Field of the invention The invention relates to novel monocyclic and polycyclic, in particular bicyclic compounds useful, among other applications, as medicines or for the manufacture of medicaments. The invention also relates to methods of treatment of diseases or functional disorders related to angiogenesis in mammals by the administration of a pharmaceutical composition comprising one or more such monocyclic and polycyclic, in particular bicyclic compounds as biologically active components in combination with one or more pharmaceutically acceptable excipients. The invention further relates to methods and intermediates for making said novel monocyclic and polycyclic compounds.

Background of the invention In the field of drug discovery there is a constant need for novel scaffolds that enable the rational design of potentially bioactive molecules. Carbohydrates have recently come under scrutiny as offering a source of scaffolds that allow for a high degree of substitution, and offer access to both functional and structural diversity. The nature of saccharide molecules is such that there are numerous different stereoisomers available that can provide access to a greater degree of molecular space than do the scaffolds presently employed in drug discovery. Simmondsin, a 2-cyanomethylidenecyclohexyl glucoside, was first isolated from seeds of the jojoba plant Simmondsia califomica, as disclosed by Elliger et al. in J. Chem. Soc. Perkin (1973) 2209-2212, and was later reported to exhibit feeding inhibitory activity in animals. Elliger (cited supra) also reported the sensitivity of simmondsin to both acid and alkaline environments. Natural simmondsin, stereoisomers and enantiomers thereof may be represented by the formula: wherein: - R4 and R5 are each methoxy, and - R3, R'2) R'3, R'4 and R'6 are each hydroxyl. Van Boven et al. in J. Agric. Food Chem. (1993) 41 : 1605 and in J. Agric. Food Chem. (1994) 42:1118 indicated that simmondsin is preliminarily co-extracted from the seed meal with its analogues 4-demethylsimmondsin and 5-demethylsimmondsin (hereinafter collectively referred as DMS; same formula as above, except R4 or R5 is hydroxyl), didemethylsimmondsin (hereinafter referred as DDMS; same formula as above, except both R4 and R5 are hydroxyl), and with the 2'- and 3'-simmondsin ferulates before purification. Whereas pure simmondsin was shown to induce anorexic behavior when ingested in minute quantities as shown by Cokelaere et al. in J. Agric. Food Chem. (1992) 40:1839, DMS and DDMS lack this biological activity. Ogawa et al. in J. Chem. Soc. Perkin Trans (1992) 1131-1137 published the absolute configuration of simmondsin and its full synthesis in a sequence of 18 steps while using L-quebrachitol as a starting material for the synthesis of its aglycone moiety. R.E. Harry-O'kuru in Industrial Crops and Products (2000) 215-221 published epoxidation of simmondsin, DMS and DDMS by means of both lipase and dioxirane catalysis. First the simmondsin nucleus was protected either by using the Kuhn methylation of reducing carbohydrates, resulting in heptamethylsimmondsin (same formula as above, except R3, R'2) R'3, R'4 and R'6 are each methoxy), or by peracetylation resulting in 3:2',3',4',6'-penta~O-acetylsimmondsin (from simmondsin), 3,4,5:2',3\4',6'~hepta-O-acetyl-simmondsin (from DDMS) and 3,4:2',3',4',6'-hexa-O- acetyl-simmondsin (from DMS). Then in a further step, catalyzed epoxidation resulted in 2,7-epoxy-3:2',3',4\6'-penta-O-acetylsimmondsin, 2,7-epoxy-3,4,5:2',3',4\6'-hepta- O-acetylsimmondsin and 2,7-epoxy-3,4:2',3',4',6'-hexa-0-acetyl-simmondsin respectively. WO 2004/004746 shows compounds having the general formula:

wherein: R4 and R5 are independently selected from the group comprising oxo, hydrogen, hydroxyl, alky], alkenyl, alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthio-carbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkoxythiocarbonyl, cyclo-alkylthioalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, cycloalkyl-carbonyloxyalkyl, silyloxyalkyl, aryl, aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, cyano, aminocarbonyl, aminoalkanoyl, aminoalkyl, CR6=NR7 or CR6=N(OR7), with R6 and R7 being independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthio-carbonylamino and arylthiocarbonylamino; and - R3, R'2, R'3, R'4 and R'6 are independently selected from the group comprising hydroxyl or an ester. Because WO 2004/004746 does not teach any synthetic procedure for making compounds having the above general formula, it is understood that only naturally- occurring compounds being isolable from jojoba seed meal and compounds that can be directly and readily obtained from the latter using standard knowledge in the art, e.g. methyl-protected simmondsin or acetyl-protected simmondsin disclosed by R. E. Harry-O'kuru (cited supra), are actually embraced within this disclosure. WO 2004/004746 demonstrates (figure 10) in an in vivo assay that refined de-oiled jojoba flour inhibits neovascularization in mice after oral treatment at a rate of 2.7 % by weight in Crispy rat food. WO 2004/004746 also demonstrates (figure 9C) in an ex vivo assay that a total polar solvent (e.g. ketone or alcohol) extract of jojoba flour containing at least 8 simmondsin analogues is more effective in inhibiting angiogenesis than marimastat, a known metalloproteinase. WO 2004/004746 also demonstrates (figure 8B) in an in vitro assay that both the above jojoba flour extract, simmondsin, 5-demethylsimmondsin and partially purified ferulates inhibit VEGF- induced tube formation in 3-D fibrin matrices provided that they are present at a ratio of at least 0.5 % (weight/volume). WO 2004/004746 also demonstrates (figure 7) in another in vitro assay that a mixture of simmondsin ferulates inhibits βFGF-induced human endothelial cell proliferation when pre-incubated or continuously incubated. WO 2004/004746 also demonstrates (figure 6) in another in vitro assay that inhibition of VEGF-α-induced human vascular endothelial cell proliferation by the above jojoba flour extract is mainly due to the presence of substances other than DDMS. All these data show an angiogenetic effect of simmondsin and certain derivatives thereof which seems to highly depend upon the biological test conditions. Example 4 of WO 2004/004746 indicates very contradictory data in a chorion aflantois membrane assay: table 3 shows the above jojoba flour extract having a significant angiogenesis inhibition comparable with tangeritin but pure DDMS having no such effect, whereas table 4 shows the reverse situation. Thus collectively these data do not teach the type of substitution pattern of a simmondsin derivative which is likely to provide improved biological activity with respect to simmondsin itself. Starting from the knowledge of several reported biological activities for naturally occurring simmondsin, and from the knowledge that these activities may be altered, and even lost, in some chemical analogues of simmondsin, there is a need in the art for developing a wider range of fully synthetic analogues or derivatives of simmondsin in view of exploring their potential biological activities and in view of securing significant amounts thereof independently from the availability of the naturally occurring simmondsin. Therefore there is also a need in the art for developing synthetic strategies being able to afford a wide range of simmondsin analogues preferably without requiring the high number of reaction steps involved in the synthesis of Ogawa et al. (cited supra) and/or while providing these simmondsin analogues in a higher global yield and/or starting from less expensive materials or reactants. Tumor angiogenesis affords new targets for cancer therapy since inhibition of angiogenesis suppresses tumor growth by cutting out the supply of oxygen and nutrients. Anti-angiogenic therapy is thought to be free of the severe side effects that are usually seen with cytotoxic anticancer drugs, and not only to eradicate primary tumor tissues but also to suppress tumor metastases. Therefore there is a constant need for angiogenesis inhibitors with improved efficiency. These various needs in the art constitute the main goals of the present invention.

Summary of the Invention It is an object of the present invention to provide novel biologically active monocyclic and polycyclic compounds, in particular bicyclic compounds having some degree of structural similarity with the simmondsin scaffold. It is another object of the invention to provide novel monocyclic compounds that may be used as intermediates for making the above-referred biologically active monocyclic and polycyclic compounds, in particular the simmondsin-like bicyclic compounds. It is another object of the invention to provide chemical synthetic methods for making said novel monocyclic, bicyclic and polycyclic compounds, either starting from the naturally occurring simmondsin or simmondsin derivatives or by a totally synthetic route. It is yet another object of the invention to provide pharmaceutical compositions based on said novel monocyclic, bicyclic or polycyclic compounds as the biologically active ingredient. It is yet another object of the invention to provide methods of treatment for diseases, in particular angiogenesis-related disorders, in humans by the administration of said pharmaceutical compositions. The present invention is based on the first unexpected finding that a significant number of novel bicyclic compounds having some degree of structural similarity with the simmondsin scaffold, as well as novel monocyclic compounds (e.g. intermediates therefor) and polycyclic compounds may be obtained by methods including a series of chemical reactions of a known type starting from readily available materials. The present invention is also based on a second unexpected finding that a significant number of novel bicyclic compounds having some degree of structural similarity with the simmondsin scaffold may be obtained by one or more chemical modifications of active substances that may be isolated, using procedures known in the art such as extraction, from the jojoba plant and other simmondsin- containing plants, and in particular simmondsin, derivatives, salts, solvates, stereoisomers or enantiomers thereof. The present invention is also based on a third unexpected finding that a significant number of these novel monocyclic, bicyclic and polycyclic compounds have one or more useful biological activities, in particular a potent angiogenesis-inhibiting activity, an endothelial cell proliferation inhibiting activity and a feeding inhibitory activity in animals, while showing low cytotoxicity in vitro and the absence of oestrogen-like activity. The present invention also provides several biological methods and assays for in vitro and in vivo testing such activities in the novel monocyclic, bicyclic and polycyclic compounds made according to the chemical modifications and synthetic routes set forth. As a consequence of these biological activities, these novel monocyclic, bicyclic and polycyclic compounds may advantageously be formulated into various kinds of pharmaceutical compositions, especially for the treatment of angiogenesis- related diseases, including arthritis and various types of cancers.

Definitions As used herein with respect to a substituting radical, and unless otherwise stated, the term " C1-20 alkyl " means straight and branched chain saturated acyclic hydrocarbon monovalent radicals having from 1 to 20 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl (isopropyl), 2-methylpropyl (isobutyl), 1 ,1-dimethylethyl (ter-butyl), 2-methylbutyl, n-pentyl, dimethylpropyl, n- hexyl, 2-methylpentyl, 3-methylpentyl, n-heptyl and the like. Furthermore, each of these radicals can be optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen, azido, oxo, hydroxyl, amino, imino, hydrazino, oximino, carboxyl, C3-10 cycloalkyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C1-20 alkenyloxy, C1-20 alkynyloxy, C3-10 cycloalkoxy, C3--I0 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, alkylamino, cycloalkylamino, alkenylamino, alkynylamino, cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercapto-alkylamino, alkynylamino, acylamino, thioacylamino, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide. As used herein with respect to a substituting radical, and unless otherwise stated, the term " acyl " broadly refers to a carbonyl (oxo) group adjacent to a C1-20 alkyl radical, a C3-10 cycloalkyl radical, an aryl radical, an arylalkyl radical or a heterocyclic radical, all of them being such as herein defined; representative examples include acetyl, benzoyl, naphthoyl and the like; similarly, the term " thioacyl " refers to a C=S (thioxo) group adjacent to one of the said radicals. As used herein with respect to a substituting radical, and unless otherwise stated, the term " C1-20 alkylene " means the divalent hydrocarbon radicals corresponding to the above defined C1-20 alkyl groups, such as methylene, bis(methylene), tris(methylene), tetramethylene, hexamethylene and the like, including such groups wherein hydrogen atoms are replaced by C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl groups such as defined herein. Furthermore, each of these radicals can be optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen, azido, oxo, hydroxyl, amino, imino, hydrazino, oximino, carboxyl, C3--I0 cycloalkyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C1-20 alkenyloxy, C1-20 alkynyloxy, C3-10 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, alkylamino, cycloalkylamino, alkenylamino, alkynylamino, cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino, alkynylamino, acylamino, thioacylamino, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide. As used herein with respect to a substituting radical, and unless otherwise stated, the terms " alkylidene ", " cycloalkylidene ", " arylidene ", "heteroarylidene ", refer to divalent hydrocarbon radicals represented by the general formula R1CH=, wherein R' is respectively C1-20 alkyl, C3-10 cycloalkyl, aryl or heteroaryl (each being as defined herein). As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-10 cycloalkyl " means a mono- or polycyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C7-10 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl, including such groups wherein one or more hydrogen atoms are replaced by C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl groups such as defined herein. Furthermore, each of these radicals can be optionally substituted with one or more substituents independently selected from the group consisting of cyano, halogen, azido, OXO, hydroxyl, amino, imino, hydrazino, oximino, carboxyl, C3--I0 cycloalkyl, aryl, heteroaryl, arylalkyl, Ci-20 alkoxy, C1-20 alkenyloxy, C1-20 alkynyloxy, C3-10 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, alkylamino, cycloalkylamino, alkenylamino, alkynylamino, cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino, alkynylamino, acylamino, thioacylamino, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide. As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-10 cycloalkyl-alkyl " refers to an aliphatic satu-rated hydrocarbon monovalent radical (preferably a C1-20 alkyl such as defined above) to which a C3-10 cycloalkyl (such as defined above) is already linked such as, but not limited to, cyclohexylmethyl, cyclopentylmethyl and the like. As used herein with respect to a substituting radical, and unless otherwise stated, the term " N-acyl substituted alkyl " refers to a carbonyl group linked to a divalent aliphatic radical (preferably a Ci-20 alkylene such as above defined) on one side and to the nitrogen atom of an N-containing group (such as alkylamino, arylamino or heterocyclic amino) on the other side. As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-10 cycloalkylene " means the divalent hydrocarbon radical corresponding to the above defined C3-i0 cycloalkyl, e.g. 1 ,2-cyclohexylene or 1 ,4- cyclohexylene. As used herein with respect to a substituting radical, and unless otherwise stated, the term " aryl " designate any mono- or polycyclic aromatic monovalent hydrocarbon radical having from 6 to 30 carbon atoms such as but not limited to phenyl, naphthyl, anthracenyl, phenantracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl, indenyl, biphenyl, indacenyl, benzocyclobutenyl, benzocyclooctenyl and the like, including fused benzoC4-8 cycloalkyl radicals (the latter being as defined above) such as, for instance, indanyl, tetrahydronaphtyl, fluorenyl and the like, each of said radicals being optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, trifluoromethyl, hydroxyl, sulfhydryl and nitro, such as for instance 4- fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-cyanophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl and the like. As used herein, e.g. with respect to a substituting radical such as a combination of substituents, and unless otherwise stated, the term "homo-cyclic" means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated hydrocarbon radical having from 4 up to 15 carbon atoms but including no heteroatom in the said ring; for instance said may form a C2-6 alkylene radical, such as tetramethylene, which cyclizes with the neighbouring carbon atoms. As used herein with respect to a substituting radical (including a combi-nation of substituents), and unless otherwise stated, the term " heterocyclic " means a mono- or polycyclic, saturated or mono-unsaturated or polyunsatu-rated monovalent hydrocarbon radical having from 2 up to 15 carbon atoms and including one or more heteroatoms in one or more heterocyclic rings, each of said rings having from 3 to 10 atoms (and optionally further including one or more heteroatoms attached to one or more carbon atoms of said ring, for instance in the form of a carbonyl or thiocarbonyl or selenocarbonyl group, and/or to one or more heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N-oxide, phosphate, phosphonate or selenium oxide group), each of said heteroatoms being independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium and phosphorus, also including radicals wherein a heterocyclic ring is fused to one or more aromatic hydrocarbon rings for instance in the form of benzo-fused, dibenzo-fused and naphto-fused heterocyclic radicals; within this definition are included heterocyclic radicals such as, but not limited to, diazepinyl, oxadiazinyl, thiadiazinyl, dithiazinyl, triazolonyl, diazepinonyl, triazepinyl, triazepinonyl, tetrazepinonyl, benzo-quinolinyl, benzothiazinyl, benzothiazinonyl, benzoxa-thiinyl, benzodioxinyl, benzodithiinyl, benzoxazepinyl, benzothiazepinyl, benzodiazepinyl, benzodioxepinyl, benzodithiepinyl, benzoxazocinyl, benzothiazocinyl, benzodiazocinyl, benzoxathiocinyl, benzodioxocinyl, benzotrioxepinyl, benzoxathiazepinyl, benzoxadiazepinyl, benzothiadiazepinyl, benzotriazepinyl, benzoxathiepinyl, benzotriazinonyl, benzoxazolinonyl, azetidinonyl, azaspiroundecyl, dithiaspirodecyl, selenazinyl, selenazolyl, selenophenyl, hypoxanthinyl, azahypoxanthinyl, bipyrazinyl, bipyridinyl, oxazolidinyl, diselenopyrimidinyl, benzodioxocinyl, benzopyrenyl, benzo- pyranonyl, benzophenazinyl, benzoquinolizinyl, dibenzocarbazolyl, dibenzoacridinyl, dibenzophenazinyl, dibenzothiepinyl, dibenzooxepinyl, dibenzopyranonyl, dibenzoquinoxalinyl, dibenzothiazepinyl, dibenzoiso-quinolinyl, tetraazaadamantyl, thiatetraazaadamantyl, oxauracil, oxazinyl, dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl, pyrimidonyl, thiopyrimidonyl, thiamorpho-linyl, azlactonyl, naphtindazolyl, naphtindolyl, naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphtotriazolyl, naphto- pyranyl, oxabicycloheptyl, azabenz-imidazolyl, azacycloheptyl, azacyclooctyl, azacyclononyl, azabicyclononyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyronyl, tetrahydroquinoleinyl, tetrahydrothienyl and dioxide thereof, dihydrothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl, thioxolyl, thiourazolyl, thiotriazolyl, thiopyranyl, thiopyronyl, coumarinyl, quinoleinyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydropyranyl, benzodihydrofuryl, benzothiopyronyl, benzothio-pyranyl, benzoxazinyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzothiadiazolyl, benzotriazinyl, benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl (benzothiofuranyl), phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl, pyrimi-dinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, furyl, dihydrofuryl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl, indazolyl, benzofuryl, quinolyl, quinazolinyl, quinoxalinyl, carbazolyl, phenoxazinyl, phenothiazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl, phenoxathiinyl, indolizinyl, quinolizinyl, isoquinolyl, phthalazinyl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl, imidazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, piperazinyl, uridinyl, thymidinyl, cytidinyl, azirinyl, aziridinyl, diazirinyl, diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl, thiiranyl, azetyl, dihydroazetyl, azetidinyl, oxetyl, oxetanyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, chromanyl, chromanonyl, thiochromanyl, thiochromanonyl, thiochromenyl, benzofuranyl, benzisothiazolyl, benzo-carbazolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocoumarinyl, phenometoxazinyl, phenoparoxazinyl, phentriazinyl, thio-diazinyl, thiodiazolyl, indoxyl, thioindoxyl, benzodiazinyl (e.g. phtalazinyl), phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dibenzopyronyl (i.e. xanthonyl), xanthionyl, isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyl, succinimido, benzylsultimyl, benzylsultamyl and the like, including all possible isomeric forms thereof, wherein each carbon atom of said heterocyclic ring may be independently substituted with a substituent selected from the group consisting of halogen, nitro, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, halo C1-20 alkyl, C3-10 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, amino, C1-20 alkylamino, cycloalkyl-amino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydra- zino, alkylhydrazino, phenylhydrazino, sulfhydryl, C1-20 alkoxy, C3-10 cyclo-alkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-20 alkyl, thio C3-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic- substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, thiocarboxylic acid or esters or thioesters or amides thereof; depending upon the number of unsaturations in the 3 to 10 membered ring, heterocyclic radicals may be sub-divided into heteroaromatic (or "heteroaryl") radicals and non-aromatic hetero-cyclic radicals; when a heteroatom of the said non- aromatic heterocyclic radical is nitrogen, the latter may be substituted with a substituent selected from the group consisting of C1-7 alkyl, C3-10 cycloalkyl, aryl, arylalkyl and alkylaryl. As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C1-20 alkoxy ", " C3-10 cycloalkoxy ", " aryloxy", "arylalkyloxy ", " oxyheterocyclic ", " C1-20 alkylthio ", " C3-10 cycloalkylthio ", "arylthio ", " arylalkylthio " and " thioheterocyclic " refer to substituents wherein a C1-20 alkyl radical, respectively a C3-10 cycloalkyl, aryl, arylalkyl or heterocyclic radical (each of them such as defined herein), are attached to an oxygen atom or a divalent sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiocyclopropyl, thiocyclobutyl, thiocyclopentyl, thiophenyl, phenyloxy, benzyloxy, mercaptobenzyl, cresoxy, and the like. As used herein with respect to a substituting atom, and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine. As used herein with respect to a substituting radical, and unless otherwise stated, the term " halo Ci-20 alkyl " means a Ci-20 alkyl radical (such as above defined) in which one or more hydrogen atoms are independently replaced by one or more halogens (preferably fluorine, chlorine or bromine), such as but not limited to difluoromethyl, trifluoromethyl, trifluoroethyl, octafluoropentyl, dodecafluoroheptyl, dichloromethyl and the like. As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C2-20 alkenyl " designate a straight and branched acyclic hydrocarbon monovalent radical having one or more ethylenic unsaturations and having from 2 to 20 carbon atoms such as, for example, vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2- hexenyl, 2-heptenyl, 1 ,3-butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and the like, including ail possible isomers thereof. As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-i0 cycloalkenyl " mean a monocyclic mono- or polyunsaturated hydrocarbon monovalent radical having from 3 to 8 carbon atoms, such as for instance cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclohepta-dienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl and the like, or a C7-i0 polycyclic mono- or polyunsaturated hydrocarbon mono-valent radical having from 7 to 10 carbon atoms such as dicyclopentadienyl, fenchenyl (including all isomers thereof, such as α-pinolenyl), bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.1] hepta-2,5-dienyl, cyclofenchenyl and the like. As used herein with respect to a substituting radical, and unless otherwise stated, the term " C2-20 alkynyl " defines straight and branched chain hydrocarbon radicals containing one or more triple bonds and optionally at least one double bond and having from 2 to 20 carbon atoms such as, for example, acetylenyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 2-pentynyl, 1-pentynyl, 3-methyl-2-butynyl, 3- hexynyl, 2-hexynyl, 1-penten-4-ynyl, 3-penten-1-ynyl, 1 ,3-hexadien-1-ynyl and the like. As used herein with respect to a substituting radical, and unless otherwise stated, the terms " arylalkyl ", " arylalkenyl " and "heterocyclic-substituted alkyl " refer to an aliphatic saturated or ethylenically unsaturated hydrocarbon monovalent radical (preferably a Ci-20 alkyl or C2-20 alkenyl radical such as defined above) onto which an aryl or heterocyclic radical (such as defined above) is already bonded, and wherein the said aliphatic radical and/or the said aryl or heterocyclic radical may be optionally substituted with one or more substituents independently selected from the group consisting of C1-4 alkyl, trifluoromethyl, halogen, amino, nitro, hydroxyl, sulfhydryl and nitro, such as but not limited to benzyl, 4-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-ter-butylbenzyl, 3- methylbenzyl, 4-methylbenzyl, phenylpropyl, 1-naphtylmethyl, phenylethyl, 1-amino- 2-phenylethyl, 1-amino-2-[4-hydroxy-phenyl]ethyl, 1-amino-2-[indol-2-yl]ethyl, styryl, pyridylmethyl (including all isomers thereof), pyridylethyl, 2-(2-pyridyl)isopropyl, oxazolylbutyl, 2-thienylmethyl, pyrrolylethyl, morpholinyl-ethyl, imidazol-1-yl-ethyl, benzodioxolylmethyl and 2-furylmethyl. As used herein with respect to a substituting radical, and unless otherwise stated, the term " alkylaryl " and "alkyl-substituted heterocyclic" refer to an aryl or heterocyclic radical (such as defined above) onto which are bonded one or more aliphatic saturated hydrocarbon mono-valent radicals, preferably one or more Ci-2o alkyl or C3-10 cycloalkyl radicals as defined above such as, but not limited to, o-toluyl, m-toluyl, p-toluyl, 2,3-xylyl, 2,4-xylyl, 3,4-xylyl, o-cumenyl, m-cumenyl, p-cumenyl, o- cymenyl, m-cymenyl, p-cymenyl, mesityl, fer-butylphenyl, lutidinyl (i.e. dimethylpyridyl), 2-methylaziridinyl, methylbenzimidazolyl, methylbenzofuranyl, methylbenzothiazolyl, methyl-benzotriazolyl, methylbenzoxazolyl and methylbenzselenazolyl. As used herein with respect to a substituting radical, and unless otherwise stated, the term " alkoxyaryl " refers to an aryl radical (such as defined above) onto which is (are) bonded one or more Ci-2o alkoxy radicals as defined above, preferably one or more methoxy radicals, such as, but not limited to, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, methoxynaphtyl and the like. As used herein with respect to a substituting radical, and unless otherwise stated, the terms " alkylamino ", "cycloalkylamino ", "alkenyl-amino", cycloalkenylamino " , " arylamino ", "arylalkylamino ", "heterocyclic amino " , " hydroxyalkylamino ", "mercaptoalkylamino " and " alkynylamino" mean that respectively one (thus monosubstituted amino) or even two (thus disubstituted amino) C1-20 alkyl, C3-10 cycloalkyl, C2-20 alkenyl, C3-10 cycloalkenyl, aryl, arylalkyl, heterocyclic, mono- or polyhydroxy C1-7 alkyl, mono- or polymercapto Ci-20 alkyl or C2- 20 alkynyl radical(s) (each of them as defined herein, respectively) is/are attached to a nitrogen atom through a single bond or, in the case of heterocyclic, include a nitrogen atom, such as but not limited to, anilino, benzylamino, methylamino, dimethylamino, ethylamino, diethyl-amino, isopropylamino, propenylamino, n-butylamino, ter- butylamino, dibutylamino, morpholinoalkylamino, morpholinyl, piperidinyl, piperazinyl, hydroxymethylamino, β-hydroxyethylamino and ethynylamino; this definition also includes mixed disubstituted amino radicals wherein the nitrogen atom is attached to two such radicals belonging to two different sub-set of radicals, e.g. an alkyl radical and an alkenyl radical, or to two different radicals within the same sub-set of radicals, e.g. methylethylamino; among disubstituted amino radicals, symetrically substituted are more easily accessible and thus usually preferred. As used herein with respect to a substituting radical, and unless otherwise stated, the terms "(thio)carboxylic acid ester ", " (thio)carboxylic acid thioester " and " (thio)carboxylic acid amide" refer to radicals wherein a carbonyl or thiocarbonyl group is bonded to an alkoxy, a mercapto, an aryloxy, an arylthio, an amino, a primary or secondary amino, or a hydroxylamino, the residue on the oxygen, nitrogen or sulfur atom thereof being selected from the group consisting of C1-2O alkyl, C2-2o alkenyl, C2- 20 alkynyl, C3-10 cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, alkylaryl, all of the latter being such as defined herein, respectively. As used herein with respect to a substituting radical, and unless otherwise stated, the term " amino-acid residue " refers to a radical derived from a molecule (by abstraction of a hydrogen atom either from the amino group or the carboxyl group of said molecule) having the chemical formula H2N-CHR-COOH, wherein R is the side group of atoms characterizing the amino-acid type; said molecule may be one of the 20 naturally-occurring amino-acids or any similar non naturally-occurring amino-acid, including cyclic amino-acids and acyclic or cyclic β-amino-acids. As used herein and unless otherwise stated, the term " stereoisomer " refers to all possible different isomeric as well as conformational forms which the compounds of the invention may possess, in particular all possible stereochemical^ and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention. As used herein and unless otherwise stated, the term " enantiomer " means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%. As used herein and unless otherwise stated, the term " solvate " includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, bases, nitriles, amides, sulfur-containing com- pounds, halogenated hydrocarbons, aromatic and aliphatic hydrocarbons. Specific examples thereof include, but are not limited to, ethanol, 2-propanol, ethyl acetate, diethyl ether, pyridine, N-methyl pyrrolidone, acetonitrile, dimethylformamide, ace¬ tone, methylethylketone, dimethylsulfoxide, dichloromethane, chloroform and toluene. As used herein and unless otherwise stated, the term " salt " refers to conventional non-toxic salts which may be formed through addition of an inorganic or organic acid or base. Examples of such acid addition salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, sulfate, butyrate, citrate, camphorate, camphor-sulfonate, propionate, digluconate, dodecyl- sulfate, erucate, ethanesulfonate, ferulate, fumarate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, hydrochloride, hydrobromide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, 3-phenyl-propionate, picrate, pivalate, propionate, salicylate, succinate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate and valerate. For therapeutic use, said salts are preferably those wherein the counter-ion is pharmaceutically or physiologically acceptable. Examples of such base addition salts include, but are not limited to, ammonium salts, alkali and alkaline-earth metal salts (e. g. lithium, sodium, potassium, magnesium and calcium salts), salts with organic bases such as benzathine, N-methyl-D-glucamine and hydrabamine, or with amino-acids such as, for example, arginine, lysine and the like. As used herein and unless otherwise stated, the term " alkanoyl " refers to a alkyl radical linked to a carbonyl moiety. As used herein and unless otherwise stated, the term " aminoalkanoyl " refers to a group derived from an amino-substituted saturated carboxylic acid wherein the amino group may be a primary, secondary or tertiary amino group. As used herein and unless otherwise stated, the term " aminocarbonyl" refers to an amino-substituted carbonyl (carbamoyl) group wherein the amino group can be a primary, secondary or tertiary amino group. As used herein and unless otherwise stated, the term " aralkanoyl " refers to a radical derived from an aryl-substituted saturated carboxylic acid such as, but not limited to, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2- naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydro-cinnamoyl and A- methoxyhydrocinnamoyl. As used herein and unless otherwise stated, the term "aralkoxycarbonyl " refers to a radical such as, but not limited to, benzyloxy-carbonyl and 4- methoxyphenylmethoxycarbonyl. As used herein and unless otherwise stated, the term " aroyl " refers to a radical derived from an aromatic carboxylic acid such as, but not limited to, benzoyl, 4-chlorobenzoyl, 4- carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 1-naphthoyl, 2- naphthoyl, 6-carboxy-2-naphthoyl, 6-benzyloxycarbonyl-2-naphthoyl, 3-benzyloxy-2- naphthoyl and 3-hydroxy-2-naphthoyl. As used herein and unless otherwise stated, the term "cycloalkylcarbonyl " refers to a group derived from a monocyclic or bridged cycloaliphatic carboxylic acid such as, but not limited to, cyclopropylcarbonyl, cyclohexylcarbonyl, adamantyl- carbonyl, or from a benzo-fused monocyclic cycloaliphatic carboxylic acid such as, but not limited to, 1 ,2,3,4-tetrahydro-2-naphthoyl and 2-acetamido-1 ,2,3,4-tetrahydro- 2-naphthoyl. The terms " angiogenesis " and " neovascularisation ", as used herein, refer to the phenomenon of new blood vessel formation. Blood vessel formation is required for normal tissue growth, placenta and embryonic development, wound healing and the like. The term " angiogenesis-inhibiting ", as used herein, refers to the ability to at least partly inhibit, prevent, or greatly reduce the formation or outgrowth of blood or lymph vessels, or the ability to destroy such vessels during sprouting or outgrowth in vitro as well as in vivo. The term " angiogenesis-related disease ", as used herein, refers to diseases wherein angiogenesis plays a crucial detrimental role such as, but not limited to, cancer, hemangiomas, atherosclerosis, inflammatory diseases, arthritis, psoriasis, pre-eclampsia, intra-uterine growth retardation, endometriosis, liver or kidney fibrosis, proliferative retinopathy, age-related maculopathy, diabetes mellitus related maculopathy, diabetic retinopathy, macular degeneration , neovascular glaucoma, retrolental fibroplasias, retinal vascularisation and the like. The term " arthritis " as used herein, refers to any form of joint inflammation and includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, bursitis, fibromyalgia, gout, infectious arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, reactive arthritis, scleroderma, systemic lupus erythematosus, tendonitis and synovitis. The term " therapeutically effective amount ", as used herein, means an amount that elicits a measurable biological response in a tissue, organ or system of an animal, preferably a human, or which alleviates the symptoms of a disease being treated.

Detailed description of the invention More specifically, the present invention relates to a class of novel monocyclic (when Y is an amino-acid residue other than a proline residue) and polycyclic compounds having the general formula 1 X-d-L-e-Y, wherein: - X is a methylidene-substituted cycloalcane or heterocycloalcane moiety represented by the general formula 2 shown below wherein:

- A and B are each independently selected from the group consisting of hydrogen, cyano, halogen, azido, C=NOR6, C=N-NR7R8, COOR6, CONR7R8, C1-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-20 alkenyl, C2- 20 alkynyl, aryl, arylalkyl, alkoxyaryl and heterocyclic, Ci-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3-10 cycloalkoxy, C3-i0 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, Ci-20 alkylthio, C3-i0 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, C1-20 alkylamino, C3-10 cycloalkylamino, C2-20 alkenylamino, C3-10 cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino and C2-20 alkynylamino, acylamino, thioacylamino, or A and B together form a homocyclic or heterocyclic group, provided that A and B are not both hydrogen, - Ti, T2, T3, T4 and T5 are carbon atoms, or alternatively one of T1, T2, T3, T4 and T5 is oxygen or nitrogen while the remaining of T1, T2, T3, T4 and T5 are carbon atoms, or alternatively two of T1, T2, T3, T4 and T5 are either both nitrogen, or oxygen and nitrogen, while the remaining of Ti, T2, T3, T4 and T5 are carbon atoms, or alternatively two of non adjacent T1, T2, T3, T4 and T5 are oxygen while the remaining of T1, T2, T3, T4 and T5 are carbon atoms, - R1, R2, R3, R4 and R5 are each substituents independently selected from the group consisting of hydrogen, cyano, halogen, azido, hydroxyl, amino, carboxyl, C1-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-20 alkenyl, C2-20 alkynyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3-i0 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, (di)C1-20 alkylamino(thio)carbonyloxy, C3-10 cycloalkylaminocarbonyloxy, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, C1-20 alkylamino, C3-10 cycloalkylamino, C2-20 alkenyl-amino, C3-10 cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino, C2-20 alkynylamino, acylamino, thioacylamino, (hetero)aroylamino, (di)C1-20 alkylamino(thio) carbonylamino, C1-20 alkoxy(thio)carbonylamino, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide, with the first proviso that if any one of T1, T2, T3, T4 and T5 is oxygen then the correspondingly borne substituent R1, R2, R3, R4 or R5 is absent, and with the second proviso that if any one of T1, T2, T3, T4 and T5 is nitrogen then the correspondingly borne substituent R1, R2, R3, R4 or R5 cannot be cyano, halogen, azido, carboxyl, C1-20 alkylthio, C3-i0 cycloalkylthio, arylthio, arylalkylthio, acylthio or thioheterocyclic, - S1, S2, S3, S4 and S5 are each substituents independently selected from the group consisting of hydrogen, cyano, halogen, carboxyl, C1-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-20 alkenyl, C2-20 alkynyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3--I0 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkyl-thio, acylthio, thioheterocyclic, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide, with the proviso that if any one of T1, T2, T3, T4 and T5 is oxygen or nitrogen then the correspondingly borne substituent S1, S2, S3, S4 and S5 is absent, - if any two adjacent atoms from the group consisting of T1, T2, T3, T4 and T5 are carbon or nitrogen atoms then a pair of substituents borne by said adjacent carbon or nitrogen atoms, e.g. (R11R2), (R21R3), (R31R4) or (R41R5), may form a fused homocyclic ring (e.g. cycloalkylene or arylene) or a heterocyclic ring, - if any one of T1, T2, T3, T4 and T5 is a carbon atom then each pair of geminal substituents borne by the same carbon atom, i.e. (R11S1), (R21S2), (R3,S3), (R41S4) or (Rs1S5), may independently form a homocyclic ring or a heterocyclic ring (e.g. 1 ,3-dioxolanyl or 1 ,3-dioxanyl), or an alkylidene, cycloalkylidene or arylalkylidene group, or a carbonyl (oxo) or thiocarbonyl (thioxo) group, or an imino, an oximino or a hydrazone group, - R6 is selected from the group consisting of hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-10 cycloalkyl, C3-i0 cycloalkenyl, aryl, arylalkyl and heteroaryl, - R7 and R8 are each independently selected from the group consisting of hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, aryl, arylalkyl and heteroaryl, or R7 and R8 together may form a homocyclic or heterocyclic group, and - m is an integer selected from 0 (X being a methylidene-substituted cyclopentane or heterocyclopentane moiety), 1 (X being a methylidene- substituted cyclohexane or heterocyclohexane moiety) and 2 (X being a methylidene-substituted cycloheptane or heterocycloheptane moiety), Y is an amino-acid residue (including a proline residue) or a glycone or glycone- like moiety represented by the general formula 3 shown below wherein:

- U1, U2, U3, U4, U5 and U6 are carbon atoms, or alternatively one of U1, U2, U3, U4, U5 and U6 is oxygen or nitrogen while the remaining of U1, U2, U3, U4, U5 and U6 are carbon atoms, or alternatively two of U1, U2, U3, U4, U5 and U6 are either both nitrogen, or oxygen and nitrogen, while the remaining of U1, U2, U3, U4, U5 and U6 are carbon atoms, or alternatively two of non adjacent U1, U2, U3. U4, U5 and U6 are oxygen while the remaining of U1, U2, U3, U4, U5 and U6 are carbon atoms, - Pi > P2, P3, P4. P5 and P6 are each substituents independently selected from the group consisting of hydrogen, cyano, halogen, azido, hydroxyl, amino, carboxyl, C1-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-i0 cycloalkenyl, C2-20 alkenyl, C2-20 alkynyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3-10 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, (di) C1-20 alkylamino(thio)carbonyloxy, C1-20 alkylthio, C3-I0 cycloalkylthio, arylthio, arylalkylthio, acylthio, thio-heterocyclic, C1-20 alkylamino, C3-10 cycloalkylamino, C2-20 alkenyl-amino, C3-10 cycloalkenyl- amino, arylannino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino, C2-20 alkynylamino, acylamino, thioacylamino, (hetero)aroylamino, (di)C1-20 alkylamino(thio)carbonylamino, C1-20 alkoxy(thio)carbonylamino, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide, with the first proviso that if any one of U1, U2, U3, U4, U5 and U6 is oxygen then the correspondingly borne substituent P1, P2, P3, P4, P5 or P6 is absent, and with the second proviso that if any one of U1, U2, U3, U4, U5 and U6 is nitrogen then the correspondingly borne substituent P1, P2. P3, P4, P5 or P6 cannot be cyano, halogen, azido, carboxyl, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio or thioheterocyclic, - Q1, Q2, Q3, Q4, Q5 and Q6 are each substituents independently selected from the group consisting of hydrogen, cyano, halogen, carboxyl, Ci-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-20 alkenyl, C2-20 alkynyl, aryl, heteroaryl, arylalkyl, C1-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3-10 cycloalkoxy, C3-10 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, (thio) carboxylic acid (thio)ester and (thio)carboxylic acid amide, with the proviso that if any one of U1, U2, U3, U4, U5 and U6 is oxygen or nitrogen then the correspondingly borne substituent Q1, Q2, Q3, Q4, Q5 and Q6 is absent, - if any two adjacent atoms from the group consisting of U-i, U2, U3, U4 U5 and U6 are carbon or nitrogen atoms then a pair of substituents borne by said adjacent carbon or nitrogen atoms, e.g. (P11P2), (P21P3), (P31P4), (P4Ps) or (P5, P6) may form a fused homocyclic ring (e.g. cycloalkylene or arylene) or heterocyclic ring, - if any one of U1, U2, U3, U4, U5 and U6 is a carbon atom then a pair of geminal substituents borne by the same carbon atom, i.e. (P11Q1), (P21Q2), (P31Q3), (P41Q4), (P51Q5) or (P61Q6) may independently form a homocyclic ring or a heterocyclic ring (e.g. 1 ,3-dioxolanyl or 1 ,3-dioxanyl), or an alkylidene, cycloalkylidene or arylalkylidene group, or a carbonyl (oxo) or thiocarbonyl (thioxo) group, or an imino, an oximino or a hydrazone group, and - n is an integer selected from 0, 1 and 2 (Y may be named a glycone moiety when n = 1 , a glycone-like moiety when n is 0 or 2), - L is a linker selected from the group consisting of a covalent bond and divalent hydrocarbon radicals such as, but not limited to, C1-20 alkylene, C3-10 cycloalkylene, C2-2o alkenylene, C3-10 cycloalkenylene, C2-20 alkynylene, hetero- alkylene, cycloheteroalkylene, arylene, heteroarylene, arylalkylene and hetero- arylalkylene, d represents a moiety for the attachment of the methylidene-substituted cyclo- alcane or heterocycloalcane moiety X and the linker L, which moiety replaces any one of the substituents R1, R2, R3, R4, Rs, S1, S2, S3, S4 and S5 being present on said methylidene-substituted cycloalcane or heterocycloalcane moiety X, - e represents a moiety for the attachment of the amino-acid residue or the glycone or glycone-like moiety Y and the linker L, said moiety e replacing (when Y is a glycone or glycone-like moiety) any one of the substituents P1, P2, P3, P4, P5, P6, Q1, Q2, Q3, Q4, Q5 and Q6 being present on said glycone or glycone-like moiety Y, and - each of d and e is independently selected from the group consisting of a covalent bond, an oxygen atom, a sulfur atom or a divalent radical selected from the group consisting of -N(Z)-, -(C=O)N(Z)-, -SO2N(Z)-, -S(=O)N(Z)-, -OP(=O)(OW)N(Z)-, -N(Z)C(=O)N(Z)-, -N(Z)C(=O)O-, -N(Z)C(=S)N(Z)-, -N(Z)C(=S)O-, -C(=O)O-, -N(Z)C(=S)S- and -C(=O)-, - Z is selected from the group consisting of hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, aminoalkyl, aminoaryl, aminoheteroaryl, aryloxy, C1-20 alkoxy, hetero- aryloxy, thioalkyl, thioaryl, thioheteroaryl, acyl, aroyl, heteroaroyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and - W is selected from the group consisting of hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, a salt, a solvate, a stereoisomer or an enantiomer thereof. An important feature of this invention is that X has a 5 to 7 membered saturated ring built up from atoms T1, T2, T4, T5 and the carbon atom bearing an optionally substituted methylidene group, and optionally one or two atoms T3, wherein T1, T2, T3, T4 and T5 are as defined hereinbefore. Another important feature of this invention is that at least three of T1, T2, T3, T4 and T5 are carbon atoms, and at most two of T1, T2, T3, T4 and T5 are heteroatoms such as oxygen and nitrogen. Suitable examples of such saturated rings include, but are not limited to, cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran, 1 ,2-tetrahydro-oxazole, 1 ,3-tetrahydro-oxazole, dioxolane, 1 ,3-dioxane, 1-4-dioxane, tetrahydro-2H-1 ,3- oxazine, tetrahydro-2H-1 ,2-oxazine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, homopiperazine, 1-azacycloheptane, 1-oxacycloheptane, 1,3- dioxacycloheptane, 1 ,4-dioxacycloheptane, 1-aza-2-oxacycloheptane, 1 ,4-dioxa-2- azacycloheptane, 1-oxa-3-azacycloheptane, 1 -oxa-4-azacycloheptane, 1 ,2- diazacycloheptane, 1 ,3-diazacycloheptane, 1 ,4-diazacycloheptane, morpholine, hexahydropyrimidine and hexahydropyridazine. The present invention also relates to a group of novel methylidene-substituted cycloalcane or heterocycloalcane compounds having the general formula 2 shown above, with all substituents thereon being as defined hereinabove and with all meanings of the 5 to 7 membered saturated ring included in X being as described hereinbefore. As will be described hereinafter, such methylidene-substituted cycloalcane or heterocycloalcane compounds are useful as intermediates for making the monocyclic and polycyclic compounds having the general formula 1 shown above. In another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 1, as well as a sub¬ class of such compounds having the general formula 2, wherein m is 1 and wherein none of R2 and S2 is hydrogen. Within this sub-class are included methylidene- substituted cyclohexane compounds and methylidene-substituted heterocyclohexane compounds such as, but not limited to, methylidene-substituted piperidine compounds, methylidene-substituted piperazine compounds, methylidene-substituted tetrahydropyran compounds and methylidene-substituted morpholine compounds. In another specific embodiment, the invention relates to a sub-class of such polycyclic compounds having the general formula 1, wherein Y is a glycone moiety having the general formula 3, and n is 1. In another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 1, as well as a sub¬ class of such methylidene-substituted cycloalcane and heterocycloalcane compounds having the general formula 2, wherein one of A and B is hydrogen and wherein the other of A and B is selected from the group consisting of hydrogen, cyano, halogen, azido, C=NOR6, C=N-NR7R8, COOR6, CONR7R8, C1-20 alkyl, halo C1-20 alkyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-20 alkenyl, C2-20 alkynyl, aryl, arylalkyl, alkoxyaryl and heterocyclic, C1-20 alkoxy, C2-20 alkenyloxy, C2-20 alkynyloxy, C3-10 cycloalkoxy, C3--I0 cycloalkenyloxy, aryloxy, arylalkyloxy, acyloxy, oxyheterocyclic, C1-20 alkylthio, C3-10 cycloalkylthio, arylthio, arylalkylthio, acylthio, thioheterocyclic, C1-20 alkylamino, C3-10 cycloalkylamino, C2-20 alkenylamino, C3-10 cycloalkenylamino, arylamino, arylalkyl- amino, heterocyclic amino, hydroxyalkylamino, mercaptoalkylamino and C2-2O alkynyl- amino, acylamino and thioacylamino. In another specific embodiment the invention relates to a sub-class of such methylidene-substituted cycloalcane compounds wherein each of S1, S2, S3, S4 and S5 is hydrogen (i.e. each ring carbon atom of the methylidene-substituted cycloalcane moiety represented by the general formula 2 is monosubstituted), and to a sub-class of such polycyclic compounds represented by the general formula 1 further wherein each of Q1, Q2, Q3, Q4, Q5 and Q6 is hydrogen (i.e. each ring atom of the glycone or glycone-like moiety represented by the general formula 3 is monosubstituted). In another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 1, as well as a sub¬ class of such methylidene-substituted cycloalcane or heterocycloalcane compounds having the general formula 2, wherein no more than two of S1, S2, S3, S4 and S5 is hydrogen and/or no more than two of Q1, Q2, Q3, Q4, Q5 and Q6 is hydrogen. In another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 1, wherein d is a covalent single bond. In another specific embodiment, the invention relates to a sub¬ class of such monocyclic and polycyclic compounds having the general formula 1, wherein e is a covalent single bond. In another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 7, wherein L is oxygen, methylene, oxymethylene or a covalent single bond. In yet another specific embodiment, the invention relates to a sub-class of such monocyclic and polycyclic compounds having the general formula 7, wherein d, L and e combined together are oxygen, methylene, oxymethylene or a covalent single bond. In another specific embodiment, the invention relates to a sub-class of such monocyclic compounds having the general formula 1, wherein Y is an amino-acid residue other than a proline residue. Whether referring to the intermediates represented by the general formula 2 or to the monocyclic and polycyclic compounds represented by the general formula 1, other specific embodiments of the invention relate to compounds simultaneously belonging to two or more of the above specified sub-classes. All of the sub-possibilities listed above may be combined at will, i.e. each of the substituents A, B, R1, R2, R3, R4, R5, S1, S2, S3, S4, S5, Q1, Q2, Q3, Q4, Q5, Q6, P1, P2, P3, P4, P5 or P6 , or each pair of substituents born by the same carbon atom, or each pair of substituents born by adjacent carbon or nitrogen atoms, may indepen- dently correspond to any of the definitions given above, in particular with any of the individual meanings (such as illustrated above) of generic terms used for substituting radicals such as, but not limited to, " C1-20 alkyl ", " C3-10 cycloalkyl ", " C2-20 alkenyl ", " C2-20 alkynyl", " aryl ", " homocyclic ", " heterocyclic ", " halogen ", " C3-10 cycloalkenyl ", "alkylaryl ", "arylalkyl ", "alkylamino", " cycloalkylamino ", " alkenyl- amino ", " alkynylamino ", " arylamino ", " arylalkylamino ", "heterocyclic amino ", " hydroxyalkylamino ", " mercaptoalkylamino ", " alkynylamino ", " C1-7 alkoxy ", " C3-10 cycloalkoxy ", " thio C1-7 alkyl ", " thio C3-10 cycloalkyl ", " halo C1-7 alkyl ", "amino- acid " and the like. Similarly, the linker L and each of the attachment moieties d and e may, in any combination with any of the above-listed substituents, correspond to any of the generic definitions given above, in particular with any of the individual meanings for such generic definitions. Each of the compounds of the invention, whatever the general formula herein¬ before, may be in the E or Z stereoisomers form. Pure stereoisomeric forms of the novel bicyclic compounds of this invention may be obtained by using procedures known in the art. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques known in the art, using chiral commercially available stationary phases. Diastereomers may be obtained by suitable conventional methods of physical separation such as, for example, selective crystallization or column chromatography. The present invention also relates to methods for making the above-referred monocyclic and polycyclic compounds being represented by the above general formulae. The compounds of this invention being represented by the general formula 1 may be prepared according to several methods, either via derivatization of simmondsin and its naturally occuring derivatives (as may be extracted for instance from jojoba flour), via hemisynthesis from simmondsin and its naturally occuring derivatives, or via fully synthetic routes, as follows. In a limited number of situations, especially when m and n are both 1 (i.e. the polycyclic compound comprises a methylidenecyclohexane moiety and a glycone moiety) and each ring being represented by the formulae 2 and 3 bears a limited number of substituents that may easily be introduced onto the molecule through conversion of a hydroxyl group or a methoxy group (both being present in natural simmondsin) into said substituent, derivatization of simmondsin or its naturally occuring derivatives may be a method of choice. This applies especially when the conversion method proceeds in a limited number of steps, preferably in a single reaction step, and in high yields. In all other situations a fully synthetic procedure may be preferred, especially because it produces chemical intermediates that may also be useful for making other compounds than the monocyclic and polycyclic compounds of the present invention, or because it is able to produce a wide range of diverse functional compounds at will. Generally speaking, a fully synthetic method for preparing such monocyclic and polycyclic compounds according to the invention involves first the preparation of a methylidene-substituted cycloalcane or heterocycloalcane intermediate represented by the general formula 2, and then the coupling of such an intermediate compound with an amino-acid or with a glycone or glycone-like compound represented by the general formula 3 (which, if not commercially available, may itself be prepared according to the following methods). When coupling of a methylene-substituted cycloalcane or heterocycloalcane intermediate compound with an amino-acid is involved, it is clearly preferred that one of Ri, S1, R2, S2, R3, S3, R4, S4, R5 and S5 comprises a primary or secondary amino group or a carboxylic acid group. When coupling of a methylidene-substituted cycloalcane or heterocycloalcane intermediate compound with an amino-acid or a glycone or glycone-like compound represented by the general formula 3 is involved, the only requirement is that one of R1, S1, R2, S2, R3, S3, R4, S4, R5 and S5 is reactive, either directly or through a linker L, with the amino or carboxylic acid group of said amino-acid, or with one of the substituents P1, Qi. P2, Q2, Pe, Q3, P4, CU> P5, Qs, Pe and Q6 being present on said glycone or glycone-like compound. When coupling is effected through a linker L, synthesis may proceed either by prior attachment of the linker to the methylidene-substituted cycloalcane or heterocycloalcane intermediate represented by the general formula 2, or by prior attachment of the linker to the amino-acid or the glycone or glycone-like compound represented by the general formula 3, or by introducing the linker during the final coupling step. However, as evidenced by the following specific embodiments, prior attachment of the linker to the methylene-substituted cycloalcane or heterocycloalcane intermediate is usually preferred. As illustrated by the following specific embodiments, the methods required for preparing a methylene-substituted cycloalcane intermediate compound represented by the general formula 2 depends significantly upon the value of m with respect to the starting material, upon the type and the number of heteroatoms in the 5 to 7 membered saturated ring, and upon the type and the number of substituents R1, S1, R2, S2, R3, S3, R4, S4, R5 and S5 to be introduced onto the cycloalcane or heterocycloaicane moiety of such intermediate. However, based on the following description and the general knowledge of organic chemistry, the skilled person will be able to determine the best suitable methodology in order to minimize the number of process steps and to optimize the global yield of the desired intermediate. As will be appreciated by the skilled person from the following exemplary embodiments, the number of synthetic steps required in the methods of this invention is significantly lower than the 18 steps reported by Ogawa et al. (cited supra) for the synthesis of simmondsin. Most often the number of such steps does not exceed six steps, including the protection and deprotection steps if necessary. Many glycone compounds (i.e. when n = 1) being suitable for introducing a glycone moiety represented by the general formula 3 into a polycyclic compound of this invention represented by the general formula 1 are commercially available or can easily be prepared by direct derivatization of a commercially available glycones or glycone analogues in one or more steps (for instance by conversion of one or more hydroxyl groups into one or more another functional groups Pi, Q1, P2, Q2, P3, Q3, P4, Q4, P5, Q5, P6 and Q6 as defined hereinabove) while making use of standard general knowledge of the person skilled in organic chemistry. The same, although often requiring a larger number of process steps, applies to glycone-like compounds (i.e. when n is 0 or n is 2). The skilled person understands that certain reaction steps may involve prior chemical protection of certain recative groups and subsequent deprotection after the desired reaction has occurred. The following is a description of a few non-limiting exemplary methods for making some methylene-substituted cycloalcane and heterocycloaicane intermediate compounds represented by the general formula 2 as well as some polycyclic compounds of this invention represented by the general formula 1,

Method 1 - synthesis via enzymatic derivatization of simmondsin Acylation is schematically shown below as an exemplary, but not limiting, one- step method for the enzymatic derivatization of simmondsin or its naturally-occurring analogues.

OMe OH

1.1 1.2

(a) vinyl hexanoate and enzyme

Starting from natural simmondsin (compound 1.1), it is possible to regioselectively introduce one or more acyl groups by using one or more suitable enzymes in combination with a suitable acyl donor and in the presence of one or more suitable organic solvents. Examples of such suitable enzymes are lipases, esterases, acylases and proteases. Examples of suitable acyl donors are aromatic, heteroaromatic, aliphatic, alicyclic, heterocyclic carboxylic acids and their activated esters, e.g. vinyl esters, 2-propenyI esters, C1-20 alkyl esters, halo C1-20 alkyl esters (e.g. chlorinated, brominated or fluorinated), or any other ester which can be used for this purpose as known to anybody skilled in the art (see e.g. K. Faber, "Biotransformations in organic synthesis", 3rd edition, Springer Verlag, Berlin, 1997, pp. 27-115 and 300-327; Bornscheuer et al. in "Hydrolases in organic synthesis, regio- and stereoselective biotransformations", Wiley-VCH, New-York, 1999, pp. 39- 172 and 179-208). The acyl donor may also be used as the solvent. Other typical suitable solvents include, but are not limited to chloroform, toluene, ethers (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether and ter-butyl methyl ether), or any other suitable solvent known to anybody skilled in the art. Preferably the molar ratio of the acyl donor to simmondsin is from about 1 :1 to about 10:1 (higher values being preferred when the acyl donor also acts as a solvent). The choice of molar ratio, type of solvent and temperature conditions is a matter of routine experimentation. This method may similarly applied to DMS, DDMS and other naturally occurring simmondsin analogues.

Method 2 - synthesis via chemical modification of simmondsin O-acylation is schematically shown below as an exemplary, but not limiting, one-step method for the chemical modification of simmondsin or its naturally- occurring analogues. (a) O-acylation step (b) deprotection step

2.1 2.2 R = functionalized aryl or alky]

Natural or synthetic simmondsin 1.1 or one of its analogues is first suitably protected by hydroxyl-protecting groups P1 and P2 such that only one hydroxyl group remains free (compound 2.1). Examples of such suitable protective groups P1 and P2 and the way to introduce them are well known in carbohydrate chemistry, and include, but are not limited to, the following classes: esters, acetals, ethers, silyl ethers, carbamates and carbonates (see e.g. T.K. Lindhorst, "Essentials of carbohydrate chemistry and biochemistry", Wiley-VCH, New-York, 2000, pp. 39-78; R. V. Stick, "Carbohydrates. The sweet molecules of life", Academia Press, New- York, 2001 , pp. 37-66; G.J. Boons, "Carbohydrate chemistry", Blackie Academic and Professional, Thomas Science London, 1998, pp. 21-45; T.W. Greene, P.G.M. Wuts, "Protective groups in organic synthesis", 3rd edition, J. Wiley & Sons, New- York, 1999, pp. 17-245). Subsequently, the free hydroxyl group is e.g. acylated (step (a) in the hereinabove scheme) or alkylated in order to introduce a desired side chain. O- acylation can be performed using e.g. carboxylic acid chlorides, carboxylic acid anhydrides or activated carboxylic acid esters including, but not limited to, para- nitrophenyl esters and succinimidyl esters. Alternatively, a carboxylic acid can be transformed into an active ester in situ using an activating agent such as N1N'- dicyclohexylcarbodiimide (DCC) in the presence of N-hydroxy-benzotriazole (HOBt) or any other activating reagent known to anybody skilled in the art. O-alkylation may be typically performed by deprotonating the free hydroxyl group, e.g. with sodium hydride or potassium terf-butoxide, in a dry aprotic solvent (typically an ether (ike diethyl ether, tetrahydrofuran or dimethoxyethane), and subsequently treating the resulting alcoholate with a C1-20 alkyl halide or C1-20 alkyl sulfonate including the desired C1-20 alkyl group. A dipolar aprotic solvent, e.g. dimethyl sulfoxide (DMSO), hexamethyl phosporic triamide (HMPA) or 1 ,3-dimethyl- 3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) may be used, and/or a crown ether, e.g. 15-crown-5 or 18-crown-6, can be added to the reaction medium as a catalyst in order to accelerate the O-alkylation reaction. Finally, careful deprotection in step (b), using methods standard in the art, affords the desired acylated simmondsin compound (represented by the formula 2.2) or alkylated simmondsin compound. Alternatively, in the case of acylation, the primary alcohol function in 2.1 may be acylated without prior protection of the other alcohol functions (P1 = H, P2 = H), thus affording compound 2.2 in fair yields. In a typical experiment, simmondsin (50 mg, 0.13 mmole) was dissolved in dry DMF (10 ml) and cooled to O0C in an ice bath. Λ/,Λ/-Diisopropyl-ethylamine (184 μl, 1.08 mmole) and caproyl chloride (72 μl, 0.52 mmole) were slowly added. The mixture was allowed to reach room temperature, and stirring was continuedfor 16 hours. DMF was removed in vacuo, and the residue was purified via reversed phase high performance liquid chromatography (HPLC Luna C- 18 column, eluent acetonitrile:water mixtures with a gradient ranging from 0:100 to 100:0 over 15 minutes). In this way, 4.2 mg of the compound 2.2 shown in the above scheme (R = (CH2)4CH3) was isolated and characterized by proton nuclear magnetic resonance as follows: 1H-NMR: δ (CD3OD) at 5.68 (d, 1 H, J = 1.8 Hz), 4.85 (m, 1 H), "4.66 (dd, 1 H, J = U and 9.1 Hz), 4.44 (dd, 1 H, J = 2.0 and 11.8 Hz), 4.39 (d, 1 H, J = 7.8 Hz), 4.08 (dd, 1 H, J = 5.9 and 11.8 Hz), 3.90 (m, 1 H), 3.46 (s, 3 H), 3.44 (s, 3 H), 3.35 (dd, app. t, 1 H, J = 9.0 Hz and 9.0 Hz), 3.26 (dd, app. t, 1 H, J = 9.0 and 9.3 Hz), 3.21 (dd, 1 H, J = 7.8 and 9.1 Hz), 2.51 (ddd, 1 H, J = 4.1 , 4.1 and 15.2 Hz), 2.36 (t, 2 H, J = 7.4 Hz), 2.19 (m, 2 H), 1.67 (ddd, 1 H, J = 3.6, 3.6 and 15.2 Hz), 1.60 (m, 4 H) and 0.91 (t, 3 H, J = 7.4 Hz) ppm.

Method 3 - synthesis of stereoisomers via chemical modification Starting from a suitably protected simmondsin or simmondsin analogue (such as described with respect to method 2 above), the configuration at the carbon atom carrying the free hydroxyl group can be inverted by one of the following methods:

3.1 3.2 - first by conversion of the alcohol function into a suitable leaving group, preferably a sulfonate, e.g. a mesylate, triflate, tosylate, nosylate or brosylate, in step (a), followed by substitution with a nucleophile in step (b). Examples of such suitable nucleophiles include, but are not limited to, carboxylate anions, amines, hydrazine, hydroxylamine, sulfides and fluorides. In the above illustrative but non limiting scheme, acetate may be used as the nucleophile in step (b), followed by ester hydrolysis in step (c). Such a substitution reaction is preferably carried out in a dipolar aprotic solvent, e.g. N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl phosporic triamide (HMPA), N-methyl-pyrrolidone (NMP) or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU), or in an ether (e.g. diethyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane or 1 ,4-dioxane) with a dipolar aprotic solvent as an optional co-solvent. The required sulfonate protecting group may be obtained by treating the free alcohol function with a suitable sulfonyl chloride preferably in a halogenated solvent (e.g. methylene chloride, ethylene chloride) and preferably in the presence of pyridine or triethylamine as a base, and a nucleophilic catalyst, e.g. N,N-dimethylaminopyridine or N-methyl- imidazole. Alternatively, such a sulfonylation reaction can also be performed in pyridine as solvent. - by an oxidation-reduction sequence, wherein oxidation of the free alcohol function in step (d) followed by reduction in step (e) leads to inversion of the configuration. Typical oxidative agents suitable for step (d) include, but are not limited to, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine-N-oxide, periodinane, and dimethylsulfoxide (DMSO) / oxalyl chloride / triethylamine (Swern oxidation). A non-limiting example of a typical solvent for such oxidation is methylene chloride. Typical reductive agents suitable for step (e) include, but are not restricted to, sodium borohydride (preferably in methanol), zinc borohydride (preferably in ether or DME), lithium aluminum hydride (in ether or THF), lithium tris(ter-butoxy)-aluminum hydride (preferably in ether or THF), diisobutyl aluminum hydride (preferably in ether, THF, DME, toluene or methylene chloride), by a Mitsunobu inversion reaction (e.g. following the teaching of O. Mitsunobu in Synthesis (1981 ) 1-28): activation of the alcohol function with diethyl azodicarboxylate (DEAD) and triphenyl phosphine in anhydrous THF, in the presence of a carboxylic acid as a nucleophile affords the corresponding ester via nucleophilic substitution with inversion of configuration in step (f), followed by hydrolysis leading to the inverted alcohol in step (g). In a similar way, a phenol can also be used as a nucleophilic agent, giving rise to the corresponding phenyl ether with inversion of configuration. Other nucleophiles, e.g. iodide, azide or sulfides may also be introduced using the Mitsunobu activation method, by replacing the carboxylic acid with zinc iodide, zinc azide or 2-mercaptobenzo- thiazole as a nucleophile (see e.g. T.K. Lindhorst, "Essentials of carbohydrate chemistry and biochemistry", Wiley-VCH, New-York, 2000, pp. 119-150; R.V. Stick, "Carbohydrates. The sweet molecules of life", Academia Press, New-York, 2001 , pp. 67-112; G.J. Boons, "Carbohydrate chemistry", Blackie Academic and Professional, Thomas Science London, 1998, pp. 46-97).

Method 4 - preparation of simmondsin aqlucone Preparing simmondsin aglucone is schematically shown below:

1.1 "4:1

Treatment of simmondsin 1.1 or its desmethyl analogues DMS under mild conditions with mineral acid (such as, but not limited to, sulfuric acid or nitric acid) diluted in water and/or an alcohol causes cleavage of the anomeric linkage in step (a). Alternatively, cleavage may be catalyzed by enzymes such as glycosidases, more in particular in this case β-D-glucosidases in step (b). Starting from a suitably protected simmondsin (see e.g. Greene et al. in "Protective groups in organic synthesis", 3rd edition, J. Wiley & Sons, New- York, 1999, pp. 17-245), the aglucone resulting from step (a) or step (b) will have only one free hydroxyl function.

Method 5 - preparation of a simmondsin analogue from a simmondsin aglucone Preparing a protected simmondsin aglucone according to method 4 is an attractive method for the further preparation of chemically modified simmondsin derivatives, as shown schematically below.

A suitably protected simmondsin aglucone 5.1, for instance obtained by method 4, may be coupled with any suitable glycosyl donor in step (a), using coupling methods well known in the art, followed by deprotection in step (b). The leaving group of the glycosyl donor may be acetate, bromide, chloride, fluoride, trichloroacetimidate, sulfide, 4-pentenyl, or any other activating group known to anybody skilled in the art (see e.g. T. K. Lindhorst, "Essentials of carbohydrate chemistry and biochemistry", Wiley-VCH, New-York, 2000, pp. 79-118; R. V. Stick, "Carbohydrates. The sweet molecules of life", Academia Press, New-York, 2001 , pp. 113-178; G.J. Boons, "Carbohydrate chemistry", Blackie Academic and Professional, Thomas Science London, 1998, pp. 98-174). This reaction may further be activated by using known Lewis acids such as, but not limited to, BF3-Et2O, SnCi4, "TMSOTF.'

Method 6 - fully synthetic preparation of a bicyclic compound The scheme below shows a four-steps method for preparing a bicyclic compound according to the invention wherein a methylidenecyclohexane moiety is linked to a glycone-like moiety (having a nitrogen atom in the ring) via a methylene linker.

6.6 6.5

(a) oxidation step (b) cyanomethylene formation e.g. through Wadsworth-Emmons reaction or Wittig reaction (c) conjugate addition step (d) deprotection step - . .. . _ _ The synthesis of the starting material 6.1 for oxidation step (a) is known in the art, e.g. from Hubrecht et al. in Synlett, 2000, 7, 971-974. The synthesis of the starting material 6.4 (isofagomine) for step (c) is also known in the art, e.g. from J. Andersch et al. in Chem. Eur. J., 2001 , 7 (17), 3744-3747. Typical suitable oxidative agents for oxidation step (a) include, but are not limited to, manganese dioxide, barium manganate, pyridinium chlorochromate, pyridinium dichromate, tetrapropylammonium perruthenate / N-methylmorpholine-N- oxide, periodinane, and dimethylsulfoxide / oxalyl chloride / triethylamine (Swern oxidation). Examples of typical suitable solvents for such oxidation step (a) are toluene and methylene chloride. Cyanomethylene formation step (b) can be performed by a Wittig reaction, using a phosphorus ylide such as, but not limited to, cyanomethylene-triphenylphosphorane (Ph3P=CHCN) (see e.g. Y. Lakhrissi et al. in Tetrahedron: Asymm., 2000, 11, 417- 421). Cyanomethylene formation step (b) can also be performed by a Wadsworth- Emmons reaction with dimethyl- or diethyl- cyanomethylphosphonate [(RO)2P(=O)CH2CN, R = Me or Et] (see e.g. Magnus et al. in J. Am. Chem. Soc, 1993, 115(18), 8116-29). In each case, reaction step (b) results in the cyanodiene 6.3 in good yield. Typical solvents for such reaction step (b) are ethers such as, but not limited to, tetrahydrofuran, diethyl ether, and aromatic hydrocarbons such as, but not limited to, toluene. The cyanohydrin formation step (b) is preferably performed at temperatures between about 200C and the reflux temperature of said solvent. The principle of a 1,6-addition of a secundary amine onto a cyanodiene is well known in the art (see e.g. L. Xu et al. in Synlett. (2003) 15:2425-2427). In this method, the 1 ,6-addition step (c) of isofagomine 6.4 onto the cyanodiene 6.3 can be performed in a solvent system such as a mixture of water and acetonitrile, preferably in the presence of a catalyst such as, but not limited to, a Cu(ll)-salt (e.g. in a 5 mole % ratio). The final deprotection step (d) can be effected by treatment with mild aqueous acid. A typical and very mild condition for cleaving an acetonide includes, but is not limited to, aqueous acetic acid at ambient temperature.

Method 7 - fully synthetic preparation of a bicyclic compound The scheme below shows a six-steps method for preparing a bicyclic compound according to the invention wherein a methylidene-tetrahydrofurane moiety is linked to a glycone moiety via an oxymethylene linker.

D

(a) selective protection of a primary alcohol (e.g. Pi = IBuMe2Si or trityl) (b) O-alkylation step (c) Wittig reaction (d) O-glycosylation step (e) deacetylation step Selective protection of primary alcohol functions of polyols -step (a) - is known in the art (see e.g. Greene et al. in " Protective groups in organic synthesis ", 3rd edition, J. Wiley & Sons, New-York, 1999). Typical protective groups for step (a) include, but are not limited to, bulky silyl ethers (such as terf-butyldimethylsilyl ethers [P1 = tert- BuMe2Si] or terf-butyldiphenylsilyl ethers [P1 = IBuPh2Si]) or bulky trityl-type ethers (such as, but not limited to, 4-methoxy- and 4,4'-dimethoxytrityl ethers). SiIyI ethers are typically formed by reaction of 7.1 with the corresponding silyl chloride or triflate (preferably in an equimolar amount) in the presence of a base such as, but not limited to, imidazole, triethylamine or DBU. Reaction preferably proceeds in a halogenated solvent (e.g. methylene chloride) or a dipolar aprotic solvent (e.g. dimethylformamide), and preferably at temperatures beween about -200C and 500C (Greene et al., cited supra, pp. 113-148). Trityl ethers are formed by reaction of 7.1 with the corresponding trityl chloride, preferably in pyridine or a halogenated solvent (e.g. methylene chloride) or a dipolar aprotic solvent (e.g. dimethylformamide), preferably in the presence of a base (e.g. triethylamine, pyridine, 4-N1N- dimethylaminopyridine) and preferably at temperatures beween about -200C and 500C (Greene et al., cited supra, pp. 102-106). Typical conditions for O-alkylation - step (b) - include, but are not limited to, reaction with methyl iodide (optionally in a polar aprotic solvent such as, but not limited to, dimethylformamide) preferably in the presence of silver oxide, barium oxide or a silver salt (e.g. silver triflate) and preferably in the presence of a base (such as, but not limited to, 2,6-di-terf-butylpyridine) (see e.g. Greene et al., cited supra, pp. 23- 27; Stick, cited supra, p. 43; and P. Collins et al. in " Monosaccharides, their chemistry and their roles in natural products " Wiley, Chichester (UK) 1995, pp. 350- 353). Cyanomethylenation - step (c) - of the protected lactone 7.2 obtained after step (b) can be performed by a Wittig reaction with cyanomethyl triphenylphosphorane preferably in a solvent, e.g. toluene (see: Y. Lakhrissi et al., cited supra). Typical solvents for such reaction step (c) are ethers such as, but not limited to, tetrahydrofuran, diethyl ether, and aromatic hydrocarbons such as, but not limited to, toluene. The cyanomethylenation step (c) is preferably performed at temperatures between about 200C and the reflux temperature of said solvent. Selective deprotection of the primary alcohol function - step (d) - can be carried out according to procedures known in the art. Typical cleavage conditions in the case of silyl ethers include, but are not limited to, the use of tetra-n-butylammonium fluoride in tetrahydrofuran (optionally admixed with acetic acid or pyridine), or the use of aqueous hydrogen fluoride in acetonitrile at temperatures preferably between about 00C and 5O0C (see e.g. Greene et al., cited supra, pp. 113-148). Typical cleavage conditions in the case of trityl ethers include, but are not limited to, aqueous acetic acid or 0.1 M aqueous hydrochloric acid in acetonitrile at temperatures preferably between about 0 0C and 50 °C (see e.g. Greene et al., cited supra, pp. 102-106). 0-Glycosylation - step (e) - can be carried out by reacting intermediate 7.3 with any suitable glycosyl donor, using coupling methods well known in the art. The leaving group of the glycosyl donor may be acetate, bromide, chloride, fluoride, trichloroacetimidate, sulfide, 4-pentenyl, or any other activating group known to those skilled in the art (see e.g. T.K. Lindhorst, " Essentials of carbohydrate chemistry and biochemistry ", Wiley-VCH, New-York, 2000). The glycosylation reaction may be activated by the use of known Lewis acids such as, but not limited to, BF3-Et2O, SnCI4 or TMSOTf. Reaction step (e) is preferably performed in the presence of a solvent. In a typical but non-limiting example, reaction of 7.3 with 2,3,4,6-tetra-O-acetyl-D- glucopyranosyM-α-trichloroacetimidate in methylene chloride, in the presence of a catalytic amount of boron trifuoride etherate (BF3. Et2O) at 00C, followed by deacetylation - step (f) - affords 7.4 in good yield. Deacetylation - step (f) - of the intermediate obtained in step (e) is preferably performed under mild conditions, as is well known in the art (see e.g. Greene et al., cited supra, pp. 150-160), e.g. using potassium cyanide in a solvent such as, but not limited to, ethanol and preferably between 00C and reflux temperature of said solvent. In another aspect, the present invention also provides a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an effective amount of a monocyclic or polycyclic compound, e.g. a bicyclic compound, having the general formula 1 , a salt, a solvate, a stereoisomer or an enantiomer thereof. Such a pharmaceutical composition may be useful, among other medical uses, for inhibiting angiogenesis or for treating angiogenesis-related diseases in mammals, preferably in humans, or other animals, or for inhibiting feeding in animals. The present invention further relates to a method of inhibiting angiogenesis or treating angiogenesis-related diseases in mammals, preferably in humans, and other animals, said method comprising administering to the mammal, preferably human, or other animal in need thereof an angiogenesis-inhibiting effective amount of a monocyclic or polycyclic compound, e.g. a bicyclic compound, having the general formula 1 , a salt, a solvate, a stereoisomer or an enantiomer thereof. The present invention also relates to a method of inhibiting feeding in mammals, preferably in humans, and other animals, said method comprising administering to said mammal, preferably human, or other animal a feeding-inhibiting effective amount of a monocyclic or polycyclic compound, e.g. a bicyclic compound, having the general formula 1 , a salt, a solvate, a stereoisomer or an enantiomer thereof. It has now surprisingly been found that some monocyclic or polycyclic compounds, e.g. bicyclic compounds such as defined above, and in particular compounds having the general formula 1 have a potent angiogenesis-inhibiting effect, especially a more potent effect than simmondsin itself, DMS or DDMS. Endothelial cells, that form the walls of blood vessels, are the source of new blood vessels and have a great ability to divide and travel. The construction of a vascular network requires different sequential steps including the following: 1. the release of proteases from activated endothelial cells, 2. a degradation of the basement membrane surrounding the existing vessel, 3. a migration of the endothelial cells into the interstitial space, 4. endothelial cell proliferation, 5. tube formation and the subsequent lumen formation, 6. generation of new basement membrane with the recruitment of pericytes, 7. fusion of the newly formed vessels, and 8. initiation of blood flow. Surprisingly, some monocyclic or polycyclic compounds, e.g. bicyclic compounds, according to this invention show a significant activity on one or more of the above sequential steps involved in the angiogenesis pathway. Angiogenesis plays an important role in a number of diseases. For instance, angiogenesis is important in the development of many malignancies in colon, breasts, endometrium, ovary, cervix, prostate and other tissues. Since the present invention provides compounds useful for inhibiting angiogenesis, these compounds are also particularly suitable for treating diseases that result from uncontrolled angiogenesis activity. Angiogenesis is of particular interest in cancer. De novo capillary production is a crucial event in tumor growth and metastasis since the cells in solid tumors must receive the necessary oxygen and nutrients to survive and grow. In particular, it is known that tumors depending on angiogenesis represent a large number of the existing cancers. Inhibition of blood vessel development results in restricted energy supply to the tumor, thus causing an arrest in its development and hence, the start of its regression. In view of the effects of angiogenesis in cancer development, the present invention provides compounds having anti-angiogenesis activity which are useful in the treatment of cancers depending on angiogenesis. Unexpectedly some monocyclic or polycyclic compounds, e.g. bicyclic compounds, according to this invention also have anti-tumor activity. In addition, monocyclic or polycyclic compounds, e.g. bicyclic compounds according to this invention surprisingly show low levels of cytotoxity in vitro, meaning that they do not induce significant detrimental effect(s) on healthy cells, tissues or organs. Also, monocyclic or polycyclic compounds, e.g. bicyclic compounds, according to this invention surprisingly show no significant oestrogen-like activity, meaning that their administration does not imply a risk of boosting cancer tumors in women. Therefore monocyclic or polycyclic compounds, e.g. bicyclic compounds, according to this invention may be safely used for the manufacture of a medicament for treating cancer. Cancers which may be treated according to the present invention include, but are not limited to, solid tumors or metastasis, i.e. the form of cancer wherein the transformed or malignant cells are traveling and spreading cancer from one organ to another. The relevant cancer may relate to one of the following organs: heart, lung, intestine, genito-urinary tract, liver, bone, nervous system, blood, skin, breast, brain, and adrenal glands. More particularly, the bicyclic compounds according to this invention may be used for treating gliomas (e.g. Schwannoma, glioblastoma, astrocytoma), melanoma, neuroblastoma, pheochromocytoma, paraganlioma, meningioma, adrenalcortical carcinoma, kidney cancer, vascular cancer, osteoblastic osteocarcinoma, prostate cancer, ovarian cancer, uterine leiomyomas, salivary gland cancer, choroid plexus carcinoma, mammary cancer, pancreatic cancer, colon cancer, and megakaryoblastic leukemia. Recent studies also suggest angiogenesis-inhibiting compounds to be effective in the treatment of other diseases where uncontrolled blood vessel growth and synovial inflammation is involved, such as arthritis. Therefore, the monocyclic or polycyclic compounds, e.g. bicyclic compounds, of the present invention may be efficiently used for the manufacture of a medicament for treating arthritis as well as for the manufacture of a medicament for treating psoriaris. The term " psoriasis " is defined herein as being a chronic skin disease characterized by scaling and inflammation and including plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, erythroderma psoriasis and the like. Since angiogenesis-inhibition plays a role in placenta and embryonic development, the present monocyclic and polycyclic compounds can also be used, according to another embodiment of the invention, for contraceptive and abortive purposes. The pharmaceutical compositions of this invention usually contain from about 0.1 % to 50 % by weight, preferably from 1 % to 40 % by weight, more preferably from 5 % to 30 % by weight, of the active monocyclic or polycyclic compound, e.g. bicyclic compound. The pharmaceutical preparations can be prepared in a manner known per se to a person skilled in the art. For this purpose, at least one active monocyclic or polycyclic compound according to the invention is admixed with one or more pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutically active components. Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art. There is no particular restriction to their selection within the present invention although special attention should be paid to the selection of suitable carrier combinations that can assist in properly formulating them in view of the expected time release profile. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 μm, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active ingredient(s). Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphtalene- sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p- nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanyl-phosphatidylcholine, dipalmitoylphoshatidylcholine and their mixtures. Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino- polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/ polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants. Suitable cationic surfactants include quaternary ammonium salts, preferably halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8-C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals. A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbuch", 2nd ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants (Chemical Publishing Co., New York, 1981). Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions and combined preparations of the invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle). Gelling agents which may be included into the pharmaceutical compositions and combined preparations of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents. Other optional excipients which may be included in the pharmaceutical compositions and combined preparations of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densification agents such as magnesium salts; and mixtures thereof. Additional ingredients may be included in order to control the duration of action of the biologically-active ingredient in the compositions and combined preparations of the invention. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino-acids, polyvinyl-pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the other above- described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition or combined preparation of the invention may also require protective coatings. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof. In a preferred embodiment the administration route of a pharmaceutical composition according to this invention is an oral, a topical or a parenteral route. According to one embodiment the pharmaceutical composition according to the invention is formulated to be applied orally to humans and animals. The present pharmaceutical composition can for instance by applied orally for the treatment of tumors or other angiogenesis-related diseases such as above described. In yet another embodiment, the pharmaceutical composition according to the invention is formulated to be applied topically. The present pharmaceutical composition can for instance by applied topically for the treatment of tumors or other angiogenesis-related diseases, e.g. on the skin of humans and animals. Preferably, said pharmaceutical composition for topical administration includes the monocyclic or polycyclic compound, e.g. bicyclic compound, of this invention in a concentration ranging from about 0.1 to 10 % by weight, preferably from 0.5 to 5 % by weight. Active monocyclic or polycyclic compounds, e.g. bicyclic compounds, according to the invention can also be lyophilized, for example for the production of injection or infusion preparations. Suitable solvents for this purpose include, but are not limited to, water, a physiological saline solution or alcohols (e. g. ethanol, isopropanol or glycerol), saccharide solutions such as glucose or mannitol solutions, or mixtures thereof. Injectable solutions or suspensions may be formulated by using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, isotonic sodium chloride solution, and/or suitable dispersing or wetting and suspending agents, such as synthetic mono- or diglycerides and fatty acids (e.g. oleic acid). In another aspect, this invention relates to pharmaceutical compositions wherein the above described monocyclic or polycyclic compound, e.g. bicyclic compound, represented by the general formula 1 is combined with an effective amount of one or more anti-angiogenic agents. The latter may be selected selected from the group consisting of inhibitors of pro-angiogenic factor, endogenous inhibitors, molecular targeting inhibitors, COX inhibitors, matrix metalloproteinase inhibitors, integrin blockers, nitric oxide inhibitors, ACE inhibitors and HMG-CoA reductase inhibitors. More specific examples of such anti-angiogenic agents include, but are not limited to, MV303, F1t2-11 , Sflt-1 , DC101 , 2C3, EG3306, CBO-P11 , IL-12, TSP-1 , endostatin, angiostatin, PD166285, lanvendustin A, ZD1839, SU5418, ZD6474, SU6668, costunolide, gleevec, PD173074, indomethacin, SC236, humulone, TIMP-2, TIMP-3, marimastat, batimastat, PEX, BAY12-9566, ONO-4817, E7820, vitaxin, SCH221153, tumstatin, thiolutin, A-170634, 1-NIL, halofuginone, cerivastatin, EGCG, TNP-470 and thalidomide. The proportions of the above described monocyclic or polycyclic compound and of the one or more anti-angiogenic agents in such a combined preparation or pharmaceutical composition may be any proportion which brings a suitable therapeutic effect in the patient to be treated, especially in relation with the treatment or prevention of an angiogenesis-related disease. Preferably, said suitable therapeutic effect is a synergistic effect of the drug combination. As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as Cl) defined by the following equation:

wherein EDx is the dose of the first or respectively second drug used alone (1a, 2a), or in combination with the second or respectively first drug (1c, 2c), which is needed to produce a given effect. The said first and second drug have synergistic or additive or antagonistic effects depending upon Cl < 1 , Cl = 1 , or Cl > 1 , respectively. As is known to the skilled person, this principle may be applied to a number of desirable effects such as, but not limited to, an activity against angiogenesis. In view of affording a suitable therapeutic effect, such as a synergistic effect of the drug combination, in a patient (e.g. a human being) with an angiogenesis-reated disease, for instance the weight ratio of said one or more anti-angiogenic agents to said monocyclic or polycyclic compound in the pharmaceutical composition or combined preparation may be from about 1 :10 to about 10:1 , preferably from 1 :5 to 5:1, more preferably from 1 :3 to 3: 1 , most preferably from 1 :2 to 2: 1. In yet another aspect, this invention relates to method of treating or preventing an angiogenesis-reated disease in a patient, said method comprising administering to said patient an effective amount of a monocyclic or polycyclic compound represented by the general formula 1 such as extensively described hereinabove. The patient to be treated may be any mammal, but is preferably a human being. The angiogenesis- reated disease to be treated by this method may be selected from the group consisting of cell proliferative disorders, hemangiomas, atherosclerosis, arthritis, psoriasis, pre-eclampsia, intra-uterine growth retardation, endometriosis, liver fibrosis, kidney fibrosis, proliferative retinopathy, age-related maculopathy, diabetes mellitus related maculopathy, diabetic retinopathy, macular degeneration, neovascular glaucoma, retrolental fibroplasias and retinal vascularisation. Cell proliferative disorders to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include any kind of tumor progression or invasion or metastasis inhibition of a cancer, preferably one selected from the group consisting of lung cancer, leukaemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, colon cancer, Iymp node tumor, glioblastoma multiforme, prostate cancer or skin carcinose. Depending upon the specific disease to be treated or, for a certain disease, depending upon the specific condition of the patient to be treated, it may be useful that the monocyclic or polycyclic compound of this invention is co-administered with one or more anti-angiogenic agents such as, but not limited to, inhibitors of pro- angiogenic factor, endogenous inhibitors, molecular targeting inhibitors, COX inhibitors, matrix metalloproteinase inhibitors, integrin blockers, nitric oxide inhibitors, ACE inhibitors and HMG-CoA reductase inhibitors. Non-limiting examples of such anti-angiogenic agents include MV303, F1t2-11 , Sflt-1 , DC101 , 2C3, EG3306, CBO- P11 , IL-12, TSP-1 , endostatin, angiostatin, PD166285, lanvendustin A, ZD1839, SU5418, ZD6474, SU6668, costunolide, gleevec, PD173074, indomethacin, SC236, humulone, TIMP-2, TIMP-3, marimastat, batimastat, PEX, BAY12-9566, ONO-4817, E7820, vitaxin, SCH221153, tumstatin, thiolutin, A-170634, 1-NIL, halofuginone, cerivastatin, EGCG, TNP-470 and thalidomide. The dose of active components, i.e. the dose of the monocyclic or polycyclic compound according to the invention and the dose of the optional anti-angiogenic agent, to be administered depends on the individual case and upon the frequency of administration, but also on the nature and severity of the disease and symptoms, as well as the age, weight and individual responsiveness of the patient. The present invention will now be described with reference to examples that are by no means limiting the protection of the invention and are given only with the purpose of enabling one skilled in the art. The following examples provide non-limiting methods and assays for evidencing the angiogenesis-inhibiting activity of monocyclic and polycyclic compounds, in particular bicyclic compounds, according to the invention, as well as the presence or absence of other undesired biological properties such as, but not limited to, oestrogen-like activity.

Example 1 - chorion allantois membrane (CAM) assay The following CAM assay is based on the teaching of Nguyen et al. in Microvasc. Res. (1994) 47 (1):31-40. Fertilized chicken eggs are incubated during 4 days at 37 0C. Subsequently, the egg shell is opened to disclose the CAM. In order to reduce the pressure on the CAM for improving its manipulating properties, 2 to 3 ml albumen is removed. The opening is closed using cellophane tape and the eggs are further incubated until day 9 for application of the test compounds using different concentrations. Dulbecco's modified Eagle medium (DMEM) is used as a negative control, whereas Vascular Endothelial Growth Factor (hereinafter referred as VEGF) is used as a positive control (i.e. a stimulator of angiogenesis). A compound of the invention and tangeritin, a commercially known angiogenesis inhibitor, are compared in their angiogenesis-inhibiting activity towards VEGF stimulated angiogenesis in this assay. Each of the solubilized test compositions is pipetted on a sterile plastic disc (10 mm diameter) and dried under sterile conditions. Each disc is treated with cortisone acetate (2 μg/μl in a suitable buffer) in order to avoid inflammatory reactions. After drying, the discs are placed on the CAM membrane with the drug loaded side facing the membrane. The control disc (DMEM) is placed at 10 mm distance from the disc containing the test compound. The opening is sealed with cellophane tape and the eggs are further incubated. At day 11 , the tape and discs are removed and 10% buffered formaline is sprayed over the membrane. Eggs are allowed to dry for 4 hours at room temperature. Then, the CAM membrane is cut out of the egg and mounted on a glass slide. The vascular density index is then measured according to the method disclosed by Harris-Hooker et al. in J. Cell. Physio. (1983) 114: 302-310), while counting all micro vessels that cross 3 concentric circles with a diameter of 6 ,8 and 10 mm. An angiogenetic index (Al) is expressed as { (t/c) x100 } -100, wherein t is the total number of crossing vessels where the disc containing the test compound is located and c is the total number of crossing vessels where the control disc is located. The test compound may be classified positively when Al exceeds 10 and negatively when Al is below 10.

Example 2 - assays based on human vascular endothelial cells (HUVEC) The following illustrates a series of assays based on HUVEC for determining the angiogenesis-inhibiting effects of the compounds of the invention. Human Vascular Endothelial Cells (HUVEC) are obtained as described by Jaffe et al. in J. CHn. Invest. (1973) 52:2745-2746 and cultured to confluence on fibronectin-coated dishes in M199 medium supplemented with 20 mM HEPES (pH 7.3), 10 % human serum, 10 % heat-inactivated new born calf serum (NBCS), 150 μg/ml crude endothelial cell growth factor (ECGF), 2 mM L-glutamine, 5 U/ml heparin, 100 U/ml penicillin and 100 μg/ml streptomycin at 37 0C under a 5% CO2 / 95% air atmosphere. The confluent HUVEC cultures (passage 0) are detached by means of trypsin / EDTA treatment, pooled and cultured after a split ratio of 1 :3 till confluence (passage 1). Then the pooled HUVEC are frozen in 10 cm3 aliquots in vials in liquid nitrogen. One week before proliferation, vials of HUVEC (passage 1) are thawed and cultured (after a split ratio of 1 : 3) to confluence (passage 2).

Experiment A: cell proliferation measured by 3H-thymidine incorporation Confluent cultures of HUVEC (passage 2) are detached by means of a trypsin / EDTA solution, and allowed to adhere and spread at an appropriate cell density on gelatin-coated dishes in a M199-HEPES medium supplemented with 10 % heat- inactivated NBCS, 100 U/ml penicillin and 100 μg/ml streptomycin. After 18 hours, HUVEC are stimulated with 6.25 ng/ml vascular endothelial growth factor type A (VEGF-A) in M199-HEPES, 100 IU/ml penicillin, 100 pg/ml streptomycin and 10 % NBCS in duplicate wells, with or without the test compound of the invention. After an incubation period of 48 hours, a tracer amount (0.5 μCi/well) of [3H]-thymidine is added and cells are incubated for another 6 hours. Subsequently, the cells are washed with PBS, [3H]-labelled DNA is fixed with methanol, precipitated in 5 % trichloroacetic acid, and finally dissolved in 0.5 ml 0.3 M NaOH and counted in a liquid scintillation counter. The level of [3H]-thymidine incorporation provides a quantitative indication of the inhibition of VEGF-a-induced HUVEC proliferation by monocyclic and polycyclic compounds of this invention.

Experiment B: cell proliferation measured by cell counting A confluent monolayer of HUVEC is detached by means of a trypsin / EDTA solution, and allowed to adhere and spread at cell density of 15% confluency in gelatine-coated flasks in M199-HEPES medium supplemented with 10% heat- inactivated NBCS and 100 IU/ml penicillin and 100 pg/ml streptomycin. After 18 hours the HUVEC are stimulated with 2.5 ng/ml basic fibroblast growth factor (FGF) in M199 medium-HEPES supplemented with penicillin/streptomycin, 10 % NBCS and 0.1% DMSO in triplicate wells for 6 days. The cell number is determined by image analysis. This experiment provides evidence for the anti-angiogenic effect of monocyclic and polycyclic compounds of this invention.

Experiment C: in vitro angiogenesis assay, tube formation in 3-D fibrin matrices Human fibrin matrices are prepared by adding 0.1 U/ml thrombin to a commercial (Chromogenix AB, Sweden) mixture of 2 mg/ml fibrinogen (final concentrations), 2 mg/ml Na-citrate, 0.8 mg/ml NaCI, 3 μg/ml plasminogen in M199 medium and 2.5 U/ml factorXIII. 100 pi aliquots of this mixture are added to the wells of 96-well plates. After clotting at room temperature, the fibrin matrices are soaked with M199 supplemented with 10 % human serum and 10 % NBCS for 2 hours at 37 °C in order to inactivate thrombin. Frozen human microvascular endothelial cells (hMVEC, 0.7 x105 cells/cm2) are thawed and seeded in a 1.8:1 split ratio on the fibrin matrices and cultured for 24 hours in M199 medium supplemented with 10 % human serum, 10% NBCS, and 100 IU/ml penicillin and 100 μg/ml streptomycin. Then, hMVEC are stimulated with a compound of the invention for 7 days. Fresh medium, containing said compound, are added every second day. Invading cells and the formation of tubular structures of hMVEC in the three-dimensional fibrin matrix are then analyzed by phase contrast microscopy. The total length of tube-like structures of four microscopic fields (7.3 minefield) are measured using an Olympus CK2 microscope equipped with a monochrome CCD camera (MX5) connected to a computer with Optimas image analysis software, and expressed as mm/cm2 according to the teaching of Koolwijk et al. in J. Cell Biol. (1996) 132:1177-1188.

Experiment D - ex vivo angiogenesis assay Such an assay may be performed as described by Deckers et al. in Lab. Invest. (2001) 81 :5-15. 17 days-old fetus are removed from pregnant Swiss albino mice and metatarsals are dissected. The isolated metatarsals are cultured in 24-well plates in 150 μl minimal essential medium (aMEM) supplemented with 10 % by volume heat-inactivated fetal bovine serum, 100 IU/ml penicillin and 100 μg/ml streptomycin for 72 hours. After this adhesion phase, metatarsals are attached to the culture plastic and medium is replaced by 250 μl fresh medium + 10 ng/ml recombinant human VEGF-A in the presence or absence of a compound of the invention. Metatarsals are cultured for 14 days, the medium being replaced every 7 days. At the end of the culture period, cultures were fixed in ZnMF fixative for 15 minutes at room temperature and subsequently stained for PECAM-1. Analysis allows the determination of the effect of monocyclic and polycyclic compounds of this invention on VEGF-induced ex vivo tube formation from fetal mouse metacarpals.

Experiment E : In vivo matriqel chamber assay This assay may be performed as described by Kragh et al. in Int. J. Oncol. (2003) 22:305-311. Plexiglas ring/nylon net filter-chambers (0.2 ml) containing growth factor-reduced Matrigel and 200 ng basic fibroblast growth factor (βFGF) are subcutaneously implanted into the flanks of 3-months old FVB/N mice. Mice are administered a compound of the invention. Chamber angiogenesis is scored superficially on day 14 post-implantation. The above-listed experiments demonstrate that monocyclic and polycyclic compounds of this invention are able to inhibit at least one of: (i) VEGF- or βFGF- induced human endothelial cells proliferation, (ii) VEGF-induced in vitro tube formation by human microvascular endothelial cells in 3-dimensional fibrin matrices, (iii) ex vivo outgrowth of tube-like structures of endothelial cells from fetal mouse metacarpals, and (iv) in vivo neovascularization of matrigel chambers in mice.

Example 3 - oestroqenic bioassay Yeast cells (Saccharomyces cerevisiae) containing a human oestrogen receptor (100 μl) is added to 25 ml of a growth medium comprising: - D-glucose (2.5 ml from a 0.25 g/ml aqueous solution of D-glucose); - L-aspartic acid (0.625 ml from a 4 g/l aqueous solution); - vitamin solution (0.250 ml from a mixture comprising 8 mg thiamine, 8 mg pyridoxine, 8 mg panthotenic acid, 40 mg inositol and 20 ml biotin solution (2 mg/100 ml in water) in 180 ml water); L-threonine (0.2 ml from a 2.4 g/100 ml aqueous solution); - Copper (II) sulfate (0.0625 ml from a 3.2 g in/I aqueous solution); and - minimal medium (22.5 ml from 11 water including 13.61 g potassium dihydrogenophosphate, 1.98 g ammonium sulfate, 4.2 g potassium hydroxide, 1 ml of a 0.8 g/l aqueous solution of iron (III) sulfate, 50 mg L- leucine, 50 mg L-histidine, 50 mg adenine, 20 mg L-arginine hydrochloride, 20 mg L-methio-nine, 30 mg L-tyrosine, 30 mg L-isoleucine, 30 mg L-lysine hydrochloride, 25 mg L-phenylalanine, 100 mg L-glutamic acid, 150 mg L-valine, 375 mg L-serine and 0.25 ml chlorophenol red beta-D- galactopyranoside). 17 beta-oestradiol (20 μl aliquots from 0.008 nM to 100 nM, prepared from 10 mg in 10ml ethanol) and a test compound of the invention, in concentrations of 1 , 10, 100 and 1000 μM respectively, are pipetted into 96-well plates in a sterile flow hood. The solvent is left to evaporate for about 40 minutes. The growth medium containing yeast is then s dispensed to all wells, except blank wells, in aliquots of 100 μl. The plates are incubated at 32 0C in a humidified atmosphere for 3 days, and then read at 540 / 360 nm by a microtiter plate reader. This experiment makes it possible to determine the presence or absence of oestrogen-like activity in the monocyclic and polycyclic compounds of this invention.

Example 4 - anti-anqiogenic activity in zebrafish Angiogenesis in zebrafish can be evaluated using the micro-agniography method of Weinstein et al. in Nat Med. (1995) 11 :1143-7. The detection of blood vessels is facilitated by the previous injection of fluorescent beads into the body of the fish, allowing the detection of vessel formation using standard fluorescence microscope techniques. An alternative method is described by Cross et al. in Arterioscler. Thromb. Vase. Biol. (2003) 23:911-2: transgenic zebrafish expressing a fusion protein of a VEGF receptor and GFP are used to detect blood vessel formation via fluorescent detection. Both detection methods may be carried out after providing the zebrafish with food comprising a predetermined amount of the compound to be tested for anti- angiogenic activity.