Synthetic analogues of xanthohumol

Abstract

The present invention relates to novel synthetic analogs of xanthohumol and the use thereof.

Claims

1. Compounds of general formula (i): ##STR00043## wherein: R.sub.1 and R.sub.2 are independently selected from the group consisting of H; methyl; straight or branched alkyl from 2 to 10 carbon atoms; straight or branched alkyl from 2 to 10 carbon atoms containing 1 or 2 insaturations; cycloalkyl from 4 to 6 carbon atoms; cycloalkyl from 4 to 6 carbon atoms containing 1 or 2 insaturations; alkoxyalkyl selected from the group consisting of CH.sub.3OCH.sub.2, CH.sub.3OCH.sub.2CH.sub.2 or CH.sub.3(OCH.sub.2CH.sub.2).sub.n, CH.sub.3(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCO(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2(NHCH.sub.2CH.sub.2).sub.n, HN(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCON(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, O(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n; benzyl; benzyl optionally substituted in any of the free positions of the ring by 1 to 5 halogen atoms independently selected from the group consisting of F, Cl, Br, I; benzyl substituted with NH.sub.2, NHCH.sub.3, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NHCH.sub.3, SO.sub.2NHCO-alkyl, NO.sub.2, OCH.sub.3, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2alkyl, alkyl being as defined above; n is an integer ranging from 1 to 5; A is a monocyclic or bicyclic aryl, or an aromatic or non-aromatic heterocyclic ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, 1H-indazole, wherein the substituents on ring A, independently from each other, are selected from the group consisting of H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH-alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above for R.sub.1 and R.sub.2; wherein at least one of the substituents on the A ring is H; provided that the compound of general formula (i) is not: (E)-3-phenyl-1-(2,4,6-trimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; or (E)-3-phenyl-1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; tautomers, pharmaceutically acceptable salts and pro-drugs thereof.

2. Compounds according to claim 1, wherein said aromatic or non-aromatic heterocyclic ring is benzofused and/or further substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, acylamido, sulphonamido, acyl, sulphonyl, aryl or heteroaryl.

3. Compounds according to claim 1, wherein when R.sub.1 is H or R.sub.2 is H, the isoprenyl group of general formula (i) forms a cycle with one of the oxygen atoms adjacent to it to give compounds of general formula (ii) or (iii) ##STR00044## wherein R.sub.1, R.sub.2 are independently selected from the group consisting of H; methyl; straight or branched alkyl from 2 to 10 carbon atoms; straight or branched alkyl from 2 to 10 carbon atoms containing 1 or 2 insaturations; cycloalkyl from 4 to 6 carbon atoms; cycloalkyl from 4 to 6 carbon atoms containing 1 or 2 insaturations; alkoxyalkyl selected from the group consisting of CH.sub.3OCH.sub.2, CH.sub.3OCH.sub.2CH.sub.2 or CH.sub.3(OCH.sub.2CH.sub.2).sub.n, CH.sub.3(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCO(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2(NHCH.sub.2CH.sub.2).sub.n, HN(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCON(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, O(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n; benzyl; benzyl optionally substituted in any of the free positions of the ring by 1 to 5 halogen atoms independently selected from the group consisting of F, Cl, Br, I; benzyl substituted with NH.sub.2, NHCH.sub.3, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NHCH.sub.3, SO.sub.2NHCO-alkyl, NO.sub.2, OCH.sub.3, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above and A is a monocyclic or bicyclic aryl, or an aromatic or non-aromatic heterocyclic ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, 1H-indazole, wherein the substituents on ring A, independently from each other, are selected from the group consisting of H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH-alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above for R.sub.1 and R.sub.2; wherein at least one of the substituents on the A ring is H.

4. Compounds according to claim 1 of general formula (iv): ##STR00045## wherein R.sub.1, R.sub.2 are independently selected from the group consisting of H; methyl; straight or branched alkyl from 2 to 10 carbon atoms; straight or branched alkyl from 2 to 10 carbon atoms containing 1 or 2 insaturations; cycloalkyl from 4 to 6 carbon atoms; cycloalkyl from 4 to 6 carbon atoms containing 1 or 2 insaturations; alkoxyalkyl selected from the group consisting of CH.sub.3OCH.sub.2, CH.sub.3OCH.sub.2CH.sub.2 or CH.sub.3(OCH.sub.2CH.sub.2).sub.n, CH.sub.3(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCO(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2(NHCH.sub.2CH.sub.2).sub.n, HN(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCON(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, O(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n; benzyl; benzyl optionally substituted in any of the free positions of the ring by 1 to 5 halogen atoms independently selected from the group consisting of F, Cl, Br, I; benzyl substituted with NH.sub.2, NHCH.sub.3, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NHCH.sub.3, SO.sub.2NHCO-alkyl, NO.sub.2, OCH.sub.3, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above and A is a monocyclic or bicyclic aryl, or an aromatic or non-aromatic heterocyclic ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, 1H-indazole and R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7, independently from each other, are selected from the group consisting of H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH-alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined for R.sub.1, R.sub.2 as above, wherein at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H; provided that when R.sub.1 is methyl, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are H, and R.sub.2 is not H or methyl.

5. Compounds according to claim 3, wherein when R.sub.1 is H or R.sub.2 is H, the isoprenyl group of general formula (iv) forms a cycle with one of the oxygen atoms adjacent to it to give compounds of general formula (v) or (vi): ##STR00046## wherein R.sub.1, R.sub.2, are independently selected from the group consisting of H; methyl; straight or branched alkyl from 2 to 10 carbon atoms; straight or branched alkyl from 2 to 10 carbon atoms containing 1 or 2 insaturations; cycloalkyl from 4 to 6 carbon atoms; cycloalkyl from 4 to 6 carbon atoms containing 1 or 2 insaturations; alkoxyalkyl selected from the group consisting of CH.sub.3OCH.sub.2, CH.sub.3OCH.sub.2CH.sub.2 or CH.sub.3(OCH.sub.2CH.sub.2).sub.n, CH.sub.3(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCO(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2(NHCH.sub.2CH.sub.2).sub.n, HN(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCON(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2N(CH.sub.2CH.sub.2).sub.2N(CH2CH.sub.2n, O(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n; benzyl; benzyl optionally substituted in any of the free positions of the ring by 1 to 5 halogen atoms independently selected from the group consisting of F, Cl, Br, I; benzyl substituted with NH.sub.2, NHCH.sub.3, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NHCH.sub.3, SO.sub.2NHCO-alkyl, NO.sub.2, OCH.sub.3, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above and A is a monocyclic or bicyclic aryl, or an aromatic or non-aromatic heterocyclic ring selected from the group consisting of pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine, 1H-indazole and R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7, independently from each other, are selected from the group consisting of H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH3, CONHSO.sub.2-alkyl, alkyl being as defined for R.sub.1, R.sub.2 above, wherein at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H.

6. Compounds according to claim 1, wherein A is a 2-, 3- or 4-pyridyl ring.

7. Compounds according to claim 1, wherein R.sub.1 and R.sub.2 are, independently from each other, hydrogen or methoxymethyl and the substituents on ring A or R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are independently H, OCH.sub.3 fluorine, chlorine, NO.sub.2, CONHCH.sub.3, SO.sub.2NH.sub.2, NHSO.sub.2CH.sub.3, or the SO.sub.2NHCOCH(Et)NHCOOCH.sub.2Ph group, wherein at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H.

8. Compound according to claim 1, selected from: (E)-3-(3,4-dichloro-phenyl)-1-(6-methoxy-2,4-bis(methoxymethyloxy)-3-(3-methyl-but-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(3,4-dichloro-phenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(3,4-dichloro-phenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(3,4-diclorophenyl)-1-(5-hydroxy-7-methoxy-2,2-dimethylchroman-6-yl)prop-2-en-1-one; (E)-3-(4-fluorophenyl)-1-[6-methoxy-2,4-di-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)prenyl]-3-(4-fluorophenyl)-prop-2-en-1-one; (E)-3-(4-fluorophenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl]-phenyl)prop-2-en-1-one; (E)-1-[6-methoxy-2,4-dimethoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-1[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-N-(4-{3-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-(oxoprop-1-enyl}phenyl)-acetamide; (E)-N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}phenyl)acetamide; (E)-N-(4-{3-[2,4-dihydroxy-6-methyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}-phenyl)acetamide; (E)-3-(3,4-difluoro-phenyl)-1-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-prop-2-en-1-one; (E)-3-(3,4-difluorophenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]prop-2-en-1-one; (E)-3-(3,4-difluorophenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[4-hydroxy-6-methoxy-2-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone; 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone; 3-(5-chloro-pyridin-3-yl)-1-[2-hydroxy-6-methoxy-4-methoxymethloxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone; 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; N-(4-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; 2-Chloro-5-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-Chloro-5-{3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-[3-(5-hydroxy-7-methoxy-2,2-dimethyl-chroman-6-yl)-3-oxo-propenyl]-benzenesulphonamide.

9. Compound as claimed claim 1, selected from: (E)-3-(2-fluorophenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(2-fluorophenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-bis (methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-bis (methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-4-hydroxy-2-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(4-nitrophenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one.

10. Method of treating tumours in subjects in need thereof, said methods comprising; administering an effective amount of compounds according to claim 1 to said subjects; and treating said tumours.

11. Methods of treating inflammatory, cardiovascular and neurodegenerative disorders in subjects in need thereof, said methods comprising; administering an effective amount of compounds according to claim 1 to said subjects; and treating said subjects.

12. Methods of treating disorders characterized by alteration of angiogenesis in patients in need thereof, said method comprising; administering an effective amount of compounds as claimed in claim 1 to said subjects; and treating said subjects.

13. Pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient.

Description

LIST OF FIGURES

(1) FIG. 1 shows the viability of HUVEC, cells evaluated with the MIT colorimetric assay.

(2) FIG. 2 shows the results of the chemotaxis assay conducted on HUVEC cells using Boyden chambers.

(3) FIG. 3 shows the results of the chemoinvasion assay conducted on HUVEC cells using Boyden chambers.

(4) FIG. 4 shows the tendency of HUVEC cells to organise themselves into capillary-like structures.

(5) FIG. 5 shows the results of the apoptosis assay conducted on HUVEC cells.

(6) FIG. 6 shows the results of the invasion assay conducted on HUVEC cells.

(7) FIG. 7 shows the results of the migration assay conducted on HUVEC cells.

(8) FIG. 8 contains tables summarising the results of the MTT assays.

(9) FIG. 9 shows reduction of NO release (a) and NF-kB action (b) by XN.

DETAILED DESCRIPTION OF THE INVENTION

(10) The present invention relates to a compound of general formula (i):

(11) ##STR00005##

(12) wherein:

(13) R.sub.1 and R.sub.2 can be, independently of one another, selected from the group comprising H; methyl; straight or branched alkyl with 2 to 10 carbon atoms; straight or branched alkyl with 2 to 10 carbon atoms containing 1 or 2 unsaturations; cycloalkyl with 4 to 6 carbon atoms; cycloalkyl with 4 to 6 carbon atoms containing 1 or 2 unsaturations; alkoxyalkyl, which can be selected from the group comprising CH.sub.3OCH.sub.2, CH.sub.3OCH.sub.2CH.sub.2 or CH.sub.3(OCH.sub.2CH.sub.2).sub.n, CH.sub.3(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCO(NHCH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2(NHCH.sub.2CH.sub.2).sub.n, HN(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nCON(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, CH.sub.3(CH.sub.2).sub.nSO.sub.2N(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n, O(CH.sub.2CH.sub.2).sub.2N(CH.sub.2CH.sub.2).sub.n; benzyl; benzyl optionally substituted in any of the substitutable positions by 1 to 5 halogen atoms independently selected from the group comprising F, Cl, Br and I; benzyl substituted by NH.sub.2, NHCH.sub.3, NHCOCH.sub.3, NHCO alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NHCH.sub.3, SO.sub.2NHCO-alkyl, NO.sub.2, OCH.sub.3, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3, CONHSO.sub.2-alkyl, alkyl being as defined above;

(14) n is an integer between 1 and 5;

(15) A can be a monocyclic or bicyclic aryl or a heterocyclic, aromatic or non-aromatic, monocyclic or bicyclic ring, selected from the group comprising pyrrole, pyrrolidine, 3-pyrroline, 2H-pyrrole, 2-pyrroline, indole, isoindole, 3H-indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-pyran, 4H-pyran, benzo[b]thiophene, thiophene, pyridine, piperidine, 4H-quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,8-naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-imidazole, imidazolidine, tetrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, benzoimidazole, purine, 1,4-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,2,4-triazine, 1,3,5-triazine, pyridazine, piperazine, quinoxaline, phenazine and 1H-indazole,

(16) wherein said aromatic or non-aromatic heterocyclic ring can be benzocondensed and/or further substituted with halogen, alkyl, alkenyl, alkinyl, alkoxy, amino, amido, acylamido, sulphonamido, acyl, sulphonyl, aryl or heteroaryl;

(17) wherein the substituents on the A ring are independently selected from the group comprising H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH-alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3 and CONHSO.sub.2-alkyl, alkyl being as defined above for R.sub.1, R.sub.2, wherein at least one of the substituents on the A ring is H;

(18) provided that the compound of general formula (i) is not: (E)-3-phenyl-1-(2,4,6-trimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; or (E)-3-phenyl-1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one.

(19) When R.sub.1 is H or R.sub.2 is H, the isoprenyl group of general formula (i) can optionally cyclise to form a benzocondensed system of 2,2-dimethylchroman, giving a compound of general formula (ii) or (iii):

(20) ##STR00006##

(21) wherein R.sub.1, R.sub.2 and A are as defined above for formula (i).

(22) In a preferred embodiment, the invention relates to compounds of general formula (iv):

(23) ##STR00007##

(24) wherein R.sub.1, R.sub.2 are as defined above for formula (i) and R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are selected independently from the group comprising H, O-alkyl, OCH.sub.3, Cl, F, Br, I, NO.sub.2, NH.sub.2, NHCH.sub.3, NH-alkyl, NHCOCH.sub.3, NHCO-alkyl, NHSO.sub.2CH.sub.3, NHSO.sub.2-alkyl, SO.sub.2CH.sub.3, SO.sub.2-alkyl, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NH-alkyl, SO.sub.2NHCOCH.sub.3, SO.sub.2NHCO-alkyl, CO.sub.2H, CONHCH.sub.3, CONH-alkyl, CO.sub.2CH.sub.3, CO.sub.2-alkyl, CONHSO.sub.2CH.sub.3 and CONHSO.sub.2-alkyl, alkyl being as defined above for R.sub.1, R.sub.2; wherein at least one of the substituents on the A ring R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H;

(25) provided that when R.sub.1 is methyl, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are H, and R.sub.2 is not H or methyl.

(26) When R.sub.1 is H or R.sub.2 is H, the isoprenyl, group of general formula (iv) can optionally cyclise to form a benzocondensed system of 2,2-dimethylchroman, giving a compound of general formula (v) or (vi):

(27) ##STR00008##

(28) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined above for formula (iv).

(29) In a preferred embodiment of the invention A is a phenyl ring, as in the compounds of general formula (iv), (v) and (vi).

(30) In another preferred embodiment of the invention A is a 2-, 3- or 4-pyridyl ring.

(31) R.sub.1 and R.sub.2 are preferably, independently of one another, hydrogen or methoxymethyl.

(32) According to a preferred aspect of the invention, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are, independently of one another, H, OCH.sub.3, F, Cl, NO.sub.2, CONHCH.sub.3, SO.sub.2NH.sub.2, NHSO.sub.2CH.sub.3, or the SO.sub.2NHCOCH(Et)NHCOOCH.sub.2Ph group; wherein at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H.

(33) According to a further preferred aspect of the invention, A is phenyl or 2-, 3- or 4-pyridyl; R.sub.1 and R.sub.2 are, independently of one another, hydrogen or methoxymethyl, and R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are, independently of one another, H, OCH.sub.3, F, Cl, NO.sub.2, CONHCH.sub.3, SO.sub.2NH.sub.2, NHSO.sub.2CH.sub.3, or the SO.sub.2NHCOCH(Et)NHCOOCH.sub.2Ph group; wherein at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is H.

(34) The preferred compounds according to the invention are: (E)-3-(3,4-dichloro-phenyl)-1-(6-methoxy-2,4-bis(methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one; (E)-3-(3,4-dichloro-phenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(3,4-dichloro-phenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(3,4-dichlorophenyl)-1-(5-hydroxy-7-methoxy-2,2-dimethylchroman-6-yl)prop-2-en-1-one; (E)-3-(4-fluorophenyl)-1-[6-methoxy-2,4-di-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)prenyl]-3-(4-fluorophenyl)-prop-2-en-1-one; (E)-3-(4-fluorophenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl]-phenyl)prop-2-en-1-one; (E)-1-[6-methoxy-2,4-dimethoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one; (E)-N-(4-{3-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-(oxoprop-1-enyl}phenyl)-acetamide; (E)-N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}phenyl)acetamide; (E)-N-(4-{3-[2,4-dihydroxy-6-methyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}-phenyl)acetamide; (E)-3-(3,4-difluoro-phenyl)-1-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl-prop-2-en-1-one; (E)-3-(3,4-difluorophenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]prop-2-en-1-one; (E)-3-(3,4-difluorophenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[4-hydroxy-6-methoxy-2-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; (E)-3-(2,4-difluoro-phenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one; 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone; 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone; 3-(5-chloro-pyridin-3-yl)-1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 3-(5-chloro-pyridin-3-yl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone hydrochloride; 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone; 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone hydrochloride; N-(4-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; N-(4-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide; 2-chloro-5-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-{3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide; 2-chloro-5-[3-(5-hydroxy-7-methoxy-2,2-dimethyl-chroman-6-yl)-3-oxo-propenyl]-benzenesulphonamide; [1-(2-chloro-5-{3-[6-methoxy-2,4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonylaminocarbonyl)-propyl]-benzyl-carbamate; [1-(2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonylaminocarbonyl)-propyl]-benzyl-carbamate.

(35) Further preferred compounds according to the invention are: (E)-3-(2-fluorophenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one, [compound (58)]; (E)-3-(2-fluorophenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one, [compound (59)]; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-bis(methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (60)]; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (61)]; (E)-3-(3-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (62)]; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-bis(methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (63)]; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (64)]; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-4-hydroxy-2-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (65)]; (E)-3-(2-fluoro-4-methoxyphenyl)-1-(6-methoxy-2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (66)]; (E)-3-(4-nitrophenyl)-1-(6-methoxy-2-hydroxy-4-methoxymethoxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (67)].

(36) Further subjects of the present invention are tautomeric mixtures of the compounds of formula (i).

(37) The present invention also relates to the pharmaceutically acceptable salts and prodrugs of the compounds of general formula (i).

(38) Pharmaceutically acceptable salts comprise salts with alkaline metals and salts with free bases or acids. In general, said salts can be prepared by conventional methods. The pharmaceutically acceptable acids and bases used to form the salts according to the present invention can be inorganic or organic. The salts, preferably metal salts, can be formed with alkaline or alkaline earth metals or other salts with physiologically acceptable metals. The salts can be also formed with aluminium, calcium, lithium, magnesium, potassium, sodium and zinc. The preferred organic salts can be prepared from tertiary amines and quaternary ammonium salts.

(39) The compounds according to the invention can also be used in the form of prodrugs, such as those obtained by reacting the compounds according to the invention containing NH.sub.2 or COOH groups with alpha-amino acids or derivatives thereof protected at the amino or carboxyl group. The alpha-amino acids can be either natural or non-natural. An alpha-amino acid which can be used for the purposes of the present invention is N-benzyloxycarbonyl-2-aminobutyric acid.

(40) The compounds according to the invention can be obtained by following the synthesis schemes described below.

(41) The synthesis scheme illustrates a method of preparing compounds of general formula (i). The key points of the syntheses are a Mitsunobu reaction (b), a Claisen-Schmidt condensation (c) and the removal of the methoxymethyl (MOM) protecting group (g) when R.sub.1 and/or R.sub.2 is hydrogen. The first step (a) involves partial functionalisation of 2,4,6-trihydroxyacetophenone, I (commercial product) with suitable halides R.sub.1X and R.sub.2X (wherein X can be chloro or bromo or iodo), alkyl sulphates (R.sub.1).sub.2SO.sub.4 and (R.sub.2).sub.2SO.sub.4, t-BuMe.sub.2SiCl (from which the corresponding ether t-BuMe.sub.2 can easily be converted to alkyl ether wherein R.sub.1 or R.sub.2 is Me or Bn), diazomethane or diazoalkyls, under suitable basic conditions, using alkaline or neutral carbonates or hydroxides as bases (see, for example, protection of phenols in Wuts P. G. M. and Greene T., Greene's Protective Groups in organic synthesis, 5th edition, John Wiley & Sons 2007). Depending on the synthesis route, said group must be stable under basic conditions and easily removed under mild acidity conditions, or stable under acid conditions and easily removed under mild alkalinity conditions, or stable under both acid and basic conditions but removable by catalytic hydrogenation. These delicate deprotection conditions avoid spontaneous intramolecular cyclisations which give undesirable flavone structures.

(42) Step (b) (Mitsunobu reaction) allows the introduction of the prenyl group onto intermediate 2, giving prenyl ether 3 with acceptable yields. In this reaction, phenol 2, solubilised in anhydrous THF or in a suitable anhydrous solvent, is reacted with the alcohol 3-methyl-2-buten-1-ol, diethylazadicarboxylate (DEAD) and triphenylphosphine (TPP). In some cases the yields of this step may be low, in which case the reaction is conducted with phenol 2 in anhydrous toluene, using DEAD as dehydrating agent and adding triphenylphosphine and 3-methyl-2-buten-1-ol in small portions. Under these new conditions, although the reaction times remain unchanged (about 20-24 h), the yield can be much better (up to 90-95%). Typically, the reaction can also be conducted with other solvents such as dichloromethane, acetonitrile, N-methylpyrrolidinone, benzene, m-xylene and mixtures thereof. The above reaction can also use other suitable condensing agents supported on polymer resins. Diisopropylazadicarboxylate (DIAD), 1,1-azodicarbonyldipiperidine (ADDP), N,N,N,N-tetramethylazodicarboxamide (TMAD), tributylphosphine (PBu.sub.3) and the like can also be used as condensing agents as well as DEAD and TPP.

(43) The third step (c) involves a Claisen rearrangement to obtain the intermediate chalcone 4. Precursor 3, solubilised in N,N-dimethylaniline, is maintained for a time of between 1 and 48 hours, preferably 4 hours, at a temperature ranging between 60 and 240 C., preferably 200 C., under stirring, to obtain the product of transposition onto the para position of aromatic ring 4 with a 44% yield when R.sub.1=R.sub.2=methoxymethyl.

(44) The fourth step (d) consists of methylation of the hydroxyl in the ortho position (position 6) using dimethylsulphate in the presence of potassium carbonate, to give derivative 5 with yields ranging between 45 and 70%.

(45) Step (f) involves aldol condensation, which leads to the protected chalcone (E)-6 (50-62%).

(46) From this, via a synthesis step of hydrolysis or controlled deprotection, such as conditions (g) if R.sub.1 and/or R.sub.2 is methoxymethyl, the compounds of general formula (i) are obtained as monodeprotected derivatives type 7a and 7b, and type 8 totally deprotected on the phenol groups in the 2 and 4 position on the phenyl substituted with the isoprenyl group. The controlled conditions allow the removal of group R.sub.1 or R.sub.2 or both, avoiding cyclisation to isoxanthohumols.

(47) ##STR00009##

(48) The compounds of formula (i), wherein A is a monocyclic aryl substituted in the 4 position by a methoxyl group and in the 2 or 3 position by a fluorine atom can also be obtained by reacting the compounds of formula (i), wherein A is a monocyclic difluoro aryl substituted in the 3,4 or 2,4 positions with sodium methylate or potassium methylate, under the classic conditions used for aromatic nucleophilic substitution reactions.

(49) Derivatives of type (ii) and (iii) can be obtained from the compounds of type (i), 7a or (i), 7b under appropriate acid conditions (pH=1 in appropriate water-alcohol solvent mixtures) and temperature conditions, as reported in synthesis scheme 2. Under certain conditions the cyclisation reaction is possible or facilitated by using microwaves in an appropriate solvent or solvent mixture. Under certain conditions, mixtures of type (i) compounds can be obtained together with the type (ii) or (iii) cyclised compounds, and then easily separated by chromatography. n-propanol, isopropanol, n-butanol, isobutanol, cyclohexanol and various glycols can be used as alcoholic solvents, depending on the necessary conditions, in addition to methanol (MeOH).

(50) ##STR00010##

(51) The synthesis of type (i-vi) isoprenylated chalcone analogue structures is therefore possible on these bases.

(52) ##STR00011##

(53) The partial protection of 2,4,6-trihydroxyacetophenone 1 with methoxymethylchloride (MOMCl) using DIPEA as base in DCM as solvent leads to di-MOM derivative 2a with yields of 66%. A subsequent Mitsunobu reaction using phenol 2a in the presence of 3-methyl-2-buten-1-ol with DEAD as dehydrating agent and TPP allows the introduction of the prenyl group, giving prenyl ether 3a (1-[2,4-di-methoxymethyloxy-6-(3-methyl-but-2-enyloxy)-phenyl]-ethanone) with yields of 38%. A subsequent Claisen rearrangement of allyl ether 3a in N,N-dimethylaniline at 200 C. for 4 hours gives chalcone 4a, 1-[6-hydroxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone, with yields of 44%. Subsequently, methylation of 4a with dimethylsulphate in the presence of potassium carbonate gives the desired key intermediate 5a (1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone), with yields of 62%.

(54) At this point, an aldol condensation using an appropriate aldehyde, conducted in methanol using 10% aqueous sodium hydroxide as base, gives di-MOM substituted 6-methoxy chalcone intermediates (E)-6a-(E)-6g with yields of around 60%. Subsequently, by deprotection of MOM under controlled temperature and acidity conditions, the mono-MOM substituted chalcones (E)-7a-(E)-7g are obtained, mixed with deprotected XN analogue chalcones with suitable 8a-8g substitutions on the B ring. Appropriate chromatography conditions on Isolute Flash (Biotage) or Flash silica gel columns allow the isolation of both the mono MOM derivatives of type (1), (E)-7a-(E)-7g and the desired deprotected chalcones of type (1), 8a-8g (Synthesis scheme 3).

(55) The compounds according to the invention exhibit antiproliferative effects against human tumour lines, such as breast cancer, hepatocarcinoma, prostate carcinoma, myeloma and leukaemia lines.

(56) The compounds according to the invention also inhibit the proliferation of human umbilical vein endothelial cells (HUVEC).

(57) The compounds according to the invention also inhibit the chemotaxis and invasion of HUVEC and human tumour cell lines, such as breast cancer and fibrosarcoma cells.

(58) The compounds according to the invention therefore possess anti-angiogenic, antioxidant and chemopreventive properties.

(59) The anti-proliferative, anti-invasive and anti-angiogenic activity possessed by the compounds according to the invention is greater than the activities exhibited by XN when used as control in parallel experiments.

(60) The compounds according to the invention modulate the catalytic activity of extracellular matrix metalloproteases, especially between MMP-2 and MMP-9, with different selectivities from XN.

(61) A further subject of the present invention is the use of the compounds according to the invention as medicaments.

(62) In particular, the compounds according to the invention can be used in the prevention and/or treatment of tumoral, inflammatory, cardiovascular or neurodegenerative disorders, or as angiogenesis inhibitors, for example in the prevention and/or treatment of tumour angiogenesis.

(63) The compounds according to the invention can be suitably formulated with pharmaceutically acceptable excipients or carriers. The suitable pharmaceutical forms can vary according to the specific compound and the administration route. The dose of active ingredient will be determined on each occasion, according to the severity of the disorder to be treated and the patient's general condition. Suitable pharmaceutical compositions can be prepared in accordance with the indications reported in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.

(64) The examples given below further illustrate the invention.

EXAMPLES

Materials and Methods

(65) All the reactions were conducted under nitrogen, in anhydrous solvents. The structure of the compounds was established by 1H-NMR, 13C-NMR and mass spectrometry. The nuclear magnetic resonance spectra were recorded on a Varian Gemini 200 spectrometer operating at 200 MHz for 1H and 50.3 MHz for 13C in CDCl3, DMSO-d6, acetone-d6, D2O and MeOD; the chemical shifts () are expressed in ppm. The reaction solvents were evaporated under vacuum in a rotary evaporator, while anhydrous Na.sub.2SO.sub.4 was used as drying agent for the organic solvent solutions. The preparatory liquid chromatographies were conducted with flash chromatography on prepacked (Biotage) Isolute Si II columns or on columns packed by us containing 230-400 mesh silica gel. The thin-layer chromatographies (TLC) were conducted with 60 F254 (MERCK) silica gel plates containing a fluorescent indicator. The various spots were highlighted with a UV lamp (256 nM). The melting points were determined under the Kofler microscope.

Preparation Example 1: Preparation of 1-(2-hydroxy-4,6-dimethoxymethyloxy-phenyl)-ethanone [compound (2)]

(66) Diisopropylethylamine, DIPEA (8.4 mL, 48.327 mmols), followed by MOM chloride (3.7 mL, 48.327 mmols), was added drop by drop to a suspension, stirred and cooled in an ice bath, of 2,46-trihydroxyacetophenone monohydrate, 1, (3 g, 16.115 mmols), in anhydrous CH2Cl2 (36 mL). When the addition was complete, the temperature was gradually increased to RT, and the reaction was maintained under stirring, under these conditions, for 6 h. After that time the reaction mixture was returned to the ice bath and treated with a saturated aqueous solution of ammonium chloride (30 mL). The reaction was then heated to RT and left under stirring for 30 min. The resulting mixture was then extracted with CH2Cl2/water [3100 mL (1:1)], and the resulting separated organic phase was dried on sodium sulphate, filtered and evaporated. The dark crude oil obtained (4.268 g) was then purified, after adsorption on 4.50 g of silica 230-400 mesh, by flash chromatography on silica gel column (silica 230-400 mesh, diameter 4 cm, height 17 cm) using n-hexane/AcOEt (6:1) as eluent, and collecting 12 mL fractions. 2.716 g of 2 in the form of a thick, transparent oil, tending to solidify at low temperature, was obtained from the fractions (test tubes 5-30, Vm: 500 mL).

(67) Yield: 66%

(68) TLC Rf: 0.16 in n-hexane/AcOEt (5:1);

(69) 1H-NMR (200 MHz, CDCl3): 6.27 (d, 1H, J=2.2 Hz, ArH), 6.24 (d, 1H, J=2.2 Hz, ArH), 5.25 (s, 2H, OCH2-O), 5.17 (s, 2H, OCH2-O), 3.51 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 2.66 (s, 3H, COCH3).

Preparation Example 2: Preparation of 1-[2,4-di-methoxymethyloxy-6-(3-methyl-but-2-enyloxy)-phenyl]-ethanone [compound (3)]

(70) Procedure A

(71) Triphenyl phosphine (1.879 g, 7.165 mmols, 1.2 equiv) and the alcohol 3-methyl-2-buten-1-ol (0.9 mL, 8.956 mmols, 1.5 equiv) were added to a solution of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone, 2 (1.530 g, 5,971 mmols, 1 equiv) in tetrahydrofuran (30 mL), placed under stirring in an ice bath. The DEAD (1.5 ml, 9.554 mmols, 1.6 equiv) was dripped and the solution was heated to RT and left under stirring for 21 h. The solvent was then evaporated and the residue suspended in ethyl ether, in which the formation of a white crystalline precipitate was observed. The solid was filtered under vacuum and the filtrate evaporated, to obtain 11.725 g of a sticky yellow oil with a pungent odour, purified with a flash chromatography column on silica gel (silica 230-400 mesh, diameter 6 cm, height 18 cm) after preparation of the absorbate (silica 230-400 mesh, 12.0 g). The eluent mixture used for the resolution of the column was n-hexane/AcOEt in the ratio of 6:1. 0.738 g of 13, which appeared as a clear oil, was obtained from evaporation of the organic fraction (test tubes 41-78, 12 mL fractions, Vm: 1100 mL).

(72) Yield: 38%

(73) TLC Rf: 0.36 in n-hexane/AcOEt 7:1;

(74) 1H-NMR (200 MHz, CDCl3): 6.44 (d, 1H J=2.01 Hz, ArH), 6.31 (d, 1H, J=2.01 Hz, ArH), 5.4 (t, 1H, J=6.6 Hz, CH), 5.14 (s, 2H, OCH2-O), 5.12 (s, 2H, OCH2-O), 4.49 (d, 2H, J=6.6 Hz, CH2), 3.47 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 2.47 (s, 3H, COCH3), 1.75 (s, 3H, CH3), 1.70 (s, 3H, CH3).

(75) Procedure B

(76) Triphenyl phosphine (2.068 g, 7.884 mmols, 1.4 equiv) and the alcohol 3-methyl-2-buten-1-ol (1.1 ml, 11.238 mmols, 2 equiv) were added to a solution of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone, 2 (1.440 g, 5.619 mmols, 1 equiv) in toluene (29 mL), placed under stirring in an ice bath. The DEAD (1.8 mL, 11.238 mmols, 2 equiv) was dripped and the solution was heated to RT and left under stirring for 21 h. The solvent was then evaporated and the residue suspended in ethyl ether, in which the formation of a white crystalline precipitate was observed. The solid was filtered under vacuum and the filtrate evaporated, to obtain a sticky yellow oil with a pungent odour (6.260 g). The crude product was purified with a flash chromatography column on silica gel (silica 230-400 mesh, diameter 6 cm, height 17 cm) after preparation of the absorbate (silica 230-400 mesh, 7.0 g). The eluent mixture used for the resolution of the column was n-hexane/AcOEt in the ratio of 7:1. 1.660 g of 3, which presented as a pale oil, was obtained from evaporation of the organic fraction (test tubes 72-123, 15 mL fractions, Vm: 750 mL).

(77) Yield: 91%

(78) TLC Rf: 0.36 in n-hexane/AcOEt 7:1;

(79) 1H-NMR (200 MHz, CDCl3): 6.44 (d, 1H J=2.01 Hz, ArH), 6.31 (d, 1H, J=2.01 Hz, ArH), 5.4 (t, 1H, J=6.6 Hz, CH), 5.14 (s, 2H, OCH2-O), 5.12 (s, 2H, OCH2-O), 4.49 (d, 2H, J=6.6 Hz, CH2), 3.47 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 2.47 (s, 3H, COCH3), 1.75 (s, 3H, CH3), 1.70 (s, 3H, CH3).

Preparation Example 3: Preparation of 1-[6-hydroxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone [compound (4)]

(80) A solution of 1-[2,4-dimethoxymethyloxy-6-(3-methyl-but-2-enyloxy)-phenyl]-ethanone 3 (0.300 g, 0.925 mmols) in N,N-dimethylaniline (8 mL, 0.063 mmols) was heated to 200 C. and maintained at that temperature for 4 h. After this interval, the resulting mixture was cooled to room temperature and extracted with AcOEt/HCl [4100 ml (1:1)], and the separated organic phase was dried on sodium sulphate, filtered and evaporated. The residue, a dark, almost black, sticky oil (0.383 g), only soluble in CHCl.sub.3, was chromatographed on silica (silica 230-400 mesh, diameter 4 cm, height 20 cm) after preparation of the absorbate (silica 230-400 mesh, 0.500 g). n-hexane/AcOEt in the ratio of 7:1 was selected as eluent mixture. 0.075 g of 4, which presented as a bright yellow oil, was obtained from evaporation of the organic fraction (test tubes 16-20, 12 ml fractions, Vm: 150 ml).

(81) Yield: 44%

(82) TLC Rf: 0.39 in n-hexane/AcOEt 5:1

(83) 1H-NMR: (200 MHz, CDCl3): 6.53 (s, 1H, ArH), 5.20 (s, 2H, OCH2-O), 5.13 (t, 1H, J=6.6 Hz, CH), 4.90 (s, 2H, OCH2-O), 3.79 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.30 (d, 2H, J=6.6 Hz, CH2), 2.49 (s, 3H, COCH3), 1.74 (s, 3H, CH3), 1.65 (s, 3H, CH3).

Preparation Example 4: Preparation of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone [compound (5)]

(84) Potassium carbonate (0.407 g, 2.948 mmols, 2 equiv) and dimethyl sulphate (0.3 mL, 2.948 mmols, 2 equiv) were added to a solution, placed under stirring, of 1-[6-hydroxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (4) (0.478 g, 1.474 mmols, 1 equiv) in acetone (25 mL). The reaction was maintained under stirring at 60 C. for 6 h. The reaction was then heated to RT and quenched with a 30% aqueous solution of NH.sub.3 (28 mL). The resulting mixture was then extracted with CH.sub.2Cl.sub.2/water [360 mL (1:1)], and the resulting separated organic phase was dried on sodium sulphate and evaporated. The residue, a bright yellow oil (0.475 g), was chromatographed on an Isolute Si II 20 g flash chromatography column using n-hexane/AcOEt 9:1. 0.380 g (1.123 mmols) of 5, a dark yellow oil, was obtained from evaporation of the organic fraction (test tubes 31-52, 5 ml fractions).

(85) Yield: 76%

(86) TLC Rf: 0.38 in n-hexane/AcOEt 3:1

(87) 1H-NMR: (200 MHz, CDCl3): 6.54 (s, 1H, ArH), 5.21 (s, 2H, OCH2-O), 5.14 (t, 1H, J=6.6 Hz, CH), 4.90 (s, 2H, OCH2-O), 3.79 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 3.27 (d, 2H, J=6.6 Hz CH2), 2.50 (s, 3H, COCH3), 1.75 (s, 3H, CH3), 1.66 (s, 3H, CH3).

Example 5: Preparation of (E)-3-(3,4-dichlorophenyl)-1-(6-methoxy-2,4-bis(methoxymethoxy)-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one [compound (6)]

(88) ##STR00012##

(89) A 10% saturated aqueous solution of NaOH (1 mL) was added to a solution, placed under stirring, of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone, 5 (0.180 g, 0.53 mmols) and 3,4-dichlorobenzaldehyde (0.0927 g, 0.53 mmols) in anhydrous methanol (21 mL). The reaction temperature was increased to 65 C. and maintained for 6 h. The reaction was then restored to RT, extracted with AcOEt (100 mL) and washed with H2O [350 mL]0.1)]. The separated organic phase was dried on sodium sulphate, filtered and evaporated, to obtain a yellow oil (0.278 g). The crude product was purified on an Isolute Si II 10g flash chromatography column using n-hexane/AcOEt 12:1 as eluent. When the organic fraction had been evaporated (test tubes 25-36, 5 mL fractions), a fluorescent yellow semisolid 6 (0.163 g) was obtained.

(90) Yield: 62%

(91) TLC Rf: 0.26 in n-hexane/AcOEt 7:1.

(92) 1H-NMR (200 MHz, CDCl3): 7.60 (d, 1H, J=16 Hz, CHArH), 7.38 (t, 2H, J=16 Hz, CHArH), 7.28 (d, 1H, J=16 Hz, CH), 6.92 (d, 1H, J=15.9 Hz, CH), 6.59 (s, 1H, ArH), 5.24 (s, 2H, OCH2-O), 5.14 (t, 1H, J=6.9 Hz, CH2CH), 4.90 (s, 2H, OCH2-0), 3.77 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.41 (s, 3H, CH2OCH3), 3.32 (d, 2H, J=6.9 Hz, CH2), 1.76 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 6: Preparation of (E)-3-(3,4-dichloro-phenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl)-phenyl-prop-2-en-1-one [compound (7)]

(93) ##STR00013##

(94) Concentrated HCl was added to a solution, placed under stirring, of (6) (0.100 g, 0.2 mmols) in MeOH/H20 (12 mL:1.3 mL) until the pH reached 1. The resulting mixture was left to react at RT for 12 h, and then extracted with AcOEt/H2O (1:1). The organic phase was dried on sodium sulphate, filtered and evaporated at 20 C., to obtain an orange solid (0.094 g). The crude product was crushed with Et2O/n-hexane to give 7 (0.082 g), an orange solid.

(95) TLC Rf: 0.5 in n-hexane/AcOEt 6:1, MP: 230-235 C.

(96) 1H-NMR (200 MHz, CDCl3): 7.82 (d, 1H, J=15.7 Hz, CHArH), 7.61 (d, 1H, J=15.7 Hz, CH), 7.47 (d, 1H, J=8.4 Hz, ArH), 7.39 (d, 1H, J=8.4 Hz, ArH), 7.38 (2d, 1H, J=1.83 e 8.4 Hz, ArH), 6.24 (s, 1H, ArH), 5.27 (s, 2H, OCH2-O), 5.17 (t, 1H, J=6.9 Hz, CH), 3.90 (s, 3H, OCH3), 3.49 (s, 3H, CH2OCH3), 3.30 (d, 2H, J=6.9 Hz, CH2), 1.78 (s, 3H, CH3), 1.67 (s, 3H, CH3).

(97) The NMR analysis demonstrated that only one of the two protecting groups of 6, namely the one in the 2 position, was hydrolysed.

Example 7: Preparation of (E)-3-(3,4-dichloro-phenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (8a)](chalcone 8) and (E)-3-(3,4-dichlorophenyl)-1-(5-hydroxy-7-methoxy-2,2-dimethylchroman-6-yl)prop-2-en-1-one [compound (8b)]

(98) ##STR00014##

(99) The procedure described in example 6 was repeated at a higher reaction temperature.

(100) Concentrated HCl was added to a solution of (E)-3-(3,4-dichlorophenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one, 7 (0.072 g, 0.16 mmols) in MeOH/H20 (12 mL:1.3 mL) until the pH reached 1. The reaction mixture was heated to 40 C. and left under stirring for 48 h. The resulting mixture was then extracted with AcOEt/H2O (1:1). The organic phase was dried on sodium sulphate, filtered and evaporated at 20 C., to obtain an orange solid (0.066 g). The crude product was chromatographed on a an Isolute Si II 5 g flash chromatography column, using n-hexane/AcOEt in the ratio of 7:1 as eluent mixture. 8a (0.008 g) was obtained from evaporation of the organic fraction (test tubes 5-10, 5 mL fractions) as a yellow solid. 8b (0.004 g) was obtained from evaporation of test tubes 1-3 (5 mL fractions) as a yellow oil.

(101) TLC (8a) Rf: 0.17 in n-hexane/AcOEt 7:1, MP: 240-246 C.

(102) 1H-NMR (200 MHz, CDCl3): 7.83 (d, 1H, J=15.6 Hz, CH), 7.61 (d, 1H, J=15.6 Hz, CH), 7.58 (d, 1H, J=8.3 Hz, CHArH), 7.37 (m, 1H, CHArH), 6.28 (s, 1H, ArH), 5.92 (d, 1H, OH), 5.28 (t, 1H, J=7.1 Hz, CH2CH), 3.88 (s, 3H, OCH3), 3.88 (d, 2H, J=7.1 Hz, CH2), 1.83 (s, 3H, CH3), 1.77 (s, 3H, CH3).

(103) TLC (8b) Rf: 0.87 in n-hexane/AcOEt 2:1

(104) 1H-NMR (200 MHz, CDCl3): 7.84 (d, 1H, J=16 Hz, CH), 7.57 (d, 1H, J=16 Hz, CH), 7.4 (d, 1H, J=8 Hz, CHArH), 7.37 (d, 1H, J=8 Hz, CHArH), 5.88 (s, 1H, ArH), 5.86 (s, 1H, OH), 3.88 (s, 3H, OCH3), 2.63 (t, 2H, J=4 Hz, CH2), 1.81 (t, 2H, J=4 Hz, CH2), 1.36 (s, 3H, CH3), 1.25 (s, 3H, CH3).

Example 8: Preparation of (E)-3-(4-fluorophenyl)-1-[6-methoxy-2,4-di-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (9)]

(105) ##STR00015##

(106) A 10% aqueous solution of NaOH (2 mL) was added to a suspension of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (5) (0.285 g, 0.842 mmols, 1 equiv) and 4-fluorobenzaldehyde (0.09 mL, 0.842 mmols, 1 equiv) in MeOH (33 mL), placed under stirring. The reaction mixture was heated to 65 C. and maintained under the same conditions for 6 h. It was then extracted with AcOEt (100 ml) and washed with H2O (350 mL). The organic phase was dried on sodium sulphate, filtered and evaporated, to obtain a yellow oil (0.183 g). The crude reaction product was purified on a an Isolute Si II 10 g flash chromatography column using n-hexane/AcOEt 14:1 as eluent mixture. 9 (0.091 g), a bright yellow oil, was obtained from evaporation of the organic fraction (test tubes 23-27, 5 mL fractions).

(107) Yield: 25%

(108) TLC Rf: 0.29 in n-hexane/AcOEt 5:1

(109) 1H-NMR (200 MHz, CDCl3): 7.49 (2d, 2H, J=8.4 Hz, CHArH), 7.34 (d, 1H, J=16 Hz, CH), 7.02 (2d, 2H, J=8.4 Hz, CHArH), 6.88 (d, 1H, J=16 Hz, CH), 6.59 (s, 1H, ArH), 5.24 (s, 2H, OCH2-O), 5.18 (t, 1H, J=6.9 Hz, CH2CH), 4.91 (s, 2H, OCH2-0), 3.76 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.42 (s, 3H, CH2OCH3), 3.33 (d, 2H, J=6.9 Hz, CH2), 1.76 (s, 3H, CH3), 1.67 (s, 3H, CH3).

Example 9: Preparation of (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)prenyl]-3-(4-fluorophenyl)-prop-2-en-1-one [compound (10)] and (E)-3-(4-fluorophenyl)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methyl-but-2-enyl]-phenyl)prop-2-en-1-one [compound (11)]

(110) ##STR00016##

(111) A solution of (E)-3-(4-fluorophenyl)-1-[6-methoxy-2,4-di-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one, 9 (0.091 g, 0.205 mmols) in MeOH/HCl 1.25 M (2.5 mL) was heated to 45 C. and left under stirring for 45 min. It was then extracted with AcOEt (100 mL) and washed with H2O (350 mL). The organic phase was dried on sodium sulphate, filtered and evaporated at 20 C., to obtain a golden yellow solid (0.074 g). The crude product was purified after adsorption on silica (silica 230-400 mesh, 0.080 g) by flash chromatography on silica gel column (silica 230-400 mesh, diameter 2 cm, height 15 cm) using n-hexane/EtOAc 7:1. 11 (0.006 g) was obtained as an orange oil and 10 (0.021 g) as a golden yellow solid from evaporation of the organic fractions (test tubes 8-10, test tubes 16-33, 8 mL fractions).

(112) TLC (11) Rf: 0.16 in n-hexane/AcOEt 5:1

(113) 1H-NMR (200 MHz, CDCl3): 7.82 (d, 1H, J=15.4 Hz, CH), 7.70 (d, 1H, J=15.4 Hz, CH), 7.59 (2d, 2H, J=8.0 Hz, CHArH), 7.13 (2d, 2H, J=8.0 Hz, CHArH), 6.24 (s, 1H, ArH), 5.27 (s, 2H, OCH2-O), 5.24 (t, 1H, J=6.8 Hz, CH2CH), 3.93 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.31 (d, 2H, J=6.8 Hz, CH2), 1.79 (s, 3H, CH3), 1.67 (s, 3H, CH3).

(114) TLC (10) Rf: 0.28 in n-hexane/AcOEt 2:1, MP: 235-237 C.

(115) 1H-NMR (200 MHz, CDCl3): 7.82 (d, 1H, J=15.4 Hz, CH), 7.70 (d, 1H, J=15.4 Hz, CH), 7.59 (2d, 2H, J=8.0 Hz, CHArH), 7.13 (2d, 2H, J=8.0 Hz, CHArH), 6.24 (s, 1H, ArH), 5.27 (s, 2H, OCH2-O), 5.24 (t, 1H, J=6.8 Hz, CH2CH), 3.93 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.31 (d, 2H, J=6.8 Hz, CH2), 1.79 (s, 3H, CH3), 1.67 (s, 3H, CH3).

Example 10: Preparation of (E)-1-[6-methoxy-2,4-dimethoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one [compound (12)]

(116) ##STR00017##

(117) A 10% aqueous solution of NaOH (1.5 mL) was added to a solution of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone, 5 (0.225 g, 1.330 mmols, 1 equiv) and 4-nitrobenzaldehyde (0.201 g, 1.330 mmols, 1 equiv) in MeOH (26 mL). The reaction mixture was heated to 65 C. and maintained under the same conditions and under stirring for 6 h. It was then extracted with AcOEt (100 mL) and washed with H2O (450 mL). The organic phase was dried on sodium sulphate, filtered and evaporated. The brown crude oil (0.382 g) was purified on an Isolute Si II 10 g flash chromatography column, using an n-hexane/AcOEt 6:1 eluent mixture. When the organic fraction (test tubes 20-44, 5 mL fractions) had evaporated, a yellow oil 12 (0.274 g) was obtained.

(118) Yield: 44%

(119) TLC Rf: 0.14 in n-hexane/AcOEt 4:1.

(120) 1H-NMR (200 MHz, CDCl3): 8.24 (d, 2H, J=8 Hz, CHArH), 7.70 (d, 2H, J=8 Hz, CHArH), 7.47 (d, 1H, J=16.2 Hz, CH), 7.11 (d, 1H, J=16.2 Hz, CH), 6.61 (s, 1H, ArH), 5.26 (s, 2H, OCH2-O), 5.16 (t, 1H, J=6.8 Hz, CH2CH), 4.91 (s, 2H, OCH2-O), 3.79 (s, 3H, OCH3), 3.51 (s, 3H, CH2OCH3), 3.43 (s, 3H, CH2OCH3), 3.25 (d, 1H, J=6.8 Hz, CH2), 1.77 (s, 3H, CH3), 1.73 (s, 3H, CH3).

Example 11: Preparation of (E)-1-[2-hydroxy-6-methoxy-4-(methoxymethyloxy)-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one [compound (13)]

(121) ##STR00018##

(122) A solution, placed under stirring, of (12) (0.274 g, 0.581 mmols) in MeOH/HCl 1.25 M (8.6 mL) was heated to 45 C. for 1.5 h. The reaction mixture was extracted with AcOEt/H2O [(350 mL), 1:1]. The organic phase was dried on sodium sulphate, filtered and evaporated at 20 C., to obtain an orange-yellow solid (0.433 g). The crude product was purified on an Isolute Si II 10 g flash chromatography column, using n-hexane/EtOAc 7:1 as eluent mixture. The organic fraction (test tubes 6-16, 5 mL fractions) was evaporated at RT to obtain (13) (0.251 g), a bright orange solid.

(123) TLC Rf: 0.2 in n-hexane/AcOEt 4:1, MP: 230-235 C. (dec).

(124) 1H-NMR (200 MHz, CDCl3): 8.25 (d, 2H, J=8.9 Hz, CHArH), 7.92 (d, 2H, J=16 Hz, CH), 7.74 (d, 1H, J=16 Hz, CH), 7.73 (d, 1H, J=8.9 Hz, CHArH), 6.27 (s, 1H, OH), 5.30 (s, 2H, OCH2-O), 5.16 (t, 1H, J=6.8 Hz, CH2CH), 3.95 (s, 3H, OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=6.8 Hz, CH2), 1.80 (s, 3H, CH3), 1.69 (s, 3H, CH3).

Example 12: Preparation of (E)-N-(4-{3-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-(oxoprop-1-enyl}phenyl)-acetamide [compound (15)]

(125) ##STR00019##

(126) A 10% aqueous solution of NaOH (1.5 mL) was added to a solution, under stirring, of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (5) (0.225 g, 1.330 mmols, 1 equiv) and 4-acetamide benzaldehyde (0.217 g, 1.330 mmols, 1 equiv) in MeOH (26 mL). The reaction mixture was heated to 65 C. for 6 h. It was then extracted with AcOEt (100 mL) and washed with H2O (450 mL). The organic phase was dried on sodium sulphate, filtered and evaporated. The crude product (0.386 g), a bright yellow oil, was purified by Isolute Si II 10 g flash chromatography using n-hexane/AcOEt 5:1 as eluent mixture. (15) (0.090 g), which presented as a yellow oil, was obtained from evaporation of the organic fraction (test tubes 115-121, 5 mL fractions).

(127) Yield: 14% TLC Rf: 0.08 in n-hexane/AcOEt 2:1.

(128) 1H-NMR (200 MHz, CDCl3): 7.79 (s, 1H, NH), 7.28 (d, 2H, J=8.6 Hz, CHArH), 7.18 (d, 2H, J=8.6 Hz, CHArH), 7.08 (d, 1H, J=16 Hz, CH), 6.64 (d, 1H, J=16 Hz, CH), 6.30 (s, 1H, ArH), 4.95 (s, 2H, OCH2-O), 4.89 (t, 1H, J=6.8 Hz, CH2CH), 4.62 (s, 2H, OCH2-O), 3.46 (s, 3H, OCH3), 3.22 (s, 3H, CH2OCH3), 3.14 (s, 3H, CH2OCH3), 3.06 (d, 2H, J=6.8 Hz, CH2), 1.88 (s, 3H, COCH3), 1.48 (s, 3H, CH3), 1.39 (s, 3H, CH3).

Example 13: Structural formulas of (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-nitrophenyl)prop-2-en-1-one [compound (14)], (E)-N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}phenyl)acetamide [compound (16)] and (E)-N-(4-{3-[2,4-dihydroxy-6-methyloxy-3-(3-methyl-but-2-enyl)phenyl]-3-oxoprop-1-enyl}-phenyl)acetamide [compound (17)]

(129) ##STR00020##

Example 14: Preparation of (E)-3-(3,4-difluoro-phenyl)-1-[6-methoxy-2,4-bis-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-prop-2-en-1-one [compound (18)]

(130) ##STR00021##

(131) A 10% aqueous solution of NaOH (0.9 mL) was added to a solution, placed under stirring, of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (5) (0.267 g, 0.789 mmols, 1 equiv) and 3,4-difluoro-benzaldehyde (0.09 mL, 0.789 mmols, 1 equiv), in MeOH (16 mL). The mixture was then left at 65 C. for 20 h. After that time, the solution was extracted with AcOEt/H2O [(350 ml), 2:1]. The organic phase was dried on sodium sulphate, filtered and evaporated. The crude product (0.434 g), a bright yellow oil, was purified after adsorption on silica (silica 230-400 mesh, 0.600 g), by flash chromatography on silica gel column (silica 230-400 mesh, diameter 3 cm, height 15 cm), using n-hexane/AcOEt 7:1 as eluent mixture. (18) (0.276 g, 0.597 mmols) was obtained as a yellow oil from evaporation of the organic fraction (test tubes 43-50, 12 mL fractions, Vm: 200 mL).

(132) Yield: 55% TLC Rf: 0.26 in n-hexane/AcOEt 2:1.

(133) 1H-NMR (200 MHz, CDCl3): 7.35 (d, 1H, J=15.7 Hz, CH), 7.26 (d, 1H, J=16 Hz, CHArH), 6.96 (d, 1H, J=16 Hz, CHArH), 6.84 (d, 1H, J=15.7 Hz, CH), 6.60 (s, 1H, ArH), 5.25 (s, 2H, OCH2-O), 5.21 (t, 1H, J=6.8 Hz, CH2CH), 4.92 (s, 2H, OCH2-O), 3.93 (s, 3H, OCH3), 3.78 (s, 3H, CH2OCH3), 3.52 (s, 3H, CH2OCH3), 3.35 (d, 2H, J=6.8 Hz CH2), 1.78 (s, 3H, CH3), 1.70 (s, 3H, CH3).

Example 15: Preparation of (E)-3-(3,4-difluorophenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]prop-2-en-1-one [compound (19)] and (E)-3-(3,4-difluorophenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (20)]

(134) ##STR00022##

(135) A solution of (18) (0.275 g, 0.595 mmols) in MeOH/HCl 1.25 M (7.3 ml) was heated to 45 C. and maintained under those conditions, under stirring, for 1.15 h. The reaction mixture was extracted with AcOEt/H2O [(360 mL), 2:1]. The organic phase was dried on sodium sulphate, filtered and evaporated at RT. The yellow crude oil (0.196 g) was purified, after adsorption on 0.300 g of silica 230-400 mesh, by flash chromatography on silica gel column (silica 230-400 mesh, diameter 2 cm, height 17 cm), using n-hexane/EtOAc 4:1 as eluent mixture. (19) (0.024 g) was obtained as an orange-yellow oil and (20) (0.111 g) as a yellow solid from evaporation of the organic fractions (test tubes 11-16, test tubes 23-36, 8 mL fractions). TLC Rf 19: 0.24 in n-hexane/AcOEt 2:1

(136) 1H-NMR (200 MHz, CDCl3): 7.85 (d, 1H, J=16 Hz, CH), 7.76 (d, 1H, J=16 Hz, CH), 7.28-7.44 (m, 2H, CHArH), 6.98 (m, 1H, CHArH), 6.29 (s, 1H, ArH), 5.32 (s, 2H, OCH2-O), 5.24 (t, 1H, J=6.9 Hz, CH2CH), 3.98 (s, 3H, OCH3), 3.54 (s, 3H, CH2OCH3), 3.35 (d, 2H, J=7.2 Hz, CH2), 1.84 (s, 3H, CH3), 1.72 (s, 3H, CH3).

(137) TLC Rf 20: 0.23 in n-hexane/AcOEt 2:1, MP: 237-240 C.

(138) 1H-NMR (200 MHz, CDCl3): 7.84 (d, 1H, J=15.4 Hz, CH), 7.73 (d, 1H, J=15.4 Hz, CH), 7.28-7.44 (m, 2H, CHArH), 6.98 (m, 1H, CHArH), 6.24 (s, 1H, ArH), 5.96 (d, 1H, OH), 5.27 (t, 1H, J=7.1 Hz, CH2CH), 3.95 (s, 3H, OCH3), 3.40 (d, 2H, J=7.4 Hz, CH2), 1.84 (s, 3H, CH3), 1.79 (s, 3H, CH3).

Example 16: Preparation of (E)-3-(2,4-difluoro-phenyl)-1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)phenyl]-prop-2-en-1-one [compound (21)]

(139) ##STR00023##

(140) A 10% aqueous solution of NaOH (0.9 mL) was added to a solution, placed under stirring, of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (5) (0.271 g, 0.802 mmols, 1 equiv) and 2,4-difluoro-benzaldehyde (0.09 mL, 0.802 mmols, 1 equiv), in MeOH (16.3 mL). The mixture was then left at 65 C. for 20 h. After that time, the solution was extracted with AcOEt/H2O [(350 mL), 2:1]. The organic phase was dried on sodium sulphate, filtered and evaporated. The crude product (0.453 g), a bright yellow oil, was purified after adsorption on silica (silica 230-400 mesh, 0.600 g), by flash chromatography on silica gel column (silica 230-400 mesh, diameter 3 cm, height 15 cm), using n-hexane/AcOEt 8:1 as eluent mixture. (21) (0.118 g, 0.255 mmols) was obtained as a yellow oil from evaporation of the organic fraction (test tubes 56-67, 12 mL fractions, Vm: 250 mL).

(141) Yield: 32% TLC Rf: 0.16 in n-hexane/AcOEt 4:1

(142) 1H-NMR (200 MHz, CDCl3): 7.73 (d, 1H, J=16 Hz, CHArH), 7.56 (d, 1H, J=16 Hz, CH) 7.50 (t, 1H, J=16 Hz, CHArH), 7.08 (d, 1H, J=16 Hz, CH), 7.02 (d, 1H, J=16 Hz, CH), 6.75-6.62 (m, 3H, CHArH), 6.59 (s, 1H, ArH), 5.24 (s, 2H, OCH2-O), 5.19 (t, 1H, J=6.9 Hz, CH), 4.92 (s, 2H, OCH2-O), 3.83 (s, 3H, OCH3), 3.77 (s, 3H, CH2OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=7.1 Hz, CH2), 1.77 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 17: Preparation of (E)-3-(2,4-difluorophenyl)-1-[2-hydroxy-6-methoxy-4-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (22)], (E)-3-(2,4-difluorophenyl)-1-[4-hydroxy-6-methoxy-2-methoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (23)] and (E)-3-(2,4-difluorophenyl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-prop-2-en-1-one [compound (24)]

(143) ##STR00024##

(144) A solution of (21) (0.100 g, 0.216 mmols) in MeOH/HCl 1.25 M (2.6 mL) was heated to 45 C. and maintained under these conditions, under stirring, for 1 h. The reaction mixture was extracted with AcOEt/H2O [(360 mL), 2:1]. The organic phase was dried on sodium sulphate, filtered and evaporated at RT. The yellow-orange crude oil (0.121 g) was purified, after adsorption on 0.200 g of silica 230-400 mesh, by flash chromatography on silica gel column (silica 230-400 mesh, diameter 2 cm, height 15 cm) using n-hexane/EtOAc 7:1 as eluent mixture. (22) (0.004 g) was obtained as a yellow oil, (23) (0.041 g) as an orange-yellow oil and (24) (0.015 g) as a yellow solid from evaporation of the organic fractions (test tubes 70-72, test tubes 73-81, test tubes 102-103, 12 mL fractions). TLC Rf 22: 0.7 in n-hexane/AcOEt 2:1

(145) 1H-NMR (200 MHz, CDCl3): 8.02 (d, 1H, J=16 Hz, CH), 7.83 (d, 1H, J=16 Hz, CH), 7.54 (t, 1H, CHArH), 6.75-6.63 (m, 2H, CHArH), 6.25 (s, 1H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(146) TLC Rf 23: 0.57 in n-hexane/AcOEt 2:1

(147) 1H-NMR (200 MHz, CDCl3): 7.95 (d, 1H, J=16 Hz, CH), 7.77 (d, 1H, J=16 Hz, CH), 7.52 (t, 1H, CHArH), 6.77-6.62 (m, 2H, CHArH), 6.24 (s, 1H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=7 Hz, CH2CH), 3.92 (s, 3H, OCH3), 3.85 (s, 3H, CH2OCH3), 3.32 (d, 2H, J=7 Hz, CH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(148) TLC Rf 24: 0.37 in n-hexane/AcOEt 2:1, MP: 245-248 C.

(149) 1H-NMR (200 MHz, CDCl3): 7.98 (d, 1H, J=16 Hz, CH), 7.87 (d, 1H, J=16 Hz, CH), 7.49 (t, 1H, CHArH), 6.77-6.63 (m, 2H, CHArH), 6.22 (s, 1H, ArH), 5.95 (d, 1H, OH), 5.28 (t, 1H, J=7.2 Hz, CH2CH), 3.90 (s, 3H, OCH3), 3.40 (d, 2H, J=7.2 Hz, CH2), 1.85 (s, 3H, CH3), 1.79 (s, 3H, CH3).

Example 18: Preparation of 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone [compound (25)]

(150) ##STR00025##

(151) A 10% aqueous solution of NaOH (0.9 mL) was added to a solution, placed under stirring, of 1-[6-methoxy-2,4-dimethoxymethyloxy-3-(3-methyl-but-2-enyl)-phenyl]-ethanone (5) (0.271 g, 0.802 mmols, 1 equiv) and pyridin-2-carbaldehyde (0.802 mmols, 1 equiv) in MeOH (16.3 mL). The mixture was then left at 65 C. for 20 h. After that time, the solution was extracted with AcOEt/H2O [(350 mL), 2:1]. The organic phase was dried on sodium sulphate, filtered and evaporated. The crude product (0.280 g), a yellow oil, was purified after adsorption on silica (silica 230-400 mesh, 0.600 g), by flash chromatography on silica gel column (silica 230-400 mesh, diameter 3 cm, height 15 cm), using n-hexane/AcOEt 2:1 as eluent mixture. Yield: 12%. 1H-NMR (200 MHz, CDCl3): 8.11 (d, 1H, J=15.6 Hz, =CHPy-H), 8.17 (d, 1H, J=15.6 Hz, CH), 8.63-7.27 (m, 4H, Py-H), 6.02 (s, 2H, OCH2-O), 5.91 (s, H, ArH), 5.19 (t, 1H, J=6.9 Hz, CH), 5.19 (t, 1H, J=6.9 Hz, CH), 4.92 (s, 2H, OCH2-O), 3.83 (s, 3H, OCH3), 3.77 (s, 3H, CH2OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=7.1 Hz, CH2), 1.77 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 19: Preparation of 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone [compound (26HCl)], 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone [compound (27HCl)] and 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-2-yl-propenone [compound (28HCl)]

(152) ##STR00026##

(153) A solution of (25) (0.216 mmols) in MeOH/HCl 1.25 M (2.6 mL) was heated to 45 C. and maintained under these conditions, under stirring, for 1 h. The reaction mixture was evaporated at LP and at RT, obtaining a golden yellow crude oil (0.98 g) which was purified, after adsorption on 0.200 g of silica 230-400 mesh, by flash chromatography on silica gel column (silica 230-400 mesh, diameter 2 cm, height 15 cm) using chloroform/methanol 8:1 as eluent mixture. The hydrochlorides were obtained in succession by evaporation of the most significant fractions: first (26HCl) (0.013 g) as a yellow oil, then (27HCl) (0.022 g) as an orange-yellow oil, and finally (28HCl) (0.011 g) as a brownish-yellow solid.

(154) 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 8.39-9.27 (m, 4H, Py-H), 5.91 (s, H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0, (brs, H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(155) 1H-NMR (200 MHz, DMSO-d6): 7.95 (d, 1H, J=16 Hz, CH), 7.77 (d, 1H, J=16 Hz, CH), 8.35-9.22 (m, 4H, Py-H), 6.02 (s, 2H, OCH2-O), 5.87 (s, H, ArH), 5.21 (t, 1H, J=7 Hz, CH2CH), 3.94 (s, 3H, OCH3), 3.79 (s, 3H, CH2OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

(156) 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 8.39-9.27 (m, 4H, Py-H), 5.87 (s, H, ArH), 5.21 (t, 1H, J=7 Hz, CH2CH), 3.73 (s, 3H, OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

Example 20: Preparation of 3-(5-chloro-pyridin-3-yl)-1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone [compound (29)]

(157) ##STR00027##

(158) Similarly to compound (25), (29) was obtained as a golden yellow oil by condensing with 5-chloro-pyridin-2-carbaldehyde.

(159) 1H-NMR (200 MHz, CDCl3): 7.90 (d, 1H, J=15.6 Hz, =CHPy-H), 7.56 (d, 1H, J=15.6 Hz, CH), 8.72-8.03 (3m, 3H, Py-H), 6.02 (s, 2H, OCH2-O), 5.91 (s, H, ArH), 5.19 (t, 1H, J=6.9 Hz, CH), 5.19 (t, 1H, J=6.9 Hz, CH), 4.92 (s, 2H, OCH2-O), 3.79 (s, 3H, OCH3), 3.77 (s, 3H, CH2OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=7.1 Hz, CH2), 1.77 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 21: Preparation of 3-(5-chloro-pyridin-3-yl)-1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone [compound (30HCl)], 3-(5-chloro-pyridin-3-yl)-1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone [compound (31HCl)] and 3-(5-chloro-pyridin-3-yl)-1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-propenone [compound (32HCl)]

(160) ##STR00028##

(161) Similarly to (26)-(28), (30HCl)-(32HCl) were obtained from (29).

(162) 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 9.36-9.31 (m, 3H, Py-H), 5.91 (s, H, ArH), 5.30 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0, (brs, H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(163) 1H-NMR (200 MHz, DMSO-d6): 7.92 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 9.36-9.31 (m, 3H, Py-H), 6.02 (s, 2H, OCH2-O), 5.88 (s, H, ArH), 5.22 (t, 1H, J=7 Hz, CH2CH), 3.73 (s, 3H, OCH3), 3.79 (s, 3H, CH2OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

(164) 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, 1H, J=16 Hz, CH), 7.67 (d, 1H, J=16 Hz, CH), 9.36-9.31 (m, 3H, Py-H), 5.87 (s, H, ArH), 5.21 (t, 1H, J=7 Hz, CH2CH), 3.75 (s, 3H, OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

Example 22: Preparation of 1-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone [compound (33)]

(165) ##STR00029##

(166) Similarly to compound (25), (33) was obtained by condensing with pyridin-4-carbaldehyde.

(167) 1H-NMR (200 MHz, CDCl3): 7.88 (d, 1H, J=15.6 Hz, =CHPy-H), 7.866 (d, 1H, J=15.6 Hz, CH), 8.71-7.51 (2m, 4H, Py-H), 6.02 (s, 2H, OCH2-O), 5.91 (s, H, ArH), 5.19 (t, 1H, J=6.9 Hz, CH), 5.19 (t, 1H, J=6.9 Hz, CH), 4.92 (s, 2H, OCH2-O), 3.73 (s, 3H, OCH3), 3.77 (s, 3H, CH2OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=7.1 Hz, CH2), 1.77 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 23: Preparation of 1-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone [compound (34HCl)], 1-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone [compound (35HCl)] and 1-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-pyridin-4-yl-propenone [compound (36HCl)]

(168) ##STR00030##

(169) Similarly to (26)-(28), (34HCl)-(36HCl) were obtained from (33).

(170) 1H-NMR (200 MHz, DMSO-d6): 7.91 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 9.35-8.63 (m, 4H, Py-H), 5.91 (s, H, ArH), 5.30 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0, (brs, H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(171) 1H-NMR (200 MHz, DMSO-d6): 7.89 (d, 1H, J=16 Hz, CH), 7.53 (d, 1H, J=16 Hz, CH), 9.35-8.60 (2m, 4H, Py-H), 6.02 (s, 2H, OCH2-O), 5.87 (s, H, ArH), 5.22 (t, 1H, J=7 Hz, CH2CH), 3.73 (s, 3H, OCH3), 3.79 (s, 3H, CH2OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

(172) 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, 1H, J=16 Hz, CH), 7.56 d, 1H, J=16 Hz, CH), 9.35-8.60 (2m, 4H, Py-H), 5.85 (s, H, ArH), 5.21 (t, 1H, J=7 Hz, CH2CH), 3.75 (s, 3H, OCH3), 3.29 (d, 2H, J=7 Hz, CH2), 1.81 (s, 3H, CH3), 1.70 (s, 3H, CH3).

Example 24: Preparation of N-(4-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide [compound (37)]

(173) ##STR00031##

(174) Similarly to compound (25), (37) was obtained by condensing with N-(4-formyl-phenyl)-methanesulphonamide.

(175) 1H-NMR (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CHArH), 7.56 (d, 1H, J=15.6 Hz, CH), 7.05-6.41 (2m, 4H, ArH), 6.02 (s, 2H, OCH2-O), 5.91 (s, H, ArH), 5.19 (t, 1H, J=6.9 Hz, CH), 5.19 (t, 1H, J=6.9 Hz, CH), 4.92 (s, 2H, OCH2-O), 4.04 (s, NH), 3.73 (s, 3H, OCH3), 3.77 (s, 3H, CH2OCH3), 3.51 (s, 3H, CH2OCH3), 3.34 (d, 2H, J=7.1 Hz, CH2), 2.82 (s, 3H, SO2CH3), 1.77 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 25: Preparation of N-(4-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide [compound (38)], N-(4-{(3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide [compound (39)] and N-(4-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-phenyl)-methanesulphonamide [compound (40)]

(176) ##STR00032##

(177) Similarly to (22)-(24), (38)-(40) were obtained from (37).

(178) 1H-NMR (200 MHz, CDCl3): 8.00 (d, 1H, J=16 Hz, CH), 7.83 (d, 1H, J=16 Hz, CH), 7.05 e 6.41 (2m, 4H ArH), 5.91 (s, H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.01 (brs, H), 4.09 (brs, H, NH), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.82 (s, 3H, SO2CH3), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(179) 1H-NMR (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CH), 7.83 (d, 1H, J=16 Hz, CH), 7.12 e 6.41 (2m, 4H ArH), 5.87 (s, H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.1 (brs, H), 4.09 (brs, H, NH), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.82 (s, 3H, SO2CH3), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(180) 1H-NMR (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.06 e 6.42 (2m, 4H ArH), 5.87 (s, H, ArH), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0 (brs, 2H), 4.01 (brs, H, NH), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.82 (s, 3H, SO2CH3), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Preparation Example 26: 4-chloro-3-chlorosulphonylbenzoic acid [compound (41)]

(181) ##STR00033##

(182) 4-chlorobenzoic acid (2.85 mmols) was cautiously added to a flask containing chlorosulphonic acid (24.9 mmols), followed by NaCl (8.45 mmols) in small portions. When the addition was complete, the reaction mixture was heated to 160 C. for 5 hours. After that time the reaction mixture was poured into an ice bath, and the solid that separated was collected and extracted with AcOEt. The organic phase was dried on Na2SO4 and evaporated in a rotavapor to give (41) as a solid purified residue by crushing from anhydrous hexane. 1H-NMR (200 MHz, CDCl3): 8.76 (m, 1H), 8.49 (m, 1H), 7.62 (t, 1H).

Preparation Example 27: 4-chloro-3-sulphamoyl benzoic acid [compound (42)]

(183) ##STR00034##

(184) A 2M solution of NH3 in methanol (20 mL) was added to (41) (10 g) and left under stirring at RT for 24 hours. After that time the resulting mixture was concentrated at LP to 50% of its volume, to obtain the formation of a precipitate which was filtered and washed with small portions of MeOH to obtain (42), which was used without further purifications in the subsequent steps.

Preparation Example 28

(185) Sulphonamides (43)-(46) were obtained similarly to (42)

(186) ##STR00035##

Preparation Example 29: Ethyl 4-chloro-3-sulphamoyl benzoate [compound (47)]

(187) ##STR00036##

(188) Gaseous HCl was bubbled through a solution of (42) (53 mmol) in 125 mL of absolute ethanol for 3 minutes. The resulting suspension was then refluxed for 16 hours. After that time the solvent was evaporated at LP to obtain (47) as a solid which was used as is in the subsequent reactions.

Preparation Example 30: Preparation of 2-chloro-5-hydroxymethyl-benzenesulphonamide [compound (48)]

(189) ##STR00037##

(190) A 2M solution of LiBH4 (49.7 mL) in THF was cautiously added, drop by drop, to a solution of ethyl ester (47) (41.5 mmol) in anhydrous THF (120 mL). The mixture was stirred under reflux for 20 hours, carefully diluted with ice and water (100 mL), cooled to 4 C. for 24 hours and filtered to give (48) (7.2 g) as a white solid.

Preparation Example 31: Preparation of 2-chloro-5-formyl-benzenesulphonamide [compound (49)]

(191) ##STR00038##

(192) MnO2 (31 g, 5.356 mmol) was added to a vigorously stirred solution of benzyl alcohol (48) (70 mmol) in THF (150 mL). The resulting suspension was reflux heated for 16 hours, filtered through celite and concentrated until dry at low pressure using a rotavapor. The semisolid residue obtained was crushed with hexane to provide the desired aldehyde (49), which was used in the subsequent steps without further purification.

Example 32: Preparation of 2-chloro-5-{3-[2-hydroxy-6-methoxy-4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide [compound (50)], 2-chloro-5-{3-[4-hydroxy-6-methoxy-2-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide [compound (51)], and 2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide [compound (52)]

(193) ##STR00039##

(194) Similarly to (22)-(24), (50)-(52) are obtained from (53).

(195) 1H-NMR (200 MHz, CDCl3): 7.91 (d, 1H, J=16 Hz, CH), 7.89 (d, 1H, J=16 Hz, CH), 7.90, 7.45 e 7.50 (3m, 3H ArH), 5.91 (s, H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.01 (brs, H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.12 (brs, 2H, SO2NH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(196) 1H-NMR (200 MHz, CDCl3 7.93 (d, 1H, J=16 Hz, CH), 7.88 (d, 1H, J=16 Hz, CH), 7.91, 7.50 e 7.48 (3m, 3H ArH), 5.87 (s, H, ArH), 5.28 (s, 2H, OCH2-O), 5.20 (t, 1H, J=6 Hz, CH2CH), 4.90 (brs, H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.01 (brs, 2H, SO2NH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(197) 1H-NMR (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.91, 7.50, e 7.42 (3m, 3H ArH), 5.87 (s, H, ArH), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0 (brs, 2H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.82 (s, 3H, SO2CH3), 2.01 (brs, 2H, SO2NH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 33: Preparation of 2-chloro-5-{3-[6-methoxy-2,4-bis-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide [compound (53)]

(198) ##STR00040##

(199) (53) is obtained by condensing (4a) with (49) under the same conditions as used for (6).

(200) 1H-NMR (200 MHz, CDCl3): 7.93 (d, 1H, J=16 Hz, CH), 7.88 (d, 1H, J=16 Hz, CH), 7.91, 7.50 e 7.48 (3m, 3H ArH), 5.87 (s, H, ArH), 5.24 (s, 2H, OCH2-O), 5.14 (t, 1H, J=6.9 Hz, CH2CH), 4.90 (s, 2H, OCH2-O), 3.77 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.41 (s, 3H, CH2OCH3), 3.32 (d, 2H, J=6.9 Hz, CH2), 2.01 (brs, 2H, SO2NH2), 1.76 (s, 3H, CH3), 1.68 (s, 3H, CH3).

Example 34: Preparation of 2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonamide [compound (52)] and 2-chloro-5-[3-(5-hydroxy-7-methoxy-2,2-dimethyl-chroman-6-yl)-3-oxo-propenyl]-benzenesulphonamide [compound (54)]

(201) ##STR00041##

(202) By operating on (53) under the same conditions as for (8a) and (8b), a mixture of (52) and (54) was obtained which were separated on an Isolute Si II 5 g flash chromatography column, using n-hexane/AcOEt in the ratio of 9:1 as eluent mixture.

(203) (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.91, 7.50, e 7.42 (3m, 3H ArH), 5.87 (s, H, ArH), 5.20 (t, 1H, J=6 Hz, CH2CH), 5.0 (brs, 2H), 3.92 (s, 3H, CH2OCH3), 3.91 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 2.82 (s, 3H, SO2CH3), 2.01 (brs, 2H, SO2NH2), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3).

(204) (200 MHz, CDCl3): 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.91, 7.50 e 7.20 (3m, 3H ArH), 5.98 (s, H, ArH), 5.0 (brs, H), 3.73 (s, 3H, OCH3), 2.84 (brs, 2H, SO2NH2), 2.55 e 1.96 (4H, 2 CH2), 1.66 (s, 3H, CH3), 1.48 (s, 3H, CH3).

(205) ##STR00042##

Example 35: Preparation of [1-(2-chloro-5-{3-[6-methoxy-2,4-methoxymethoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonylaminocarbonyl)-propyl]-benzyl-carbamate [compound (56)]

(206) CBZ aminoacid (55) (2-(N-benzyloxycarbonylamino)butyric acid) (25 mmol), dimethylaminopyridine (50 mmol) and the condensing agent EDCI (25 mmol) were added to a solution of (53) (22 mmol) dissolved in anhydrous DMF (50 mL) cooled to 0 C. and maintained under Ar atmosphere. When the addition was complete, the reaction mixture was heated to room temperature and left under stirring under those conditions for 5 hours. At the end of that time, after TLC monitoring the mixture was evaporated at LP and at a temperature of less than 20 C. using a mechanical pump operating at 0.05 mmHg. The semisolid residue was chromatographed on a silica gel column, eluting with a CHCl3/MeOH 8:1 mixture. A solid residue, mainly consisting of pure (56), was obtained from the most significant intermediate fraction (TLC).

(207) (200 MHz, CDCl3): 8.20 (brs, 1H, SO2NHCO), 8.0 (brs, H, NHCO), 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.91, 7.50, e 7.42 (3m, 3H ArH), 7.19 (m, 5H, Ar); 5.87 (s, H, ArH), 5.30 (s, 2H, CH2Ar), 5.24 (s, 2H, OCH2-O), 5.14 (t, 1H, J=6.9 Hz, CH2CH), 4.90 (s, 2H, OCH2-O), 4.53 (m, H), 3.77 (s, 3H, OCH3), 3.50 (s, 3H, CH2OCH3), 3.41 (s, 3H, CH2OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.83 (m, 2H), 1.80 (s, 3H, CH3), 1.68 (s, 3H, CH3), 0.96 (m, 3H).

Example 36: Preparation of [1-(2-chloro-5-{3-[2,4-dihydroxy-6-methoxy-3-(3-methyl-but-2-enyl)-phenyl]-3-oxo-propenyl}-benzenesulphonyl-aminocarbonyl)-propyl]-benzyl-carbamate [compound (57)]

(208) When (56) was treated similarly to the preparation of (22)-(24) of example 17, (57) was obtained as a vitreous residue.

(209) (200 MHz, CDCl3): 8.20 (brs, 1H, SO2NHCO), 8.0 (brs, H, NHCO), 7.90 (d, 1H, J=16 Hz, CH), 7.56 (d, 1H, J=16 Hz, CH), 7.91, 7.50, e 7.42 (3m, 3H ArH), 7.19 (m, 5H, Ar); 5.87 (s, H, ArH), 5.30 (s, 2H, CH2Ar), 5.24 5.14 (t, 1H, J=6.9 Hz, CH2CH), 5.0 (brs, 2H), 4.53 (m, H), 3.77 (s, 3H, OCH3), 3.32 (d, 2H, J=6 Hz, CH2), 1.83 (m, 2H), 1.83 (s, 3H, CH3), 1.68 (s, 3H, CH3), 0.96 (m, 3H).

(210) Compounds 58, 59, 61, 62 and 64-67 were prepared in a one-pot reaction from their precursors, using the same reaction conditions as described for compounds 10 and 11.

(211) Compounds 60 and 63 were prepared using higher temperatures (85 C.) and longer times (48 hours) than for their analogues 18 and 21.

Example 37: Biological Activity of Synthetic Analogues of Xanthohumol

(212) The following table shows the correspondences between the codes of the compounds shown in FIGS. 5-12 and their numbering in accordance with examples 1-36.

(213) TABLE-US-00001 TABLE Correspondences between codes of inhibitors and their numbering Code Numbering XN Xanthohumol EN233 7 EN234 8a LR6 10 LR7 11 LR10 13 LR14 18 LR15 19 LR16 20 LR17 21 LR18 22 LR18b 23 LR19 24

(214) MTT Assay

(215) The viability of the HUVEC cells was evaluated with the MTT colorimetric assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The cells (1000/well) were plated in complete medium in 96-well plates, and after complete adherence the medium was replaced with a new medium with or without the various inhibitors at different concentrations. The plates were processed at different incubation times (24, 48, 72 and 96 hours), and the absorbance was measured at 570 nm.

(216) Results:

(217) Significant inhibition of cell growth was observed in the presence of compounds LR6 (10) and LR7 (11) at the concentration of 20 M after only 24 hours' treatment. Compound LR6, used at the concentration of 10 M, proved able to reduce cell proliferation after 72 and 96 hours' treatment. At higher concentrations (10 and 20 M), compound LR7 exhibited cytostatic activity after only 48 hours' incubation. At lower concentrations (1-100 nM and 1 M), the inhibitors exhibited no significant effect on cell proliferation. The results are shown in FIG. 1.

(218) Migration Assay

(219) The chemotaxis assay was conducted with Boyden chambers [Albini A, Iwamoto Y, Kleinman H K, Martin G R, Aaronson S A, Kozlowski J M, McEwan R N. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987 Jun. 15; 47(12):3239-45; Albini A, Benelli R. The chemoinvasion assay: a method to assess tumor and endothelial cell invasion and its modulation. Nat Protoc. 2007; 2(3):504-11]. The HUVEC cells (510.sup.4) were pre-treated for 24 hours with the inhibitors, resuspended in serum-free medium, and plated in the upper compartment of the Boyden chamber. The complete medium was added in the lower compartment of the chamber, and used as chemoattractant. The two chambers were separated by polycarbonate filters (12 M) coated with collagen (50 g/mL). After 6 hours' incubation at 37 C., the filters were recovered, the cells present on the upper surface of the filter were mechanically removed, and those on the lower surface were fixed in absolute ethanol and stained with DAPI. The cells were then counted in eight consecutive fields on each filter by fluorescence microscopy.

(220) Results:

(221) Significant inhibition of migration (*P<0.05) of the HUVEC cells was observed after 24 hours' pre-treatment with inhibitors LR6. (10) and LR7 (11) at the concentrations of 10 M and 20 M. The results are shown in FIG. 2. XN was used as control.

(222) Invasion Assay

(223) The chemoinvasion assay was conducted with Boyden chambers [Albini A, Iwamoto Y, Kleinman H K, Martin G R, Aaronson S A, Kozlowski J M, McEwan R N. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987 Jun. 15; 47(12):3239-45; Albini A, Benelli R. The chemoinvasion assay: a method to assess tumor and endothelial cell invasion and its modulation. Nat Protoc. 2007; 2(3):504-11]. The HUVEC cells (510.sup.4) were pre-treated for 24 hours with the inhibitors, resuspended in serum-free medium, and plated in the upper compartment of the chamber. The complete medium was added in the lower compartment of the chamber, and used as chemoattractant. The 12 m polycarbonate filters were coated with matrigel (1 mg/mL). After 18 hours' incubation, the cells in the upper compartment of the chamber were mechanically removed, while those adhering to the lower surface of the filter were fixed in absolute ethanol and stained with DAPI. The cells were counted double-blind in eight consecutive fields by fluorescence microscopy.

(224) Results:

(225) 24 hours' pre-treatment with inhibitors LR6 (10) and LR7 (11) significantly reduces invasion in the presence of serum (FBS, Foetal Bovine Serum) (*P<0.05), even at low concentrations (10 M). The results are shown in FIG. 3.

(226) Morphogenesis

(227) A 24-well plate was coated with 300 l/well of liquid matrigel (10 mg/mL) at 4 C., using cold pipettes and avoiding bubbles. The plate was then incubated for one hour at 37 C., until the matrigel polymerised. The HUVEC cells, pre-treated with the different inhibitors, were resuspended in 1 mL of complete medium and then plated in the different wells. The serum-free medium was used as negative control (CTRL). After 6 hours' incubation, the organisation of the cells in capillary-like structures was examined with an inverted microscope equipped with a camera for the acquisition of images and a digital analysis system.

(228) Results:

(229) The HUVEC cells tend to organise themselves into capillary-like structures when plated on a layer of matrigel, imitating in vitro the events that take place in vivo during angiogenesis. 24 hours' pre-treatment with inhibitors LR6 (10) and LR7 (11) interferes with FBS-dependent morphogenesis. Xanthohumol (XN) was used as control. The results are shown in FIG. 4.

(230) Apoptosis Assay

(231) The HUVEC cells (110.sup.5) were plated in six-well plates and left to adhere for 18 hours. The next day, the cells were pre-treated with inhibitors LR6 and LR7 (10 M) in the presence of complete medium. After 24 hours, the cells were detached, washed with PBS and transferred to tubes for cytofluorimetric analysis. The cells were pelletted and resuspended in Annexin V-binding buffer (0.01M HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid) (pH 7.4); 0.14 M NaCl; 2.5 mM CaCl.sub.2. Fluorescein isothiocyanate Annexin V and 7-amino-actinomycin D were added to the tubes, and the cells were incubated for 15 minutes at room temperature in the dark. The cells were then washed in PBS, the supernatant was removed and the cells resuspended in 400 mL of binding buffer. The samples were analysed on a FACSCanto cytofluorimeter (BD Biosciences), and analysed with FACSDiva Software 6.1.2.

(232) Results:

(233) The endothelial cells treated for 24 hours with inhibitors LR6 (10) and LR7 (11) at the concentration of 10 M presented a high percentage of viability (about 90%) and absence of apoptosis (FIG. 5). The data obtained suggest that the inhibitors are non-toxic, and do not induce apoptosis in endothelial cells. The results are shown in FIG. 5. XN was used as control.

(234) The cumulative comparison tables of the biological activities of XN and its synthetic analogues are reported in FIGS. 6-8.

(235) Invasion AssaysHUVEC Pre-Treated for 24 Hours; Values Standardised on Control

(236) As shown in FIG. 6, the XN control at the concentration of 10 M reduces endothelial cell invasion by about 60%; some of the novel derivatives, such as LR16 and LR17, at the same concentration, exhibit a greater inhibitory effect (a reduction of about 80% and 75% respectively). The inhibitory effect of the novel compounds is most evident at the concentration of 20 M.

(237) Migration AssaysHUVEC Pre-Treated for 24 Hours; Values Standardised on Control

(238) As shown in FIG. 7, the XN control at the concentration of 10 M reduces endothelial cell migration by about 50%; some of the novel derivatives, such as LR19 and LR6, at the same concentration, exhibit a greater inhibitory effect (a reduction of about 80% and 75% respectively). The inhibitory effect of the novel compounds is most evident at the concentration of 20 M.