg (76%). [α] D 7.7 (c 1.0, CH2Cl2). Rf 0.50 (5: 1 AcOEt-MeOH). 1 H NMR (500 MHz, CDCl 3) δ 7.35 (bs, 2 H, NH), 5.64 (dd, 1 H, J7.8 = 9.0 Hz, J6.7 = 3.0 Hz, H-7), 5.40 (sa, 1 H, H-6), 5.33 (bs, 1 H, H-5), 5.14 (t, 1 H, J7.8 = 9.0 Hz, H-8), 4.55 (t, 1 H, J1a, 1b = J8a , 1a = 8.5 Hz, H-1a), 4.43 (m, 1 H, H-8a), 4.37 (dd, 1 H, J8a, 1b = 6.0 Hz, H-1b), 3.32 (m, 2 H, CH2NH ), 2.13, 2.07, 2.00 (3 s, 9 H, MeCO), 1.64 (m, 2 H, CH2), 1.34 (m, 2 H, CH2), 1.26 (m, 8 H, CH2), 0.86 (t , 3 H, 3 JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2NH), 31.9, 29.3, 29.2, 28.5, 26.8, 22.7 (CH2), 20.9, 20.8, 20.7 (MeCO), 14.2 (CH3) . FABMS: m / z 507 (5%, [M + Na] +), 485 (100%, [M H] +). Analysis calculated for C22H37ClN4O8: C, 50.72; H, 7.16; N, 10.75. Found: C, 50.60; H, 7.003; N, 10.58.

Example 33

(5S, 6R, 7S, 8R, 8aR) -5- (N’-octylguanidino) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine hydrochloride

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-H2O-NH4OH 10: 1: 1). The product was freeze dried at room temperature of a 0.1 M HCl solution. Yield: 27 mg (75%). [α] D 11.79 (c 0.36, H2O). Rf 0.66 (6: 3: 1 CH3CN-H2O-NH4OH). 1H NMR (500 MHz, D2O) δ 5.36 (d, 1 H, J1.2 = 1.9 Hz, H-5), 4.70 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H-1a) , 4.46 (dd, 1 H, J8a, 1b = 6.0 Hz, H-1b), 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, 3JH, H = 6.8 Hz, CH2NH), 1.63 (m, 2 H, CH2), 1.33 (m, 10 H, CH2),

0.89 (t, 3H, 3JH, H = 7.1 Hz, CH3). 13C NMR (125.7 MHz, D2O) δ 159.4 (CO), 155.4 (CN), 70.1 (C-7), 69.9 (C-6, C8), 68.2 (C-1), 62.9 (C-5), 54.1 (C-8a), 41.9 (CH2NH), 31.1, 28.4, 28.3, 27.6, 25.8, 22.1 (CH2), 13.5 (CH3). FABMS: m / z 381 (10%, [M + Na] +), 359 (70%, [M H] +). Analysis calculated for C16H31ClN4O5: C, 48.66; H, 7.91; N, 14.19. Found: C, 48.32; H, 7.725; N, 13.84.

Example 34

(5S, 6S, 7S, 8R, 8aR) -5- (Acetamido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

To a solution of (5R, 6R, 7S, 8R, 8aR) -3-oxohexahydro-1H-oxazolo [3,4-a] pyridine-5,6,7,8-tetrayl tetraacetate (75 mg, 0.20 mmol) in Acetonitrile / TfOH (4: 1, 0.75 mL) was stirred at room temperature for 30 min, placed on ice and the mixture was extracted with CH2Cl2 (25 mL x 3). The organic phase was washed with a saturated solution of NaHCO3 (15 mL x 2), dried (Na2SO4) and concentrated to dryness. The residue was acetylated by treatment with Ac2O-pyridine (1: 1, 1 mL) for 1 h and the crude reaction was purified by column chromatography (AcOEt). Yield: 38 mg (51%). Rf 0.51 (9: 1 AcOEt-MeOH). [α] D +25.0 (c 0.5, MeOH). 1 H NMR (500 MHz, MeOD) δ 6.18 (d, 1 H, J5.6 = 5.5 Hz, H-5), 5.56 (t, 1 H, J6.7 = J7.8 = 10.0 Hz, H-7) , 5.14 (t, 1 H, J8.8a = 10.0 Hz, H-8), 5.11 (dd, 1 H, H-6), 4.48 (dd, 1 H, J1a, 1b = 9.0 Hz, J1a, 8a = 8.0 Hz, H-1a), 4.31 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b), 4.14 (ddd, 1 H, H-8a), 2.07-2.02 (4 s, 12 H, MeCO ). 13C NMR (125.7 MHz, MeOD) δ 172.0 (NHCOMe), 170.2-169.7 (MeCO), 155.9 (CO), 71.7 (C-8), 69.2 (C7), 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 C15H20N2O9: C 48.39, H 5.41, N 7.52. Found: C 48.11, H 5.10, N 7.19.

Example 35

(5S, 6S, 7S, 8R, 8aR) -5- (Butanamido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

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%). Rf 0.28 (3: 1 AcOEt-petroleum ether). [α] D +29.8 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3-MeOD 7: 1) δ 6.03 (d, 1 H, J5.6 = 6.0 Hz, H-5), 5.39 (t, 1 H, J6.7 = J7.8 = 9.5 Hz , H-7), 4.98 (m, 1 H, H-6), 4.92 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.34 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.25 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b),

4.02 (m, 1 H, H-8a), 2.15 (t, 2 H, NHCOCH2), 2.00-1.94 (3 s, 9 H, MeCO), 1.58 (m, 2 H, CH2), 0.88 (t, 3 H, CH3) .13C NMR (125.7 MHz, CDCl3-MeOD 7: 1) δ 174.5 (NHCO), 170.4-169.5 (MeCO), 155.4 (CO), 71.9 (C-8), 69.5 (C7), 68.7 ( C-6), 66.0 (C-1), 55.6 (C-5), 52.4 (C-8a), 37.6 (NHCOCH2), 20.3-20.1 (MeCO), 18.9 (CH2), 13.3 (CH3). ESIMS: m / z 423.2 [M + Na] +. Analysis calculated for C17H24N2O9: C 51.00, H 6.04, N 7.00.

Example 36

(5S, 6S, 7S, 8R, 8aR) -5- (Octanamido) -6,7,8-tri-O-acetyl-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. Puri fi cation by column chromatography (AcOE petroleum ether 1: 1 → 2: 1). Yield: 40 mg (67%). Rf 0.31 (AcOEt-petroleum ether 2: 1). [α] D +14.5 (c 1.0, CHCl3) .1 H NMR (500 MHz, CDCl3, 313 K) δ 6.31 (sa, 1 H, NH), 5.97 (t, 1 H, J5.6 = J5, NH = 6.0 Hz, H-5), 5.53 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7), 5.12 (dd, 1 H, H-6), 5.01 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.42 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a), 4.25 (dd, 1 H, J1b, 8a = 5.0 Hz, H -1b), 4.13-4.06 (m, 1 H, H-8a), 2.32-2.24 (m, 2 H, NHCOCH2), 2.08

2.06 (3 s, 9 H, MeCO), 1.70-1.61 (m, 2 H, CH2), 1.38-1.25 (m, 8 H, CH2), 0.91 (t, 3 H, 3JH, H = 7.0 Hz, CH3 ). 13C NMR (125.7 MHz, CDCl3) δ 173.9 (NHCO), 170.1-169.1 (MeCO), 155.1 (CO), 72.2 (C-8), 69.9 (C-7), 68.7 (C6), 66.0 (C-1 ), 56.6 (C-5), 52.5 (C-8a), 36.4 (NHCOCH2), 31.7-22.6 (CH2), 20.6-20.5 (MeCO), 14.1 (CH3). ESIMS: m / z 478.9 [M + Na] +. Analysis calculated for C21H32N2O9: C 55.25, H 7.07, N 6.14. Found: C 54.99, H 6.84, N 5.88.

Example 37

(5S, 6S, 7S, 8R, 8aR) -5- (Adamantane-1-carboxamido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

Following a procedure analogous to that described in example 34 using adamantane-1-carbonitrile (445 mg,

2.7 mmol) in CH2Cl2 (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%). Rf 0.19 (AcOEt-petroleum ether 1: 1). [α] D +33.4 (c 1.0, CH2Cl2). 1 H NMR (500 MHz, CDCl 3) δ 6.24 (d, 1 H, NH), 5.87 (t, 1 H, J5.6 = J5, NH = 6.0 Hz, H-5), 5.57 (t, 1 H, J6 , 7 = J7.8 = 9.0 Hz, H-7), 5.10 (dd, 1 H, H-6), 4.99 (t, 1 H, J8.8a = 9.0 Hz, H-8), 4.40 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a),

4.22 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b), 4.12 (m, 1 H, H-8a), 2.07-2.01 (12 H, MeCO, CH), 1.86-1.67 (m, 12 H, CH2). 13C NMR (125.7 MHz, CDCl3) 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 (CH2), 28.1 (CH) 20.8-20.6 (MeCO). ESIMS: m / z 515.2 [M + Na] +. Analysis calculated for C24H32N2O9: C 58.53, H 6.55, N 5.69.

Example 38

(5S, 6S, 7S, 8R, 8aR) -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: 11 mg (98%). Rf 0.37 (CH2Cl2-MeOH 4: 1). [α] D +31.4 (c 0.7, MeOH). 1 H NMR (500 MHz, MeOD) δ

5.85 (d, 1 H, J5.6 = 5.5 Hz, H-5), 5.51 (s, 1 H, NH), 4.46 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a ), 4.29 (dd, 1 H, J1b, 8a =

4.5 Hz, H-1b), 3.71 (ddd, 1 H, J8.8a = 9.5 Hz, H-8a), 3.63 (t, 1 H, J6.7 = J7.8 = 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). 13C 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 C9H14N2O6: C 43.90, H 5.73, N 11.38. Found: C 43.56, H 5.39, N 11.01.

Example 39

(5S, 6S, 7S, 8R, 8aR) -5- (Butanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 35 (82 mg, 0.20 mmol). Yield: 56 mg (99%). Rf 0.24 (CH2Cl2-MeOH 5: 1). [α] D +40.6 (c 0.7, MeOH). 1H NMR (500 MHz, MeOD) δ 5.86 (d, 1H, J5.6 = 5.5 Hz, H-5), 4.47 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a), 4.30 (dd, 1 H, J1b, 8a = 4.0 Hz, H-1b), 3.71 (ddd, 1 H, H-8a), 3.65 (t, 1 H, J6.7 = 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, NHCOCH2),

1.68 (m, 2 H, CH2), 0.99 (t, 3 H, CH3). 13C 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 (NHCOCH2), 31.5-22.3 (CH2), 13.0 (CH3). ESIMS: m / z

297.1 [M + Na] +. Analysis calculated for C11H18N2O6: C 48.17, H 6.61, N 10.20.

Example 40

(5S, 6S, 7S, 8R, 8aR) -5- (Octanamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 36 (20 mg, 0.04 mmol). Yield: 13 mg (90%). Rf 0.27 (7: 1 CH2Cl2-MeOH). [α] D +22.1 (c 0.7, MeOH). 1H NMR (500 MHz, MeOD) δ 5.84 (d, 1H, J5.6 = 5.5 Hz, H-5), 4.47 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a), 4.29 (dd, 1 H, J1b, 8a = 4.5 Hz, H-1b), 3.68 (ddd, 1 H, J8.8a = 9.5 Hz, H-8a), 3.63 (t, 1 H, J6.7 = J7 , 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, 3JH, H = 7.5Hz, 4JH, H = 2.0 Hz, NHCOCH2), 1.69-1.60 (m, 2 H, CH2), 1.40-1.28 (m, 8 H, CH2), 0.92 ( t, 3H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, MeOD) δ 175.6 (NHCO), 156.6 (CO), 73.5 (C-8), 73.0 (C7), 69.8 (C-6), 66.0 (C-1), 58.6 (C-5 ), 53.8 (C-8a), 35.3 (NHCOCH2), 31.5-22.3 (CH2), 13.0 (CH3). ESIMS: m / z

352.9 [M + Na] +. Analysis calculated for C15H26N2O6: C 54.53, H 7.93, N 8.48. Found: C 54.16, H 7.60, N

8.10.

Example 41

(5S, 6S, 7S, 8R, 8aR) -5- (Adamantane-1-carboxamido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 37 (58 mg, 0.12 mmol). Yield: 43 mg (99%). Rf 0.71 (30: 10: 1 CH2Cl2-MeOH-H2O). [α] D -1.02 (c 0.5 in MeOH). 1H NMR (500 MHz, Me2SOd6) δ 7.13 (d, 1 H, NH), 5.69 (t, 1 H, J5.6 = J5, NH = 6.5 Hz, H-5), 4.36 (t, 1 H, J1a , 1b = J1a, 8a = 9.0 Hz, H-1a), 4.14 (dd, 1H, J1b, 8a = 3.5 Hz, H-1b), 3.71 (ddd, 1 H, H-8a), 3.64 (t, 1 H, J6.7 = J7.8 = 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 sa, 12 H, CH2). 13C NMR (125.7 MHz, Me2SO-d6) 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 (CH2), 28.6 (CH). FABMS: m / z 389 [M + Na] +. Analysis calculated for C18H26N2O6: C 59.00, H 7.15, N

7.65.

Example 42

(5S, 6S, 7S, 8R, 8aR) -5- (N’-Octylureido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

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 µL) 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 (AcOEt-petroleum ether 2: 1). Yield: 93 mg (70%). Yield: 16 mg (23%). Rf 0.79 (AcOEt-MeOH 6: 1). [α] D +39.1 (c 0.6 in CHCl3). 1 H NMR (500 MHz, CDCl 3, 313 K) δ 5.68 (d, 1 H, J5.6 = 6.0 Hz, H-5), 5.50 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H -7), 5.07 (dd, 1 H, H-6), 4.96 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.50 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.34 (dd, 1 H, J1b, 8a = 7.0 Hz, H-1b), 4.12 (bq, 1 H, H8a), 3.21 (t, 2 H, 3JH, H = 7.0 Hz , NHCH2), 2.12-2.07 (3 s, 9 H, MeCO), 1.60-1.50 (m, 2 H, NHCH2CH2), 1.40-1.22 (m, 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (NHCH2) , 31.8-22.6 (CH2), 20.6-20.5 (MeCO), 14.1 (CH3). ESIMS: m / z 508.0 [M + Na] +. Analysis calculated for C22H35N3O9: C 54.42, H 7.27, N 8.65. Found: C 54.23, H 7.12, N 8.43.

Example 43

(5S, 6S, 7S, 8R, 8aR) -5- (N’-Octylureido) -6,7,8-trihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 42 (15 mg, 0.03 mmol). Yield: 9 mg (81%). Rf 0.17 (AcOEt-MeOH 6: 1). [α] D +18.5 (c 0.7 in MeOH). 1H NMR (500 MHz, MeOD) δ 5.58 (d, 1H, J5.6 = 5.5 Hz, H-5), 4.46 (t, 1 H, J1a, 1b = J1a, 8a = 8.5 Hz, H-1a), 4.29 (dd, 1 H, J1b, 8a = 4.0 Hz, H-1b), 3.67 (ddd, 1 H, J8.8a = 9.5 Hz, H-8a), 3.59 (dd, 1 H, J6.7 = 9.5 Hz, H-6), 3.51 (t, 1 H, J7.8 = 9.5 Hz, H-7), 3.31 (t, 1 H, H-8), 3.15 (dd, 1 H, 2JH, H = 10.5 Hz, 3JH, H = 6.5 Hz, NHCH2), 3.12 (dd, 1 H, NHCH2), 1.53-1.46 (m, 2 H, NHCH2CH2), 1.39-1.28 (m, 10 H, CH2), 0.92 (t, 3 H, 3 JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, MeOD) δ 159.1 (CO), 156.7 (CO), 73.6 (C8), 73.3 (C-7), 69.8 (C-6), 66.0 (C-1), 60.3 (C-5 ), 53.4 (C-8a), 39.5 (NHCH2), 31.6-22.3 (CH2), 13.0 (CH3). ESIMS: m / z 382.0 [M + Na] +. Analysis calculated for C16H29N3O6: C 53.47, H 8.13, N 11.69. Found: C 53.14, H 7.91, N

11.33.

Example 44

(5S, 6R, 7S, 8R, 8aR) -5- (Octylureido) -6,7,8-tri-O-acetyl-2-oxa-3-oxoindolizidine

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 µL) 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 (AcOEt-petroleum ether 2: 1). Yield: 110 mg (82%). [α] D 4.3 (c 1.0, CH2Cl2). Rf 0.25 (AcOEt-petroleum ether 2: 1). 1 H NMR (500 MHz, CDCl 3) δ 6.91 (sa, 1 H, J5, NH = 7.0 Hz, NH), 5.77 (sa, 1 H, NH '), 5.43 (dd, 1 H, J6.7 = 3.0 Hz , J7.8 = 9.5 Hz, H-7), 5.36 (dd, 1 H, H-6), 5.31 (dd, 1 H, H-5), 4.46 (t, 1 H, J8a, 1a = J1a, 1b = 9.0 Hz, H-1a), 4.35 (dd, 1 H, J8a, 1b = 5.5 Hz, H-1b), 4.10 (ddd, 1 H, H-8a),

3.16 (m, 2H, CH2NH), 2.14, 2.07, 2.02 (MeCO), 1.49 (m, 2 H, CH2), 1.28 (m, 4 H, CH2), 0.86 (t, 3 H, 3JH, H = 7.0 Hz,

CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2NH), 31.9, 29.8, 29.4, 29.3, 27.0, 22.8 (CH2), 20.9, 20.8, 20.7 (MeCO), 14.2 (CH3 ). FABMS: m / z 508 (100%, [M + Na] +), 486 (20%, [M H] +). Analysis calculated for C22H35N3O9: C, 54.42; H, 7.27; N, 8.65. Found: C, 54.40; H, 7.41; N, 8.47.

Example 45

(5S, 6R, 7S, 8R, 8aR) -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 CO2. Purification by column chromatography (AcOEt-EtOH-H2O 45: 5: 3). Yield: 58 mg (86%). [α] D 6.76 (c 0.42, MeOH). Rf 0.34 (AcOEt-EtOH-H2O 45: 5: 3). 1H NMR (500 MHz, MeOD) δ 5.54 (d, 1 H, J5.6 = 2.0 Hz, H-5),

4.49 (t, 1 H, J1a, 1b = J8a, 1a = 9.0 Hz, H-1a), 4.31 (dd, 1 H, J8a, 1b = 4.0 Hz, H-1b), 3.98 (t, 1 H, J6 , 7 = 9.5 Hz, H-6), 3.73 (t, 1H, J7.8 = 9.5 Hz, H-7), 3.68 (td, 1 H, H-8a), 3.63 (dd, 1 H, H- 8), 3.14 (m, 2 H, CH2NH), 1.50 (m, 2 H, CH2CH2NH),

1.34 (sa, 10 H, CH2), 0.93 (t, 3H, 3JH, H = 6.5 Hz, CH3). 13C 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 (CH2NH), 33.0, 31.2, 30.4, 30.4, 28.0, 23.7 (CH2), 14.4 (CH3). FABMS: m / z 382 (100%, [M + Na] +). Analysis calculated for C16H29N3O6: C, 53.47; H, 8.13; N, 11.69. Found: C, 53.22; H, 7,991; N, 11.75.

Example 46

(5S, 6R, 7S, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-thioxoindolizidine

To a solution of (5S, 6R, 7S, 8R, 8aR) -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) octylamine (69 µL, 0.42 mmol) was added and the mixture was stirred under Ar atmosphere at 40 ° C for 24 h The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (CH2Cl2MeOH-H2O 100: 10: 1). Yield: 104 mg (75%). [α] D-7.4 (c 1.0, MeOH). Rf 0.11 (CH2Cl2-MeOH-H2O 70: 10: 1). UV (CH2Cl2) 284 nm (εmM 15.4). 1 H NMR (500 MHz, MeOD) δ 5.23 (d, 1 H, J5.6 = 2.1 Hz, H-5), 4.71 (t, 1 H, J1a, 1b = J8a, 1a = 9.3 Hz, H-1a) , 4.46 (dd, 1 H, J8a, 1b = 6.3 Hz, H-1b), 4.00 (m, 2 H, H-2, H-8a), 3.72 (dd, 1 H, J7.8 = 9.4 Hz, J6.7 = 2.8 Hz, H-7), 3.68 (t, 1 H, J8.8a = 9.4 Hz, H-8), 2.61 (m, 2 H, CH2N), 1.57, 1.47 (2 m, 2 H , CH2CH2N), 1.31 (m, 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C NMR (125.7 MHz, MeOD) δ 189.8 (CS), 75.2 (C-5), 73.3 (C-6), 72.4 (C7, C-8), 70.1 (C-1), 59.0 (C-8a) , 47.2 (CH2N), 33.0, 30.7, 30.6, 30.4, 28.4 (CH2), 14.4 (CH3). ESIMS: m / z 355 [M + Na] +, 333 [M + H] +. Analysis calculated for C15H28N2O4S: 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, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-tri-O-acetyl-2-oxa-3-thioxoindolizidine

To a solution of (5S, 6R, 7S, 8R, 8aR) -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 CH2Cl2

(7.5 mL) at 0 ° C and under Ar's atmosphere, octanotiol (86 µL, 0.50 mmol) and BF3 · Et2O (104 µL, 0.86 mmol) were added. The reaction mixture was stirred for 2 h, CH2Cl2 (25 mL) was diluted, washed with saturated aqueous NaHCO3 solution (15 mL) and water (15 mL), dried (MgSO4), and concentrated. The resulting residue was purified by column chromatography (AcOEt-petroleum ether 1: 2 → 1: 1). Yield: 53 mg (46%). [α] D -33.0 (c 1.0, CH2Cl2). Rf 0.62 (AcOEt-petroleum ether 1: 1). UV (CH2Cl2) 256 nm (εmM 18.3). 1 H NMR (500 MHz, CDCl 3) δ 5.90 (d, 1 H, J5.6 = 2.2 Hz, H-5), 5.38 (dd, 1 H, J6.7 = 2.9 Hz, H-6), 5.36 (dd , 1 H, J7.8 = 9.5 Hz, H-7), 5.28 (t, 1 H, J8.8a = 9.5 Hz, H-8), 4.67 (dd, 1 H, J1a, 1b = J8a, 1a = 9.5 Hz, H-1a), 4.58 (dd, 1 H, J8a, 1b = 6.0 Hz, H-1b), 4.41 (td, 1 H, H-8a), 2.81, 2.67 (2 m, 2 H, CH2S ), 2.14, 2.10, 2.04 (3 s, 9 H, MeCO), 1.68 (m, 2 H, CH2), 1.38 (m, 2 H, CH2), 1.29 (m, 8 H, CH2), 0.90 (t , 3 H, 3 JH, H = 6.9 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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 (CH2S), 31.8, 29.7, 29.1, 29.0, 28.7 22.6 (CH2), 20.8, 20.6 (MeCO), 14.1 (CH3). FABMS: m / z 498 (67%, [M + Na] +), 476 (18%, [M + H] +). Analysis calculated for C21H33NO7S2: 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, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-thioxoindolizidine

The title compound was obtained by conventional deacetylation of the compound of example 47 (50 mg, 0.11 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 CO2, concentrated and the resulting residue was purified by column chromatography (CH2Cl2-MeOH-H2O 70: 10: 1). Yield: 35 mg (90%). [α] D -32.0 (c 1.0, MeOH). Rf 0.38 (CH2Cl2-MeOH-H2O 70: 10: 1). UV (CH2Cl2) 213 nm (εmM 7.57). 1 H NMR (500 MHz, MeOD) δ 5.79 (d, 1 H, J5.6 = 2.2 Hz, H-5), 4.78 (t, 1 H, J1a, 1b = J8a, 1a = 9.5 Hz, H-1a) , 4.46 (dd, 1 H, J8a, 1b = 7.0 Hz, H-1b), 4.16 (td, 1 H, J8.8a = 9.5 Hz, H-8a), 4.07 (dd, 1 H, J6.7 = 2.9 Hz, H-6), 3.72 (t, 1 H, J7.8 = 9.5 Hz, H-8), 3.64 (dd, 1 H, H-7), 2.80, 2.62 (2 m, 2 H, CH2S ), 1.68 (m, 2 H, CH2CH2S), 1.37 (m, 10 H, CH2), 0.90 (t, 3 H, 3JH, H = 7.2 Hz, CH3). 13C 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 (C5), 58.9 (C-8a) , 32.8 (CH2), 32.1 (CH2S), 31.2 (CH2CH2S), 30.2, 30.1, 29.7, 23.6 (CH2), 14.3 (CH3). ESIMS: m / z 372 [M + Na] +. Analysis calculated for C15H27NO4S2: 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

(5R, 6R, 7S, 8R, 8aR) -7,8-Dihydroxy-5,6-O-isopropylidene-2-oxa-3-oxoindolizidine

A mixture of (5R, 6R, 7S, 8R, 8aR) -5,6,7,8-tetrahydroxytetrahydro-1H-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 4h30min. The reaction mixture was diluted with AcOEt (75 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The aqueous phase was extracted with AcOEt (3 x 30 mL). The organic phase was dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (CH2Cl2-MeOH 10: 1). Yield: 30 mg (51%). Rf 0.73 (CH2Cl2-MeOH 5: 1). [α] D +34.3 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.72 (d, 1 H, J5.6 = 5.5 Hz, H-5), 4.59 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a) , 4.31 (dd, 1 H, J1b, 8a = 6.5 Hz, H-1b), 4.07 (dd, 1 H, J6.7 = 7.0 Hz, H-6), 3.85 (td, 1 H, J8.8a = 9.0 Hz, H-8a), 3.63 (dd, 1 H, J7.8 = 9.0 Hz, H-7), 3.35 (t, 1 H, H-8), 1.54, 1.43 (2 s, 6 H, CMe2 ). 13C NMR (125.7 MHz, MeOD) δ 157.2 (CO), 108.9 (CMe2), 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 (CMe2). ESIMS: m / z 267.9 [M + Na] +. Analysis calculated for C10H15NO6: C, 48.98; H, 6.17 ;, N, 5.71. Found: C, 48.82; H, 6.04; N, 5.66.

Example 50

(5R, 6R, 7S, 8R, 8aR) -7,8-Di-O-acetyl-5,6-O-isopropylidene-2-oxa-3-oxoindolizidine

The title compound was obtained by conventional acetylation of the compound of example 49 (200 mg, 0.82 mmol) with Ac2O-pyridine (1: 1, 4 mL) at room temperature for 2 h and purification by column chromatography (AcOEt-petroleum ether 1 :one). Yield: 215 mg (80%). Rf 0.62 (AcOEt-petroleum ether 2: 1). [α] D +1.8 (c 1.0, CHCl3) .1 H NMR (500 MHz, CDCl3) δ 5.82 (d, 1 H, J5.6 = 5.5 Hz, H-5), 5.30 (t, 1 H, J6, 7 = J7.8 = 5.5 Hz, H-7), 4.74 (dd, 1 H, J8.8a = 8.0 Hz, H-8), 4.55 (dd, 1 H, J1a, 1b = 9.5Hz, J1a, 8a = 8.0 Hz, H-1a), 4.34 (t, 1 H, H-6), 4.32 (dd, 1 H, J1b, 8a =

6.0 Hz, H-1b), 4.01 (td, 1 H, H-8a), 2.12-2.11 (2 s, 6 H, MeCO), 1.58, 1.43 (2 s, 6 H, CMe2). 13C NMR (125.7 MHz, CDCl3) δ 170.2-169.4 (MeCO), 155.9 (CO), 110.3 (CMe2), 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 (CMe2), 20.7-20.6 (MeCO). ESIMS: m / z 351.9 [M + Na] +. Analysis calculated for C14H19NO8: C, 51.06; H, 5.82; N, 4.25. Found: C, 50.78; H, 5.74; N, 4.17.

Example 51

(5R, 6R, 7R, 8R, 8aR) -7,8-Di-O-acetyl-5,6-dihydroxy-2-oxa-3-oxoindolizidine

The title compound was obtained by treating the compound obtained in example 50 (96 mg, 0.29 mmol) with TFA-H2O (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 (CH2Cl2-MeOH 7: 1). Yield: 82 mg (97%). Rf 0.56 (CH2Cl2-MeOH 9: 1). [α] D +47.3 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.38 (d, 1 H, J5.6 = 5.5 Hz, H-5), 5.37 (t, 1 H, J6.7 = J7.8 = 9.5 Hz, H-7) , 4.96 (t, 1 H, J8.8a = 9.0 Hz, H-8), 4.48 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.25 (dd, 1 H, J1b, 8a =

7.5 Hz, H-1b), 4.14 (dt, 1 H, H-8a), 3.72 (dd, 1 H, H-6), 2.08-2.05 (2 s, 6 H, MeCO). 13C 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 311.9 [M + Na] +. Analysis calculated for C11H15NO8: C, 45.68; H, 5.23; N, 4.84. Found: C, 45.44; H, 5.00; N, 4.51.

Example 52

At a solution of the compound obtained in example 51 (118 mg, 0.41 mmol, 1.0 equiv.) And acetonitrile (213 μL, 4.1 mmol, 10 equiv.) In CH2Cl2 (4 mL) at -40 ° C and under Ar's atmosphere, added TfOH (53 μL, 0.61 mmol,

1.5 equiv.). The reaction mixture was stirred at -40 ° C for 30 min. Et3N was added, the solvents were removed under reduced pressure and the residue was purified by column chromatography (AcOEt). Yield: 106 mg (83%). Rf 0.59 (AcOEt-MeOH 16: 1). [α] D -17.8 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 6.00 (d, 1 H, J5.6 = 9.0 Hz, H-5), 5.24

(t, 1 H, J6.7 = J7.8 = 5.5 Hz, H-7), 4.91 (t, 1 H, J8.8a = 5.5 Hz, H-8), 4.82 (dd, 1 H, H- 6), 4.61 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.36 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b), 3.93 (td, 1 H, H-8a), 2.10 (2 s, 9 H, 2 MeCO, CH3). 13C 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 (CH3). ESIMS: m / z 334.9 [M + Na] +. Analysis calculated for C13H16N2O7: C, 50.00; H, 5.16; N, 8.97. Found: C, 50.12; H, 5.05; N, 8.75.

Example 53

The title compound was obtained from the compound obtained in example 51 (57 mg, 0.20 mmol) and a solution of octanonitrile (300 µL, 2.0 mmol) in CH2Cl2 (2 mL) and TfOH (26 µL, 0.30 mmol). Puri fi cation by column chromatography (AcOEt-petroleum ether 2: 3). Yield: 51 mg (65%). 1H NMR (500 MHz, CDCl3) δ 6.02 (d, 1H, J5.6 = 9.0 Hz, H-5), 5.19 (t, 1 H, J6.7 = J7, 8 = 5.5 Hz, H-7), 4.76 (t, 1 H, J8.8a = 6.0 Hz, H-8), 4.58 (dd, 1 H, H-6),

4.52 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.28 (dd, 1 H, J1b, 8a = 4.5 Hz, H-1b), 3.77 (ddd, 1 H, H -8a), 2.34 (t, 2 H, 3JH, H = 8.0 Hz, CH2), 2.11-2.08 (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, 3JH, H =

6.5 Hz, CH3). 13C NMR (125.7 MHz, CDCl3) 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] +.

Example 54

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 CH2Cl2 (5 mL) and TfOH (39 μL, 0.44 mmol). Puri fi cation by column chromatography (CH2Cl2-MeOH 20: 1). Yield: 118 mg (93%). Rf 0.32 (CH2Cl2-MeOH 20: 1). [α] D -26.8 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ 5.92 (d, 1 H, J5.6 = 5.5 Hz, H-5), 5.10 (t, 1 H, J6.7 = J7.8 = 5.5 Hz, H7), 4.66 (t, 1 H, J8.8a = 5.5 Hz, H-8), 4.47 (dd, 1 H, H-6), 4.43 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H- 1a), 4.23 (dd, 1 H, J1b, 8a = 4.0 Hz, H-1b), 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, CH2) .13C NMR (125.7 MHz, CDCl3) 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 (CH2), 36.4 (CH), 27.7 (CH2), 20.7, 20.6 (MeCO). Analysis calculated for C22H28N2O7: C, 61.10; H, 6.53; N, 6.48.

Example 55

The title compound was obtained by conventional deacetylation of the compound obtained in example 52 (58 mg,

0.18 mmol). Puri fi cation by column chromatography (CH2Cl2-MeOH 5: 1). Yield: 30 mg (71%). Rf 0.60 (CH2Cl2

MeOH 4: 1). [α] D -2.0 (c 0.7, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.88 (dd, 1 H, J5.6 = 8.5Hz, 5J5, Me = 1.0 Hz, H5), 4.56 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz , H-1a), 4.55 (dd, 1 H, J6.7 = 7.0 Hz, H-6), 4.36 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b),

3.66 (td, 1 H, J8.8a = 9.0 Hz, H-8a), 3.47 (dd, 1 H, J7.8 = 9.0 Hz, H-7), 3.40-3.30 (m, 1 H, H-8 ), 2.07 (d, 3 H, Me). 13C 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 (CH3). ESIMS: m / z 250.8 [M + Na] +. Analysis calculated for C9H12N2O5: C, 47.37; H, 5.30; N, 12.28. Found: C, 47.19; H, 5.12; N, 11.98.

Example 56

The title compound was obtained by conventional deacetylation of the compound obtained in example 53 (24 mg,

0.06

mmol. Puri fi cation by column chromatography (CH2Cl2-MeOH 8: 1). Yield: 11 mg (59%). Rf 0.58 (CH2Cl2-MeOH 6: 1). [α] D -1.6 (c 0.7, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.88 (d, 1 H, J5.6 = 8.5 Hz, H-5), 4.56 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a) , 4.54 (dd, 1 H, J6.7 = 7.0, H-6), 4.37 (dd, 1 H, J1b, 8a = 5.0 Hz, H-1b), 3.64 (td, 1 H, J8.8a = 9.0 Hz, H-8a), 3.43 (dd, 1 H, J7.8 = 9.5 Hz, H-7), 3.36-3.30 (m, 1 H, H-8), 2.37 (t, 2 H, 3JH, H = 7.5 Hz, CH2), 1.74

1.63

(m, 2 H, CH2), 1.44-1.27 (m, 8 H, CH2), 0.93 (t, 3 H, 3JH, H = 7.0 Hz, CH3). 13C 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 (CH2), 13.0 (CH3). ESIMS: m / z 334.9 [M + Na] +. Analysis calculated for C15H24N2O5: C, 57.68; H, 7.74; N, 8.97. Found: C, 57.40; H, 7.62; N, 8.73.

Example 57

The title compound was obtained by conventional deacetylation of the compound obtained in example 54 (84 mg,

0.19 mmol). Puri fi cation by column chromatography (CH2Cl2-MeOH 20: 1). Yield: 43 mg (65%). Rf 0.32 (CH2Cl2-MeOH 20: 1). [α] D -7.2 (c 1.0, MeOH). 1 H NMR (500 MHz, MeOD) δ 5.90 (d, 1 H, J5.6 = 9.0), 4.60 (t, 1 H, J1a, 1b = J1a, 8a = 9.0 Hz, H-1a), 4.55 (dd, 1 H, J6.7 = 7.0 Hz, H-6), 4.42 (dd, 1 H, J1b, 8a = 5.5 Hz, H-1b), 3.67 (dt, 1 H, J8.8a = 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, CH2).

Example 58

Biological test 1

Inhibition of glycosidases

Table 1 summarizes the inhibitory activity of synthesized castanospermine analog glycosides (examples 2, 7 and 11) against selected glycosidases.

TABLE 1

Ki values (μM) for examples 2, 7, 11 and castanosperminaa

The compounds of examples 2, 7 and 11 showed total con fi gurational selectivity for glucosidases (no inhibition was observed for α- and β-mannosidases or α- and β-galactosidases) and high affinity towards the neutral α-glucosidase II enzyme (RE ). The α-versus β-glucosidase selectivity was considerably higher for neutral S-and C-glycosides (examples 7 and 11) than for basic N-glycoside (example 2). None of the castanospermine analog sp2-iminoazúcares glycosides were active against human lysosomial acid α-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 α-glucosidase II, but it has been shown to inhibit human liver α-glucosidase II RE, with 100 times lower potency compared to the lysosomial enzyme (Ki 10 before 0.1 μM). 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 Ki values (yeast α-glucosidase, μM) 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 Ki (α-Mannosidase of Jack beans, μM) values of 27 , 4.5 and 62 respectively.

Example 59

Biological test 2

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

The cytostatic and cytotoxic activity of Examples 2, 7 and 11 against the human breast carcinoma MCF-7 cell line is shown in Figures 1A-C (Antiproliferative and cytotoxic activity of the compounds of Examples 2, 7 and 11 in breast cancer MCF-7 cells (3 independent experiments) N-octyl 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 μM, respectively, with a very low cytotoxic profile, only 2% mortality was observed at 100 μM (Figure 1, example 2) S-octyl 7 glycoside showed a Prolonged dose-dependent antiproliferative activity between 0-50 μM (29 μM IC50; 34.2 ± 9.5% proliferation at 50 μM; P <0.01) without virtually observing cellular mortality in this range (Figure 1, example 7). C-glycoside 11 proved to be a more potent antiproliferative agent at low concentrations (IC50 22 μM). At 50 μM cell proliferation was reduced to 16.7 ± 5.3% (P <0.01), but with 40% cell mortality (Figure 1, example 11). In comparison, the anti-cancer drug doxorubicin shows more than 50% mortality at concentrations necessary to inhibit 50% proliferation in this cell line.

Claims (19)

1. A compound of formula I: or a salt thereof, where: X represents O, So-NR5; And represents OOS; R1 represents C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, -COCONR6R6, -SR6, -SOR6, -SO2 R6, -SO2NR6R6, -SO2NR5COR6, -NR6R6, -NR5COR O) NR6R6, -NR5 (C = S) NR6R6, -NR5 (C = NR5) NR6R6, -NR5CO2R6 or -NR5SO2R6, where C1-12alkyl, C2-12alkenyl and C2-12alkyl are independently optionally substituted by one or more R7; R2 represents hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkyl are independently optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8; or two R1 and R2 groups are optionally linked to form a 3- to 7-membered monocyclic ring that may be carbocyclic or heterocyclic in which case it may contain from 1-4 heteroatoms selected from N, S and O, which may be saturated or partially unsaturated, and where one or more C or S atoms of the ring may optionally be oxidized forming CO, SO or SO2 groups, and which is optionally substituted by one or more R8 R3 and R4 independently represent hydrogen, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, -COR6, -CONR6R6, oCy1, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7 and Cy1 are optionally replaced by one or more R8; each R5 represents hydrogen or C1-12 alkyl; each R6 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl, cyanoC1-12alkyl or Cy1, where Cy1 is optionally substituted by one or more R8; Each R7 independently represents halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9, -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5ROR9, -NN , -NR5COR9, -NR5CONR9R9, -NR5CO2R9, -NR5SO2R9 oCy1, where Cy1 is optionally substituted by one or more R8; Each R8 independently represents C1-12 alkyl, hydroxy C1-12 alkyl, halo C1-12 alkyl, C1-12 alkylC1-12 alkyl, halogen, -CN, -NO2, -COR9, -CO2R9, -CONR9R9, -OR9, -OCOR9, -OCONR9R9, -OCO2R9 , -SR9, -SOR9, -SO2R9, -SO2NR9R9, -SO2NR5COR9, -NR9R9, -NR5COR9, -NR5CONR9R9, -NR5CO2R9 or -NR5SO2R9; each R9 independently represents hydrogen, C1-12alkyl, haloC1-12alkyl, C1-12alkoxyC1-12alkyl, hydroxyC1-12alkyl or cyanoC1-12alkyl; Y each Cy1 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 Cy1 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 can be optionally oxidized to form CO, SO or SO2 groups, with the proviso 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.

Four.

A compound according to claims 1 to 3 wherein R 1 represents C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 ( C = NR5) NR6R6, where C1-12alkyl, C2-12alkenyl and C2-12alkynyl are independently optionally substituted by one or more R7.

5.

A compound according to claim 4 wherein R1 represents C1-12 alkyl, -SR6, -NR6R6, -NR5COR6, -NR5 (C = O) NR6R6, -NR5 (C = S) NR6R6 or -NR5 (C = NR5) NR6R6, C1-12alkyl, is optionally substituted by one or more R7.

6.

A compound according to claim 5 wherein R1 represents C1-12 alkyl, -SR6 or -NR6R6, wherein C1-12 alkyl is optionally substituted by one or more R7.

7.

A compound according to claim 6 wherein R1 represents C1-12 alkyl or -NR6R6, wherein C1-12 alkyl is optionally substituted by one or more R7.

8.

A compound according to any one of claims 1 to 7 wherein R2 represents hydrogen, C1-12alkyl, -COR6, -CONR6R6 or Cy1, wherein C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8.

9.

A compound according to reinvindication 8 where R2 represents hydrogen, C1-12alkyl or Cy1, where C1-12alkyl is optionally substituted by one or more R7 and Cy1 is optionally substituted by one or more R8.

10. A compound according to reinvindication 9 where R2 represents hydrogen.

eleven.

A compound according to any one of claims 1 to 10 wherein R 3 and R 4 independently represent hydrogen or C 1-12 alkyl, wherein C 1-12 alkyl is optionally substituted by one or more R 7.

12.

A compound according to claim 11 wherein R3 and R4 independently represent hydrogen.

13.

A compound according to any of claims 1-12 selected from: (5S, 6S, 7S, 8R, 8aR) -5-Octylamino-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; (5R, 6R, 7S, 8R, 8aR) -5-Octylthio-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine; Y (5R, 6S, 7R, 8R, 8aR) -5-Octyl-6,7,8-trihydroxy-2-oxa-3-oxoindolizidine.

14.

A pharmaceutical composition comprising a compound of formula I according to any of claims 1 to 13 a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

fifteen.

Use of a compound of formula I according to any of claims 1 to 13 a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases mediated by αglycosidases.

16.

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 at least one disease selected from cancer, viral infections, tuberculosis, diabetes and storage disorders of glycosipolipids.

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 II with a compound of formula III: where A represents a halogen group; Z represents a nucleophilic group; and where X, Y, R1, R2, R3 and R4 have the meaning described above; or (b) reacting a compound of formula II with a compound of formula IV: where R1 represents C1-12alkyl, C2-12alkenyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; A represents a halogen group; M represents a metal, n represents 1 to 4; and where X, Y, R2, R3 and R4 have the meaning described above; or (c) reacting a compound of formula V with a compound of formula VI: where B represents hydrogen or -COR6; C represents -NH2, -SH or -CN; R1 represents C1-12alkyl, C2-12alkyl or C2-12alkynyl, where each C1-12alkyl, C2-12alkenyl or C2-12alkynyl is independently optionally substituted by one or more R7; and where X, Y, R2, 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. SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201030867 SPAIN Date of submission of the application: 04.06.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: C07H19 / 044 (2006.01) A61K31 / 7056 (2006.01) RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

WO 2010046517 A1 (SUP COUNCIL OF SCIENTIFIC RESEARCH, UNIVERSITY OF SEVILLA, INT UNIV OF HEALTH AND WELFARE AND TOTTORI UNIVERSITY) 04/29/2010, the whole document 1-18

TO

E SÁNCHEZ-FERNÁNDEZ et al., Organic Letters 2009, vol 11, pp 3306-3309. "Generalized anomeric effect in gem-diamines: stereoselective synthesis of a-N-linked disaccharide mimics," abstract. one

TO

M I GARCÍA-MORENO et al., Journal Organic Chemistry 2003, vol 68, pp. 8890-8901. "Synthesis and evaluation of isourea-type glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families", summary. one

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 04.05.2011

Examiner M. Fernández Fernández Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201030867 Minimum documentation sought (classification system followed by classification symbols) C07H, A61K Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENTIONS, EPODOC, WPI, CAS, REGISTRY State of the Art Report Page 2/4 WRITTEN OPINION Application number: 201030867 Date of Written Opinion: 04.05.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-18 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-18 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986). Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4 WRITTEN OPINION Application number: 201030867 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

WO 2010046517 A1 (SUPPORT OF SCIENTIFIC RESEARCH, UNIVERSITY OF SEVILLA, INT UNIV OF HEALTH AND WELFARE AND TOTTORI UNIVERSITY) 04/29/2010

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application refers to the compounds of formula (I) (claim 1), a process for their preparation (claim 18), their use for the preparation of a medicament (claims 15-17) for the treatment of diseases mediated by alpha- glycosidases and the pharmaceutical composition (claim 14) comprising a compound of formula (I). Document D1 is considered the most representative of the state of the art, discloses glycosidase enzyme inhibitor compounds of general formula (I) (see claim 1 of D1), its preparation and the pharmaceutical composition containing them. The compounds described in the application differ from those disclosed in D1 because they carry a substituent adjacent to the N of cyclohexane, so they are considered new. On the other hand, a technician in the field could not a priori and without experimental data relate this difference to an increase in inhibitory activity and this possibility has not been found in the state of the art. Therefore, claims 1-18 of the application are considered to meet the conditions of novelty and inventive activity as set forth in Art. 6.1 and 8.1 of Patent Law 11/1986. State of the Art Report Page 4/4