SILVERED RESVERATROL DERIVATIVES AND THEIR USE IN NEURODEGENERATIVE, NEUROLOGICAL OR INFLAMMATORY DI

专利摘要:
Silylated derivatives of resveratrol and its use in neurodegenerative, neurological or inflammatory diseases. The present invention relates to a group of compounds derived from resveratrol which have as substituents at least one silyl group which in turn can be substituted by different groups. The invention also relates to the therapeutic use of these compounds in inflammatory, neurological and neurodegenerative diseases. (Machine-translation by Google Translate, not legally binding)
公开号:ES2674744A1
申请号:ES201631535
申请日:2016-11-30
公开日:2018-07-03
发明作者:Juan Carlos Morales Sánchez；Pablo PEÑALVER PUENTE；Efres BELMONTE RECHE；Elena GONZÁLEZ REY；Maria Luisa MATEOS MARTÍN
申请人:Consejo Superior de Investigaciones Cientificas CSIC；
IPC主号:

专利说明:

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Silylated derivatives of resveratrol and their use in neurodegenerative, neurological or inflammatory diseases
DESCRIPTION
The present invention relates to a group of compounds derived from resveratrol which have as substituents at least one silyl group which in turn can be substituted by different groups. The invention also relates to the therapeutic use of these compounds in inflammatory, neurological and neurodegenerative diseases. Therefore, the present invention is encompassed in the field of pharmaceutical chemistry and pharmacology.
STATE OF THE TECHNIQUE
Resveratrol is a phenolic compound. The chemical structure of the phenolic compounds consists of at least one aromatic ring and a hydroxyl group. And within the phenolic compounds resveratrol is a stilbene, characterized in that this group of phenolic compounds have a structure of two phenolic rings joined by two carbon atoms (C6-C2-C6). Resveratrol is present in grapes and derived products such as wine, and other foods, although in much smaller quantities, such as peanuts and some berries. In these foods, it is free or as piceid (resveratrol-3-O-glycoside). This compound has antioxidant, anti-inflammatory and anti-tumor properties that prolong the longevity of the cells.
Resveratrol has chemopreventive cancer activity in trials that represent three main stages of carcinogenesis: it acts as an antioxidant and antimutagen, it has anti-inflammatory effects and it inhibits cyclooxygenase (COX) and hydroperoxidase, and induces cell differentiation in human promyelocytic leukemia. In addition, as indicated above, resveratrol has been studied extensively for its correlation with the cardiovascular utility of red wine. Neurological uses for resveratrol have also been proposed.
Taking into account the amount of beneficial physiological effects that resveratrol presents, there are numerous projects that have focused on obtaining derivatives of this molecule that improve its health properties. In the document Int.
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Immunopharmacology 25 (2015) 528-537, the anti-inflammatory properties of various resveratrol derivatives and their potential one as neuroinflammation inhibitors are studied.
In J. Med. Chem 2010 July 8; 53 (13): 5033-5043, the synthesis of sulfated resveratrol derivatives and their effect on various physiological activities such as TNF-a inhibition or cyclooxygenase activity is described.
WO2011 / 073482 describes derivatives of resveratrol that contain glycidic substituents and that have the capacity to modulate inflammation, especially in intestinal pathologies such as irritable bowel or Crohn's disease.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to the use of a compound of formula (I):
image 1
where R4, R5 and R6 are independently selected from linear C1-C6 alkyl or
branched or a phenyl group and R7 is a linear or branched C1-C12 alkyl,
with the proviso that at least one of R1, R2 and R3 is a group SiR4R5R6;
for the manufacture of a medicine for the treatment or prevention of
inflammatory, neurological or neurodegenerative diseases.
In a preferred embodiment, R1 and R2 are a SiR4R5R6 group.
In a more preferred embodiment, R3 is H.
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In another more preferred embodiment, R3 is -NH (CO) R7.
In another more preferred embodiment, R3 is the following carbohydrate:
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R8 is selected from H or -C (O) -R9 with R9 being a C1-C22 alkyl group or a C2-C22 alkenyl group.
In a more preferred embodiment when R1 and R2 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment R4, R5 and R6 are ethyl. In another more preferred embodiment R4, R5 and R6 are isopropyl.
In another preferred embodiment, R1 and R3 are a SiR4R5R6 group.
In a more preferred embodiment, R2 is H.
In another more preferred embodiment, R2 is -NH (CO) R7.
In another more preferred embodiment R2 is the following carbohydrate:
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R8 is selected from H or -C (O) -R9 with R9 being a C1-C22 alkyl group or a C2-C22 alkenyl group.
In a more preferred embodiment when R1 and R3 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment R4, R5 and R6 are ethyl. In another more preferred embodiment R4, R5 and R6 are isopropyl.
In another preferred embodiment, R1, R2 and R3 are a SiR4R5R6 group.
In a more preferred embodiment when R1, R2 and R3 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment R4, R5 and R6 are ethyl. In another more preferred embodiment R4, R5 and R6 are isopropyl.
In another preferred embodiment, the compound of formula (I) is selected from the following group:
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In a preferred embodiment, the neurological or neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, temporal fronto-dementia, ischemia and epilepsy.
Another aspect of the invention relates to a compound of formula (I ’):
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image17
wherein R4, R5 and R6 are independently selected from linear or branched C1-C6 alkyl or a phenyl group and R7 is a linear or branched C1-C12 alkyl, with the proviso that at least one of R1, R2 and R3 is a group SiR4R5R6 and
that it is not one of the following compounds:
- (E) - (5- (4- (trimethylsilyloxy) styryl) -1,3-phenylene) bis (oxy) bis (trimethylsilane),
- (E) -4- (3,5-bis (triisopropylsilyloxy) styryl) phenol,
- (E) -3- (te / f-butyldimethylsilyloxy) -5- (4- (te / f-butyldimethylsilyloxy) styryl) phenol,
- (E) -4- (3,5-bis (te / f-butyldimethylsilyloxy) styryl) phenol,
- (E) -3- (te / f-Butyldimethylsilyloxy) -5- (4-hydroxystyryl) phenol,
- (E) -5- (4- (tert-butyldimethylsilyloxy) styryl) benzene-1,3-diol,
- (E) - (5- (4- (fe / f-butyldimethylsilyloxy) styryl) -1,3-phenylene) bis (oxy) bis (fe / f-butyldimethylsilane).
In a preferred embodiment, R1 and R2 are a SiR4R5R6 group.
In a more preferred embodiment, R3 is H.
In another more preferred embodiment, R3 is -NH (CO) R7.
In another more preferred embodiment, R3 is the following carbohydrate:
image18
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where R8 is selected from H or -C (O) -R9 where R9 is a C1-C22 alkyl group or a C1-C22 alkenyl group.
In a more preferred embodiment when R1 and R2 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment R4, R5 and R6 are ethyl. In another more preferred embodiment R4, R5 and R6 are isopropyl.
In another preferred embodiment, R1 and R3 are a SiR4R5R6 group.
In a more preferred embodiment, R2 is H.
In another more preferred embodiment, R2 is -NH (CO) R7.
In another more preferred embodiment, R2 is the following carbohydrate:
image19
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R8 is selected from H or -C (O) -R9 with R9 being a C1-C22 alkyl group or a C1-C22 alkenyl group.
In a more preferred embodiment when R1 and R3 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment R4, R5 and R6 are ethyl. In another more preferred embodiment R4, R5 and R6 are isopropyl.
In another preferred embodiment, R1, R2 and R3 are a SiR4R5R6 group.
In a more preferred embodiment when R1, R2 and R3 are a SiR4R5R6 group, R4 and R5 are methyl and R6 is tert-butyl. In another more preferred embodiment, R4, R5 and R6 are ethyl. In another more preferred embodiment, R4, R5 and R6 are isopropyl.
In another more preferred embodiment of the substituents that are the group SiR4R5R6, R4 and R5 are phenyl and R6 is tert-butyl. And in another more preferred embodiment, R4, R5 and R6 are methyl.
In a preferred embodiment, the compound of formula (I ’) is selected from the following group:
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Another aspect of the invention relates to the use of the compound of formula (I ’) described above for the manufacture of a medicament.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I ’) as described above.
Another aspect of the invention relates to a method of treating an inflammatory, neurological or neurodegenerative disease comprising the administration of a therapeutically effective amount of a compound of formula (I) or (I ’) to a patient in need.
In the sense used in this description, the term "therapeutically effective amount" refers to the sufficient amount of active compound to produce the desired effect in which the symptoms of the disease are attenuated. The dose should not be used in proportions that cause unwanted side effects, whose clinical assessment makes them adverse and not therapeutically treatable.The dose will generally vary with the age, condition, sex and extent of the disease in the patient as well as with the route and frequency of administration and can be determined in each case .
The term "alkyl" refers, in the present invention, to hydrocarbon radicals, linear or branched, having 1 to 22 carbon atoms, preferably 1 to 12 and more preferably 1 to 6, and which bind the rest of the molecule by a single bond, for example, propyl, ethyl, methyl, isopropyl, undecanoyl, heptadecanoyl, octadecanoyl, etc. These alkyl radicals may be
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optionally substituted in one or more positions by one or more groups such as hydroxyl, amines, amides, oxo, cyano, halogens, aryl, etc.
The term "alkenyl" refers, in the present invention, to unsaturated, linear or branched aliphatic chains, having 2 to 22 carbon atoms, and having between one and six unsaturations, depending on the number of carbons, for example, not limited to vinyl, allyl, oleyl, linoleyl, linolenyl, eicosapentaenoyl, docosahexaenoyl, etc. These alkyl radicals may be optionally substituted in one or more positions by one or more groups such as hydroxyl, amines, amides, oxo, cyano, halogens, aryl, etc.
The compounds of the present invention represented by the formula (I) and (I '), and more specifically, the specific compounds belonging to this general formula described above may include isomers, depending on the presence of multiple bonds (e.g., Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
The compounds of the invention may be in crystalline form as free compounds or as solvates and both forms are intended to be within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) or (I ') that can be used in the manufacture of a medicament, such as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods well known to those skilled in the art.
For application in therapy, the compounds of formula (I) or (I '), their isomers, salts or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically pure level acceptable excluding normal pharmaceutical additives such
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as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I) or (I ’), or of its isomers, salts or solvates.
Unless otherwise indicated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having such a structure, with the exception of replacing a hydrogen with a deuterium or tritium, or replacing a carbon with a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.
The compounds of formula (I) or (I ’) for therapeutic use are prepared in solid form or aqueous suspension, in a pharmaceutically acceptable diluent. These preparations may be administered by any appropriate route of administration, for which said preparation will be formulated in the pharmaceutical form appropriate to the route of administration chosen. For example, the compounds of formula (I) or (I ') will be combined with excipients such as starch or lactose or adjuvants such as cyclodextrins as well as any type of pharmaceutical carriers known to one skilled in the art for the preparation of solid formulations or liquid In a particular embodiment, the administration of the compound of formula (I) or (I ') provided by this invention is carried out orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.). A review of the different pharmaceutical forms of medication administration and of the excipients necessary to obtain them can be found, for example, in the "Galician Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, SA Ediciones , Madrid, or in other habitual or similar ones of the Spanish, European or American Pharmacopoeias.
The compounds described in the present invention, their pharmaceutically acceptable salts, and solvates, as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Such additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to that of the drug.
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Pharmaceutical composition comprising a compound of formula (I) or (I ’), or an isomer, solvate or a pharmaceutically acceptable salt thereof.
Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. Cellular viability in neuroblastoma SH-SY5Y after damage with H2O2 and
treatment with the different compounds 2-9. The controls are DMSO: 1% DMSO; H2O2: H2O2 in 1% DMSO; RES 10 uM + H2O2: resveratrol in H2O2 in 1% DMSO.
FIG. 2. Cell viability in neuroblastoma SH-SY5Y after damage with H2O2 and
treatment with the different compounds 10-11. The controls are DMSO: 1% DMSO; H2O2: H2O2 in 1% DMSO; RES 10 uM + H2O2: resveratrol in H2O2 in 1% DMSO.
FIG. 3. Cell viability in neuroblastoma SH-SY5Y after damage with H2O2 and
treatment with the different compounds 12-13. The controls are DMSO: 1% DMSO; H2O2: H2O2 in 1% DMSO; RES 10 uM + H2O2: resveratrol in H2O2 in 1% DMSO.
FIG. 4. Cell viability in neuroblastoma SH-SY5Y after damage with H2O2 and
treatment with the different compounds 14-15. The controls are DMSO: 1% DMSO; H2O2: H2O2 in 1% DMSO; RES 10 uM + H2O2: resveratrol in H2O2 in 1% DMSO.
FIG. 5. Cell viability in neuroblastoma SH-SY5Y after damage with H2O2 and
treatment with the different compounds 16-20. The controls are DMSO: 1% DMSO; H2O2: H2O2 in 1% DMSO; RES 10 uM + H2O2: resveratrol in H2O2 in 1% DMSO.
FIG. 6. Cell viability in RAW macrophages after inflammation produced with LPS and treatment with the different compounds 2-9. The controls are DMSO: 1% DMSO; LPS alone: LPS (100 ng / mL); LPS + RES 10 uM: LPS (100 ng / mL) + resveratrol.
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FIG. 7. Cellular viability in RAW macrophages after inflammation produced with LPS and treatment with the different compounds 10-11. The controls are DMSO: 1% DMSO; LPS alone: LPS (100 ng / mL); LPS + RES 10 uM: LPS (100 ng / mL) + resveratrol.
FIG. 8. Cellular viability in RAW macrophages after inflammation produced with LPS and treatment with the different compounds 12-13. The controls are DMSO: 1% DMSO; LPS alone: LPS (100 ng / mL); LPS + RES 10 uM: LPS (100 ng / mL) + resveratrol.
FIG. 9. Cellular viability in RAW macrophages after inflammation produced with LPS and treatment with the different compounds 14-15. The controls are DMSO: 1% DMSO; LPS alone: LPS (100 ng / mL); LPS + RES 10 uM: LPS (100 ng / mL) + resveratrol.
FIG. 10. Cellular viability in RAW macrophages after inflammation produced with LPS and treatment with the different compounds 16-20. The controls are DMSO: 1% DMSO; LPS alone: LPS (100 ng / mL); LPS + RES 10 uM: LPS (100 ng / mL) + resveratrol.
FIG. 11. Concentration of TNF-alpha in culture medium after LPS inflammation in RAW macrophages and treatment with the different compounds 2-9.
FIG. 12. Concentration of NO in culture medium after LPS inflammation in RAW macrophages and treatment with the different compounds 2-9.
FIG. 13. Concentration of IL6 in culture medium after LPS inflammation in RAW macrophages and treatment with the different compounds 2-9.
FIG. 14. AChE activity with respect to the control of RES, 6, 8 and 9 compounds. An ANOVA statistical test was carried out followed by Dunnett's multiple comparison test. Significance is considered when #P <0.05 with respect to the Control; * P <0.05, ** P <0.01 with respect to Control + PTZ.
FIG. 15. AChE activity with respect to the control of RES compounds, 11, 14, 15 and 17. An ANOVA statistical test was carried out followed by Dunnett's multiple comparison test. Significance is considered when #P <0.05 with respect to the Control; * P <0.05, ** P <0.01 with respect to Control + PTZ.
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EXAMPLES
The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the product of the invention.
Example 1: synthesis of silylated derivatives of resveratrol.
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General silylation method.
Resveratrol (1 eq.) And imidazole (2.5 eq.) Was added to a round bottom flask with DMF (3 ml / mmol of resveratrol) under stirring and cooled to 0 ° C. The corresponding silyl chloride (1.4-1.55 eq.) Was then added dropwise in two batches, the first half at t = 0 h and the second half at t = 3 h. The reaction was stirred for a total of 6 h at room temperature. Then the reaction mixture was filtered, diluted in water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried with MgSO4, filtered, concentrated to dryness and purified by silica gel column chromatography eluting with hexane / ethyl acetate mixtures.
Series of tertbutyldimethylsilyl resveratrol derivatives.
Following the general method, resveratrol (830 mg, 3.64 mmol) and terbutyldimethylsilyl chloride (849.55 mg, 5.64 mmol) were used to obtain compounds 1, 2 and 3 in addition to the monosilylated derivatives after purifying the mixture Reaction by column chromatography using a gradient of hexane / ethyl acetate (8: 1 to 2: 1).
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3,4 ', 5-O-tri-tertbutyldimethylsilyl resveratrol, compound 1. Yield = 5.8%; Rf = 0.9 (Hexane: ethyl acetate - 7: 3).
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3,4’-O-di-tertbutyldimethylsilyl resveratrol, compound 2. Yield = 22.1%; Rf = 0.65 (Hexane: ethyl acetate - 7: 3).
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3,5-O-di-tertbutyldimethylsilyl resveratrol, compound 3. Yield = 6.4%; Rf = 0.55 (Hexane: ethyl acetate - 7: 3).
15 Series of triisopropylsilyl resveratrol derivatives.
Following the general method, resveratrol (816 mg, 3.57 mmol) and triisopropylsilyl chloride (1.19 mL, 5.54 mmol) were used to obtain compounds 4, 5 and 6, in addition to the monosilylated derivatives after purifying the reaction mixture by column chromatography using a gradient of hexane / ethyl acetate (10: 1 to 1: 1).
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3,4 ', 5-O-tri-triisopropylsilyl resveratrol, compound 4. Yield = 19.4%; Rf = 0.9 (Hexane: ethyl acetate - 3: 1). 1H NMR (400 MHz, CDCfe): 5 = 7.47 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 16.2 Hz, 1H, CH), 6.95 (dd, J = 12.4, 6.4 Hz, 3H , CH and H), 6.74 (s, 2H, H2 and H6), 6.44 (s, 1H, H4), 1.41 - 1.33 (m, 9H, CH-Si), 1.29 - 1.16 (m, 54H, 5 CH3) . 13C NMR (101 MHz, CDCl3): 5 = 157.10, 155.96, 139.44, 130.45, 128.39,
127.73, 126.83, 120.17, 111.26, 110.94, 18.02, 12.78.
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10 3,4’-O-di-triisopropylsilyl resveratrol, compound 5. Yield = 26.1%; Rf = 0.65
(Hexane: ethyl acetate - 3: 1). 1H NMR (400 MHz, CDCh): 5 = 7.34 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 16.2 Hz, 1H), 6.83 (t, J = 12.0 Hz, 3H), 6.64 ( s, 1H), 6.55 (s, 1H), 6.33 (s, 1H), 1.30-1.22 (m, 6H), 1.11 (dd, J = 16.0, 7.4 Hz, 36H). 13C NMR (101 MHz, CDCl3): 5 = 158.14, 157.12, 155.68, 139.63, 130.56, 127.98, 127.47, 126.57, 15 119.77, 109.57, 106.15, 106.06, 17.40, 17.37, 17.10, 12.62, 12.59, 12.32. TOF MS-
ES, calculated mass: C32H51O3Si2 [M - H] = 539.3377, found mass: [M - H] = 539.3390.
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3,5-O-di-triisopropylsilyl resveratrol, compound 6. Yield = 8.7%; Rf = 0.5 (Hexane: ethyl acetate - 3: 1).
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Series of derivatives of triethylsilyl resveratrol.
Following the general method, resveratrol (809 mg, 3.54 mmol) and ethylsilyl chloride (0.92 mL, 5.49 mmol) were used to obtain compounds 7, 8 and 9, in addition to the
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monosilylated derivatives after purifying the reaction mixture by column chromatography using a gradient of hexane / ethyl acetate (10: 1 to 1: 1).
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3,4 ', 5-O-tri-triethylsilyl resveratrol, compound 7. Yield = 3.8%; Rf = 0.95 (Hexane: ethyl acetate - 3: 1). 1H NMR (400 MHz, CDCfe): 5 = 7.40 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 16.2 Hz, 1H), 6.90 - 6.82 (m, 3H), 6.64 (d, J = 2.0 Hz, 2H), 6.31 (t, J = 2.0 Hz, 1H), 1.04 (td, J = 7.8, 2.8 Hz, 26H), 0.78 (q, J = 7.9 Hz, 18H). 13C NMR (101 MHz, CDCl3): 5 = 156.61, 155.45, 139.48, 130.60, 128.44, 127.73, 126.76, 120.17, 111.41, 110.93, 6.66, 5.03. calculated mass: C32H55O3Si3 [M + H] = 571.3459, found mass: [M + H] = 571.3460.
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3,4’-O-di-triethylsilyl resveratrol, compound 8. Yield = 14.9%; Rf = 0.6 (Hexane: ethyl acetate - 3: 1). 1H NMR (400 MHz, CDCl3): 5 = 7.40 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 16.2 Hz, 1H), 6.91 - 6.82 (m, 3H), 6.62 (s, 1H ), 6.61 (s, 1H), 6.32 (s, 1H), 1.09 - 1.02 (m, 18H), 0.80 (q, J = 7.9 Hz, 12H). 13C NMR (101 MHz, CDCl3): 5 = 156.92, 156.69, 155.45, 139.94, 130.58, 128.82, 127.83, 126.47, 120.25, 110.96, 106.52, 106.40, 6.67, 6.64, 5.03. TOF MS-ES +, calculated mass: C26H41O3Si2 [M + H] = 457.2594, found mass: [M + H] = 457.2593.
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3,5-O-di-triethylsilyl resveratrol, compound 9. Yield = 6.8%; Rf = 0.5 (Hexane: ethyl acetate - 3: 1). 1H NMR (400 MHz, CDCl3): 7.37 (d, J = 8.3 Hz, 2H), 6.96 (d,
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J = 16.2 Hz, 1H), 6.82 (t, J = 12.6 Hz, 3H), 6.63 (s, 2H), 6.25 (s, 1H), 1.02 (t, J = 7.9 Hz, 18H), 0.76 (q, J = 7.9 Hz, 12H). 13C NMR (101 MHz, CDCI3): 5 = 157.11, 156.55, 140.04, 128.84, 128.66, 127.64, 127.55, 125.16, 115.19, 110.99, 110.08, 48.34, 48.13, 47.92, 47.70, 47.49, 47.28, 47.06, 5.77, 4.66. TOF MS-ES +, calculated mass: C26H41O3Si2 [M + H] = 457.2594, found mass: [M + H] = 457.2586.
Series of triisopropylsilyl and ethyl carbamide resveratrol derivatives.
To a solution of 3,4-dithriisopropylsilyl resveratrol or 3,5-dithriisopropylsilyl resveratrol (1 eq.) In dichloromethane was added ethyl isocyanate (1.5 eq.) And triethylamine (2 eq.). After 1 h of reaction at room temperature, the reaction was concentrated and purified on a chromatography column eluting with hexane: ethyl acetate (from 2: 1 to 0: 1).
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3,4’-0-dithriisopropylsilyl-5-ethylcarbamate resveratrol, compound 10. Yield = 80.2%. Rf = 0.9 (Hexane: ethyl acetate - 5: 1). 1H NMR (300 MHz, CDCfe): 5 = 7.39 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 16.2 Hz, 1H), 6.89 (dd, J = 14.6, 5.9 Hz, 5H), 6.60 (s, 1H), 3.40 - 3.26 (m, 2H), 1.30 (ddd, J = 10.6, 7.4, 3.7 Hz, 9H), 1.15 (dd, J = 7.0, 3.1 Hz, 36H). 13C NMR (75 MHz, CDCl3): 5 = 157.04, 156.29, 152.30, 139.75, 130.38, 129.38, 128.01, 126.25, 120.39, 115.12, 112.30, 36.38, 18.21, 18.18, 17.97, 15.40, 12.95, 12.93, 12.57. TOF MS-ES +, calculated mass: C35H5rNO4Si2 [M + H] = 612.3904, found mass: [M + H] = 612.3907.
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3,5-0-dithriisopropylsilyl-4-ethylcarbamate resveratrol, compound 11. Yield = 85.6%. Rf = 0.9 (Hexane: ethyl acetate - 5: 1). 1H NMR (300 MHz, CDCfe): 5 = 7.51
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(d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 16.4 Hz, 1H), 6.93 (d, J = 16.1 Hz, 1H), 6.67 (s , 2H), 6.38 (s, 1H), 3.41-3.28 (m, 2H), 1.32-1.22 (m, 9H), 1.15 (d, J = 7.2 Hz, 36H). 13C NMR (75 MHz, CDCl3): 5 = 157.31, 157.25, 139.15, 128.14, 128.00, 127.59, 121.99, 116.20, 116.04, 112.17, 111.61, 111.38, 45.95, 36.41, 18.20, 12.95. TOF MS-ES +, calculated mass: C35H57NO4Si2 [M + H] = 612.3904, found mass: [M + H] = 612.3900.
Series of triisopropylsilyl glucosyl resveratrol derivatives.
Under stirring and inert atmosphere of argon, 3,4'-dithriisopropylsilyl resveratrol or 3,5-dithriisopropylsilyl resveratrol (1 eq.) Was dissolved in 15 mL of anhydrous dichloromethane and peracetylglucose trichloroacetidate (1.5 eq.) And trifluoro of boron eterato (0.1 eq.). After 30 min of reaction, 5 mL of triethylamine was added, concentrated and added to a silica gel purification column eluting with a mixture of hexane and ethyl acetate (5: 1). The product obtained was dissolved in a mixture of dichloromethane, water and methanol (5 mL, 2: 1: 2) and sodium bicarbonate (3 eq.) Was added. After deprotection of the acetate groups of the glucose unit (24-48 h), the reaction was concentrated and purified by column chromatography eluting with hexane: ethyl acetate (1: 1 to 1: 3).
image38
3,4’-0-dithriisopropylsilyl-5-glucosyl resveratrol, compound 12. Yield = 70.6%. Rf = 0.05 (Hexane: ethyl acetate - 1: 3). 1H NMR (500 MHz, CD3OD): 5 = 7.43 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 16.3 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.70 (s, 1H), 6.55 (t, J = 2.0 Hz, 1H), 4.92 - 4.88 (m, 1H), 3.94 - 3.88 (m, 1H), 3.75 (dd, J = 11.9, 4.8 Hz, 1H), 3.52 - 3.38 (m, 4H), 1.36 - 1.23 (m, 6H), 1.18 - 1.10 (m, 36H). 13C NMR (126 MHz, CD3OD): 5 = 158.94, 156.93, 155.80, 139.83, 130.51, 128.55, 127.51, 126.04, 119.69, 111.96, 107.30, 107.07, 101.13, 76.86, 76.59, 73.48, 69.90, 61.01, 17.05, 16.99, 12.53, 12.51. TOF MS-ES +, calculated mass: C38H2O8Si2 [M + Na] = 725.3881, found mass: [M + Na] = 725.3682.
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image39
3,5-0-dithriisopropylsilyl-4’-glucosyl resveratrol, compound 13. Yield = 75.3%. Rf = 0.05 (Hexane: ethyl acetate - 1: 3). 1H NMR (500 MHz, CD3OD): 5 = 7.48 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.95 (q, J = 16.3 Hz, 3H), 6.66 ( d, J = 2.0 Hz, 2H), 6.32 (t, J = 2.1 Hz, 1H), 4.96 - 4.90 (m, 1H), 3.91 (dd, J = 12.1, 1.9 Hz, 1H), 3.73 (dd, J = 12.1, 5.3 Hz, 1H), 3.51 - 3.47 (m, 2H), 3.45 (dd, J = 5.0, 1.7 Hz, 1H), 3.44 - 3.38 (m, 1H), 1.31 - 1.23 (m, 6H), 1.14 (d, J = 7.3 Hz, 36H). 13C NMR (126 MHz, CD3OD): 5 = 157.41, 156.96, 139.63, 131.54, 128.05, 127.37, 126.65, 116.54, 110.93, 110.28, 100.83, 76.75, 76.57, 73.49, 69.94, 61.10, 17.05, 12.55. TOF MS-ES +, calculated mass: C38H62O8Si2 [M + Na] = 725.3881, found mass: [M + Na] = 725.3907.
Series of triisopropylsilyl octanoyl-glucosyl resveratrol derivatives.
3,4'-0-dithriisopropylsilyl-5-glucosyl resveratrol or 3,5-0-dithriisopropylsilyl-4'-glucosyl resveratrol (1 eq.) Was dissolved in methyl tert-butyl ether and vinyl octanoate (3 eq. ) and the enzyme Lypozyme TL IM ® (same amount in grams as the resveratrol derivative). After 3 days of reaction, the enzyme was filtered and washed with ethyl acetate and methanol. After concentration of the solvent, it was purified by silica column chromatography eluting with hexane: ethyl acetate (from 2: 1 to 1: 3).
image40
3,4’-0-dithriisopropylsilyl-5- (6-octanaoyl) glucosyl resveratrol, compound 14. Yield = 75.3%. Rf = 0.05 (Hexane: ethyl acetate - 1: 3). 1H NMR (500 MHz, CDCh): 5 = 1H NMR (500 MHz, cdcl3) 5 = 7.37 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 16.1 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 6.73 (s, 1H), 4.94 - 4.87 (m, 1H), 4.75 - 4.70 (m, 1H ), 4.59-4.48 (m, 2H), 3.69-3.60 (m, 3H), 1.28-1.25 (m, 18H), 1.15-1.07 (m, 36H), 0.91-0.89 (m, 3H). 13C NMR (126 MHz, CDCh): 5 = 171.07, 139.75, 130.16, 127.72, 126.19, 120.16, 119.68, 115.09, 112.90, 109.58,
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107.50, 106.00, 104.78, 102.13, 100.89, 66.80, 60.38, 45.71, 38.73, 34.00, 31.91, 30.40, 29.69, 29.35, 28.91, 24.47, 23.78, 22.68, 21.03, 20.82, 17.94, 17.89, 17.86, 14.18, 14.10, 12.67, 12.62, 12.54, 10.96, 8.76. TOF MS-ES-, calculated mass: C46H76O9Si2 [M - H] = 827.4950, found mass: [M - H] = 827.4922.
image41
3,5-0-dithriisopropylsilyl-4 ’- (6-octanaoyl) glucosyl resveratrol, compound 15. Yield = 15.5%. Rf = 0.07 (Hexane: ethyl acetate - 1: 2). 1H NMR (300 MHz, CDCh): 5 7.45 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.93 (q, J = 16.2 Hz, 2H), 6.66 (s , 2H), 6.37 (s, 1H), 4.96 (d, J = 6.0 Hz, 1H), 4.43 (m, 2H), 3.77 - 3.55 (m, 4H), 2.36 (t, J = 7.5 Hz, 2H) , 1.63 (d, J = 6.8 Hz, 2H), 1.29 - 1.24 (m, 8H), 1.14 (d, J = 7.0 Hz, 36H), 0.92 - 0.84 (m, 3H). 13C NMR (75 MHz, CDCh): 5 = 174.78, 157.28, 139.28, 132.63, 127.93, 117.30, 111.52, 74.32, 73.59, 34.47, 31.88, 29.97, 29.36, 29.17, 25.12, 22.84, 18.18, 14.29, 12.94. TOF MS-ES +, calculated mass: C4aH7aO9Si2 [M + Na] = 851.4926, found mass: [M + Na] = 851.4966.
Series of triethylsilyl resveratrol derivatives with acyl groups.
3,5-0-triethylsilyl resveratrol (9) (1 eq) was dissolved in tert-butanol and the corresponding fatty acid vinyl ester (6 eq) and Novozyme 435® (ca. 100mg) were added. The reaction was allowed to evolve at 50 ° C under orbital shaking for 60 h. After this time the reaction was filtered to remove the enzyme and dragged with a little methanol. The crude obtained was purified by gradient silica gel column chromatography using as a mobile phase a mixture of hexane and ethyl acetate (100: 0-1: 1).
F
 r


 ,or  16
F
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3,5-0-triethylsilyl-4'-propanoyl resveratrol, compound 16. Yield = 34.0%. Rf = 0. 35 (Hexane: ethyl acetate - 8: 1). 1H NMR (400 MHz, CDCh): 5 = 7.37 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 16.2 Hz, 1H), 6.87 - 6.73 (m, 3H), 6.60 (d, J = 2.3 Hz, 2H), 6.28 (t, J = 2.1 Hz, 1H), 2.33 (q, 2H), 1.66 (t, 3H), 1.01 (t, J = 7.9 Hz, 18H), 0.75 (q, J = 7.9 Hz, 12H). 13C NMR (101 MHz, CDCl3): 5 = 180.10 (CO), 156.55 (2x Cq), 155.26 (Cq), 139.39 (Cq), 130.20 (Cq), 128.24 (CH arom), 127.91 (2x CH arom) , 126.60 (CH arom), 115.56 (2x CH arom), 111.38 (2x CH arom), 110.93 (CH arom), 29.67 (CH2CO), 14.06 (CH3 CH2CO), 6.60 (6xCH2Si), 5.00 (6x CH3CH2Si).
image42
(Hexane: ethyl acetate - 8: 1). 1H NMR (400 MHz, CDCh): 5 = 7.37 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 16.2 Hz, 1H), 6.87 - 6.76 (m, 3H), 6.60 (d, J = 2.2 Hz, 2H), 6.27 (t, J =
2.1 Hz, 1H), 2.34 (t, 2H), 1.66 (m, 2H), 1.00 (t, J = 7.9 Hz, 18H), 0.94 (t, 3H), 0.74 (q, J = 7.9 Hz, 12H) . 13C NMR (101MHz, CDCl3): 5 = 179.26 (CO), 156.55 (2x Cq), 155.32 (Cq), 139.40 (Cq), 130.14 (Cq), 128.25 (CH arom), 127.91 (2x CH arom), 126.56 (CH arom), 115.57 (2x CH arom), 111.38 (2x CH arom), 110.91 (CH arom), 29.65 (CH2CO), 22.66 (CH2CH3), 14.06 (CH3), 6.60 (6xCH2Si), 4.99 (6x CH3CH2Si ).
image43
3,5-0-triethylsilyl-4-hexanoyl resveratrol, compound 18. Yield = 66.0%. Rf = 0.29 (Hexane: ethyl acetate - 8: 1). 1H NMR (400 MHz, CDCh): 5 = 7.36 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 16.2 Hz, 1H), 6.85 - 6.76 (m, 3H), 6.59 (d, J = 2.2 Hz, 2H), 6.26 (t, J =
2.2 Hz, 1H), 2.33 (t, J = 7.5 Hz, 2H), 1.70 - 1.56 (m, 2H), 1.32 (m, 2H), 1.00 (t, J = 7.9 Hz, 18H), 0.92 - 0.84 ( m, 3H), 0.79-0.69 (m, 12H). 13C NMR (101 MHz, CDCh): 5 = 180.26 (CO), 156.54 (2x Cq), 155.39 (Cq), 139.41 (Cq), 130.07 (Cq), 128.28 (CH arom), 127.88 (2x CH arom) , 126.49 (CH arom), 115.57 (2x CH arom), 111.36 (2x CH
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arom), 110.88 (CH arom), 34.02 (CH2CO), 31.16 (CH2 CH2), 24.33 (CH2 CH2), 22.24 (CH2 CH3), 13.80 (CH3), 6.58 (6XCH2YES), 4.98 (6x CH3CH2YES).
image44
3,5-0-triethylsilyl-4'-octanoyl resveratrol, compound 19. Yield = 63.0%. Rf = 0.25 (Hexane: ethyl acetate - 8: 1). 1H NMR (400 MHz, CDCI3): 5 = 7.36 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 16.3 Hz, 1H), 6.87 - 6.72 (m, 3H), 6.59 (d, J = 2.2 Hz, 2H), 6.26 (t, J =
2.2 Hz, 1H), 2.33 (t, J = 7.5 Hz, 2H), 1.62 (q, J = 7.4 Hz, 2H), 1.29 (m, 8H), 1.00 (t, J = 7.9 Hz, 18H), 0.86 (t, J = 6.6 Hz, 3H), 0.74 (q, J = 7.9 Hz, 12H). 13C NMR (101 MHz, CDCI3): 5 = 180.38 (CO), 156.54 (2x Cq), 155.43 (Cq), 139.40 (Cq), 130.04 (Cq), 128.27 (CH arom), 127.87 (2x CH arom) , 126.48 (CH arom), 115.56 (2x CH arom), 111.34 (2x CH arom), 110.87 (CH arom), 34.07 (CH2CO), 31.58 (CH2 CH2), 28.97 (CH2 CH2), 28.85 (CH2 CH2), 24.64 (CH2 CH2), 22.54 (CH2 CH3), 13.98 (CH3), 6.58 (6xCH2Si), 4.98 (6x CH3CH2Si).
image45
3,5-0-trietiIsiIiI-4'-decaverate resveratrol, compound 20. Yield = 89.0%. Rf = 0.25 (Hexane: ethyl acetate - 8: 1). 1H NMR (400 MHz, CDCI3): 5 = 7.36 (d, J =
8.2 Hz, 2H), 6.93 (d, J = 16.2 Hz, 1H), 6.88 - 6.74 (m, 3H), 6.59 (d, J = 2.2 Hz, 2H), 6.26 (t, J = 2.2 Hz, 1H) , 2.33 (t, J = 7.5 Hz, 2H), 1.62 (q, J = 7.4 Hz, 2H), 1.41 - 1.18 (m, 12H), 1.00 (t, J = 7.9 Hz, 18H), 0.86 (t, J = 6.8 Hz, 3H), 0.74 (q, J = 7.8 Hz, 12H). 13C NMR (101 MHz, CDCI3): 5 = 180.43 (CO), 156.54 (2x Cq), 155.48 (Cq), 139.42 (Cq) ,, 130.00 (Cq), 128.30 (CH arom), 127.86 (2x CH arom ), 126.44 (CH arom), 115.57 (2x CH arom), 111.34 (2x CH arom), 110.86 (CH arom), 34.08 (CH2CO), 31.82 (CH2 CH2), 29.35 (CH2 CH2), 29.21 (CH2 CH2) , 29.20 (CH2 CH2), 29.02 (CH2 CH2), 24.64 (CH2 CH2), 22.62 (CH2 CH3), 14.02 (CH3), 6.57 (6xCH2Si), 4.98 (6x CH3CH2SO.
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Example 2: Feasibility and neuroprotection tests.
The SH-SY5Y neuroblastoma line was cultured in petri dishes pre-treated with collagen (100 ^, g / ml) with F12 medium supplemented with penicillin / streptomycin and 10% of inactivated fetal bovine serum.
Cell viability tests with neurons were done in 96-well plates pre-treated with collagen by sowing 20,000 cells / well in a volume of 100 ^ .L and incubating the cells 24h before the addition of the compounds. The compounds to be tested were dissolved in DMSO and added at three different concentrations (1, 10 and 100 ^ .M) to determine their toxicity. The final percentage of DMSO in each well was adjusted to 1%. Cell viability was evaluated 24h after the addition of the compounds by the MTT assay, according to the manufacturer's procedure. The mean values and standard deviations were calculated from at least eight different measurements of several independent experiments.
For the neuroprotection assay, neurons were cultured and seeded in the same manner as for the cell viability assay. The compounds to be tested were dissolved in DMSO and added at three different concentrations (1, 10 and 100 ^ M) and after a 10 minute incubation hydrogen peroxide (100 ^ .M) was added to the medium. The final percentage of DMSO in each well was adjusted to 1%. Cell viability was evaluated 24h after the addition of the compounds by the MTT assay, according to the manufacturer's procedure. The mean values and standard deviations were calculated from at least eight different measurements of several independent experiments. Neural recovery was calculated by normalizing the results of the neuronal viability experiments after the addition of the compounds of the invention and H2O2 to the positive control of each experiment (neurons + H2O2).
It is observed that the control of RES 10 ^ .M recovers up to 50% cell viability (Fig. 1 to 5, indicated by the dashed line). In contrast, many of the silylated derivatives of the invention recover between 80 and 120% viability at concentrations between 1 and 100 ^ .M. Some at 100 ^ .M seem to show toxicity.
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Example 3: Inflammation test.
RAW 264.7 macrophages were cultured in P75 with high glucose DMEM supplemented with penicillin / streptomycin and 10% inactivated fetal bovine serum.
Cell viability assays with RAW macrophages were done in 96-well plates by seeding 25,000 cells / well in a volume of 100 ^ .L and incubating the cells for 4h before adding the compounds. The compounds to be tested were dissolved in DMSO and added at three different concentrations (1, 10 and 100 ^ M) to determine their toxicity. The final percentage of DMSO in each well was adjusted to 1%. Cell viability was evaluated 24h after the addition of the compounds by the MTT assay, according to the manufacturer's procedure. The mean values and standard deviations were calculated from at least eight different measurements of several independent experiments.
For the damage mitigation test caused by the addition of LPS, RAW 264.7 macrophages were cultured according to the procedure described above. The compounds to be tested were dissolved in DMSO and added at three different concentrations (1, 10 and 100 ^ .M) and after a 10 minute incubation LPS (100 ng / mL) was added to the medium. The final percentage of DMSO in each well was adjusted to 1%. Cell viability was evaluated 24h after the addition of the compounds by the MTT assay, according to the manufacturer's procedure. The mean values and standard deviations were calculated from at least eight different measurements of several independent experiments.
In this test it is observed that the 10 ^ .M resveratrol control recovers up to 62% of cell viability (Fig. 6 to 10, indicated by the dashed line). In contrast, several of the silylated derivatives of the invention recover greater cell viability at concentrations between 1 and 100 ^ .M. Some at 100 ^ M seem to show toxicity.
Example 4: Measures of inflammation parameters in LPS assay.
To determine cytokine production, 5 * 105 RAW 264.7 macrophages were seeded in 24-well plates (0.5 ml per well). The compounds to be tested (10 ^ M) were then added and the addition of LPS (1 ^ .g / ml) to the culture medium was stimulated or not stimulated to the macrophages. After 24 hours, IL-6 levels were measured
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and TNF-a in the supernatants by ELISA using the capture and biotinylated antibodies of BD PharMingen and PrepoTech following known protocols. NO levels in the 24-hour supernatants were measured indirectly by determining the concentration of nitrite in the medium using the Griess reagent according to established protocol. A minimum of two independent experiments and three replicates per experiment were performed for each measured value. Values are expressed as the mean ± standard deviation.
In the previous test, the levels of various inflammation parameters (TNF- a, NO and IL-6) are measured by ELISA after treatment with RES or with some of the compounds of the invention (2, 3, 5, 6, 8 and 9).
It is observed that the control of RES 10 uM considerably decreases the inflammatory parameters (TNF-alpha, NO and IL-6) (Fig. 11, 12 and 13 respectively, indicated by the bold bar). In contrast, several of the silylated derivatives of the invention improve at RES and further decrease these parameters.
Example 4: Evaluation of the neuroprotective capacity of several silylated compounds in a zebrafish larval neurodegeneration model induced by pentylenetetrazole (PTZ).
The objective of this trial was to analyze the protective effect of several resveratrol derivatives in a neurotoxin model induced by the pentylentetrazole neurotoxin (PTZ). As an experimental model, the zebrafish larva (Danio rerio) was used to study the effect of the compounds on acetylcholinesterase activity (AChE) in 5-day post-fertilization larvae (dpf).
Studies of the central nervous system (CNS) in zebrafish, show that after 24 hours of development the embryo already has a segmented brain and some structures such as the neural tube, the notocorda and somites (muscle and bone precursors) . At 5 days post-fertilization (5 dpf), the animal has the sensory organs formed like the eyes and otoliths. In addition, the heart, liver, kidneys and pancreas as well as the circulatory, digestive and nervous systems are fully functional. At this time, the animal is able to respond to visual, olfactory and mechanical stimuli and the search for food begins.
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Zebrafish embryos were seeded in 50 mL of dilution water (AD) in a Petri dish and grown to 5 dpf (larval state). To carry out the test, only those larvae that did not present any external anomaly were used. Then, using a Pasteur pipette, the larvae were transferred to a 24-well microplate, so that each well contained five larvae, making ten replicates per condition. First, the pretreatment of the 5 dpf larvae was performed. For this, the larvae were incubated in a volume of 2 mL of AD for the two groups Control (Control and Control + PTZ), of physostigmine 20 pM (Phys, from the English term Physostigmine) which is a commercial AChE enzyme inhibitor for the Phys group, and of the test compounds at 10 pM concentration at 26 ± 1 ° C for 1 hour. Subsequently, a replacement of the medium was performed and the larvae were incubated with the compounds in combination with 5 mM PTZ for 6 hours at 26 ± 1 ° C. After this incubation time, all the larvae were examined and it was determined that the general condition of the larvae was completely normal, without any visible anomaly or abnormal behavior. Finally, the larvae were processed for the analysis of AChE activity.
For the determination of AChE levels, once the experimental period was over, larval processing was carried out to determine AChE according to the established technical study protocol. The larvae were mechanically homogenized and the samples were centrifuged to obtain the supernatant, which were used to determine AChE enzyme levels based on the treatments administered. Additionally, the determination of total protein of each experimental group was carried out according to the established technical study protocol. Finally, the AChE levels determined in the control group were taken as a reference measure, considering them as 100%.
The results of this test showed that silylated derivatives 9 (3,5-ditriethylsilyl-resveratrol) and 15 (3,5-0-dithriisopropylsilyl-4 '- (6-octanaoyl) glucosyl resveratrol) significantly prevent the decrease in AChE activity induced by PTZ in the 5dpf larvae, showing a clear neuroprotective effect (see Fig. 14 and 15). The silylated derivatives 8, 14 and 17 show a lower neuroprotective effect similar to that observed for resveratrol (RES).

权利要求:
Claims (33)
[1]
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1. Use of a compound of formula (I):
image 1
ORs
where R1, R2 and R3 are independently selected from an H, a group - SiR4R5R6, a group -NH (CO) R7 or a carbohydrate,
wherein R4, R5 and R6 are independently selected from linear or branched C1-C6 alkyl or a phenyl group and R7 is a linear or branched C1-C12 alkyl, with the proviso that at least one of R1, R2 and R3 is a group SiR4R5R6; for the manufacture of a medicament for the treatment or prevention of inflammatory, neurological or neurodegenerative diseases.
[2]
2. Use of the compound according to claim 1, wherein R1 and R2 are a group
SiR4R5R6.
[3]
3. Use of a compound according to claim 2 wherein R3 is H.
[4]
4. Use of a compound according to claim 2 wherein R3 is -NH (CO) R7.
[5]
5. Use of a compound according to claim 2 wherein R3 is the following carbohydrate:
r8o
image2
R8 is selected from H or -C (O) -R9 where R9 is a C1-C22 alkyl or a CrC22 alkenyl.
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[6]
6. Use of the compound according to claim 1, wherein R1 and R3 are a SiR4R5R6 group.
[7]
7. Use of a compound according to claim 6 wherein R2 is H.
[8]
8. Use of a compound according to claim 6 wherein R2 is -NH (CO) R7.
[9]
9. Use of a compound according to claim 6 wherein R2 is the following carbohydrate:
RsO '
HO
OH
OH
R8 is selected from H or -C (O) -R9 where R9 is a C1-C22 alkyl or a C1-C22 alkenyl.
[10]
10. Use of the compound according to claim 1, wherein R1, R2 and R3 are a group
SiR4R5R6.
[11]
11. Use of a compound according to any of the preceding claims wherein R4 and R5 are methyl and R6 is tert-butyl.
[12]
12. Use of a compound according to any of claims 1 to 10 wherein R4, R5 and R6 are ethyl.
[13]
13. Use of a compound according to any one of claims 1 to 10 wherein R4, R5 and R6 are isopropyl.
[14]
14. Use of a compound according to claim 1 which is selected from the following group:
image3
image4
image5
image6
5
image7
image8
image9
image10
"^ S¡-0
. T (HH0O ^ 00HO
image11
or
Yes
image12
image13
image14
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image15
image16
[15]
15. Use of a compound according to any of the preceding claims wherein the neurological or neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, fronto-temporal dementia, ischemia and epilepsy.
[16]
16. Compound of formula (I ’):
image17
OR3
where R1, R2 and R3 are independently selected from an H, a group - SiR4R5R6, a group -NH (CO) R7 or a carbohydrate,
wherein R4, R5 and R6 are independently selected from linear or branched C1-C6 alkyl or a phenyl group and R7 is a linear or branched C1-C12 alkyl, with the proviso that at least one of R1, R2 and R3 is a group SiR4R5R6 and that it is not one of the following compounds:
- (E) - (5- (4- (trimethylsilyloxy) styryl) -1,3-phenylene) bis (oxy) bis (trimethylsilane),
- (E) -4- (3,5-bis (triisopropylsilyloxy) styryl) phenol,
- (E) -3- (fe / f-butyldimethylsilyloxy) -5- (4- (te / f-butyldimethylsilyloxy) styryl) phenol,
- (E) -4- (3,5-bis (te / f-butyldimethylsilyloxy) styryl) phenol,
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- (E) -3- (fe / f-butyldimethylsilyloxy) -5- (4-hydroxystyryl) phenol,
- (E) -5- (4- (tert-butyldimethylsilyloxy) styryl) benzene-1,3-diol,
- (E) - (5- (4- (fe / f-butyldimethylsilyloxy) styryl) -1,3-phenylene) bis (oxy) bis (fe / f-butyldimethylsilane).
[17]
17. Compound according to claim 16, wherein R1 and R2 are a SiR4R5R6 group.
[18]
18. Compound according to claim 17 wherein R3 is H.
[19]
19. Compound according to claim 17 wherein R3 is -NH (CO) R7.
[20]
20. Compound according to claim 17 wherein R3 is the following carbohydrate:
Rso
OH
R8 is selected from H or -C (O) -R9 where R9 is a C1-C22 alkyl or a C1-C22 alkenyl.
image18
[21]
21. Compound according to claim 16, wherein R1 and R3 are a SiR4R5R6 group.
[22]
22. Compound according to claim 21 wherein R2 is H.
[23]
23. Compound according to claim 21 wherein R2 is -NH (CO) R7.
[24]
24. Compound according to claim 21 wherein R2 is the following carbohydrate:
r8o
HO
OH
OH
R8 is selected from H or -C (O) -R9 where R9 is a C1-C22 alkyl or a C1-C22 alkenyl.
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[25]
25. Compound according to claim 16, wherein R1, R2 and R3 are a SiR4R5R6 group.
[26]
26. Compound according to any of claims 16 to 25 wherein R4 and R5 are methyl and R6 is tert-butyl.
[27]
27. Compound according to any of claims 16 to 25 wherein R4, R5 and R6 are ethyl.
[28]
28. Compound according to any of claims 16 to 25 wherein R4, R5 and R6 are isopropyl.
[29]
29. Compound of formula (I ’) according to claim 16 which is selected from the following group:
image19
image20
5
image21
10
image22
[30]
30. Use of the compound of formula (I ’) according to claims 16 to 29 for the manufacture of a medicament.
fifteen
[31]
31. Pharmaceutical composition comprising a compound of formula (I ’) according to any of claims 16 to 29.
DRAWINGS
FIG. one
image23
FIG. 2
120
100
__ 80
sP
OR'''
■ a
fD
60
fifteen
.S
40
twenty
0
■ 1uM
image24
Viability (%) Viability (%)
100
80
60
40
twenty
0
image25
12 13 DMSO / H2O2 / RES 10uM + H2O2
Compound
FIG. 4
120
100
80
60
40
twenty
0
image26
image27
14
15 DMSO / H2O2 / RES 10uM + H2O2
Viability (%) Viability (%)
160
140
120
100
80
60
40
twenty
0
■ 1uM
image28
16 17 18 19 20 DMSO / H2O2 / RES
10uM + H2O2
Compound
FIG. 6
140
120
100
80
60
40
twenty
11uM 10uM
 - ■
 H    r1
 "*eleven

DMSO / LPS only / LPS + RES 10uM
0
Viability (%) Viability (%)
160
140
120
100
80
60
40
twenty
0
 ■ 1uM -10uM
 ■ 100uM
image29
10 11 DMSO / LPS only / LPS + RES 10uM
Compound
FIG. 8
40
120
100
80
60
40
twenty
0
image30
Viability (%)
100
"OR
(C
60
-Q
(C
>
40
twenty
0
image31
14
15 DMSO / LPS only / LPS + RES 10uM
Compound
FIG. 10
180
160
140
 ■ 1uM
 T 100uM
120
100
80
60
40
twenty
image32
image33
image34
16 17
18 19
Concentration (ng / ml) Concentration (ng / ml)
30
25
twenty
fifteen
10
5
0
1+ LPS
TNFa
 ■ - LPS

 - - - - - - - - -    - - i- - —T - - i - -
6 8
Compound
BEEF
LPS only / DMSO
FIG. 12
[3]
3.5 3
[2]
2.5 2
1.5 1
0.5
0
 NO ■ + LPS
 m m
image35
2
6 8 9 RES LPS
Compound only ° / DMS °
 + LPS ■ - LPS  IL6

 ± É I
 rirlinr
3
eü¡
C
C
2
or
re
one
u x
C
or
or
RES LPS only / DMSO
Compound
4
0
one
FIG. 14
image36

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同族专利:

---

公开号 | 公开日

---

JP2020514249A|2020-05-21|

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US20190284213A1|2019-09-19|

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EP3549929A4|2020-07-08|

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CA3044908A1|2018-06-07|

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AU2017368843B2|2021-12-16|

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ES2674744B1|2019-04-08|

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WO2018100219A1|2018-06-07|

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CN109996777A|2019-07-09|

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MX2019006169A|2019-07-10|

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AU2017368843A1|2019-06-06|

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EP3549929A1|2019-10-09|

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优先权:

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申请号 | 申请日 | 专利标题

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ES201631535A|ES2674744B1|2016-11-30|2016-11-30|SILVERED DERIVATIVES OF RESVERATROL AND ITS USE IN NEURODEGENERATIVE, NEUROLOGICAL OR INFLAMMATORY DISEASES|ES201631535A| ES2674744B1|2016-11-30|2016-11-30|SILVERED DERIVATIVES OF RESVERATROL AND ITS USE IN NEURODEGENERATIVE, NEUROLOGICAL OR INFLAMMATORY DISEASES|

---

MX2019006169A| MX2019006169A|2016-11-30|2017-11-23|Silylated derivatives of reservatrol and the use thereof in neurodegenerative, neurological or inflammatory diseases.|

---

US16/465,536| US20190284213A1|2016-11-30|2017-11-23|Silylated derivatives of reservatrol and the use thereof in neurodegenerative, neurological or inflammatory diseases|

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AU2017368843A| AU2017368843B2|2016-11-30|2017-11-23|Silylated derivatives of resveratrol and the use thereof in neurodegenerative, neurological or inflammatory diseases|

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JP2019528888A| JP2020514249A|2016-11-30|2017-11-23|Silylated derivatives of resveratrol and their use in neurodegenerative, neurological or inflammatory diseases|

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PCT/ES2017/070776| WO2018100219A1|2016-11-30|2017-11-23|Silylated derivatives of reservatrol and the use thereof in neurodegenerative, neurological or inflammatory diseases|

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CN201780073748.6A| CN109996777A|2016-11-30|2017-11-23|The silylation derivative of resveratrol and its purposes for being used for neurodegeneration, nerve or inflammatory disease|

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CA3044908A| CA3044908A1|2016-11-30|2017-11-23|Silylated derivatives of reservatrol and the use thereof in neurodegenerative, neurological, or inflammatory diseases|

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EP17875307.5A| EP3549929A4|2016-11-30|2017-11-23|Silylated derivatives of reservatrol and the use thereof in neurodegenerative, neurological or inflammatory diseases|