Compounds with antioxidant activity and its uses (Machine-translation by Google Translate, not legal

专利摘要:
Compounds with antioxidant activity and their uses. The invention relates to polyphenolic compounds derived from amide and urea and their use as antioxidants, in addition to pharmaceutical, cosmetic and food compositions, among others, comprising them. (Machine-translation by Google Translate, not legally binding)
公开号:ES2639762A1
申请号:ES201630362
申请日:2016-03-29
公开日:2017-10-30
发明作者:Rosario GONZÁLEZ MUÑIZ；Marta Miguel Castro；Mª Jesús PÉREZ DE VEGA；Beatriz BALSERA PAREDES；Silvia MORENO FERNÁNDEZ
申请人:Consejo Superior de Investigaciones Cientificas CSIC；
IPC主号:

专利说明:

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Compounds with antioxidant activity and its uses DESCRIPTION
The present invention relates to polyphenolic compounds derived from amides and ureas and their use as antioxidants, in addition to pharmaceutical, cosmetic and food compositions, among others, which comprise them.
STATE OF THE TECHNIQUE
Antioxidants have a wide variety of applications in the industry. In food and cosmetics they are used as additives and preservatives, to maintain the quality of the products and extend their useful life. Since antioxidants are chemical substances that protect cells, by neutralizing the damage caused by free radicals, they are also used in cosmetics to retard skin aging. They are added to fuels, lubricants and polymers to prevent oxidation. It is also known that cell damage caused by free radicals and reactive oxygen species is behind a wide variety of diseases, including different cardiovascular problems, neurodegenerative processes and cancer. There is numerous experimental evidence that antioxidants have beneficial effects on these pathologies (Wahlqvist, ML, Asia Pac J Clin Nutr 2013; 22 (2): 171-176).
Natural polyphenols come from the secondary metabolism of plants and chemically have at least one aromatic ring to which one or more hydroxyl groups are attached. They are classified into flavonoids, (flavonols, flavones, isoflavones, anthocyanins, proanthocyanidins, flavanones, etc.) not flavonoids (phenolic acids). Other compounds of polyphenolic nature are stilbenes, tannins, lignins and lignans. In recent years, natural polyphenols have gained great interest for their beneficial health properties, especially as antioxidant agents. (Scalbert, A. et al, Am J Clin Nutr 2005; 81 (suppl): 215S-7S.)
Due to the wide variety of possible applications, it is necessary to find new compounds that have high antioxidant capacity and that their potency as an antioxidant is comparable or superior to that of other compounds described above, such as hydroxytyrosol, which is a component of the oil of
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Olive, considered one of the most potent antioxidants known, or the resveratrol present in grapes and wine, also with high antioxidant capacity.
DESCRIPTION OF THE INVENTION
The present invention provides a family of compounds that possess high antioxidant capacity. Therefore, the compounds of the invention can be useful for the food and cosmetic industry as additives and preservatives, to maintain the quality of the products and extend their useful life, also in the chemical industry in compositions such as fuels, lubricants or polymers to prevent oxidation. In addition, since antioxidants are chemical substances that protect cells, by neutralizing the damage caused by free radicals, the compounds of the invention are also useful in the cosmetic industry to retard skin aging, and in the pharmaceutical industry, since cell damage caused by free radicals and reactive oxygen species are behind a wide variety of diseases, including different cardiovascular problems (hypertension), metabolic syndrome (obesity, diabetes), inflammation, neurodegenerative processes and cancer.
A first aspect of the present invention relates to the use as an antioxidant of a compound of general formula (I) or any of its salts:
image 1
where:
X represents CH2 or NR12;
R1 and R12 independently represent hydrogen or optionally substituted aryl; R2 to R11 independently represent hydrogen, -OH, -C1-C4 alkyl or C1-C4 alkyl;
n and m are each, independently 0 or 1;
with the proviso that at least one radical R2 to R11 is a -OH group.
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According to the present specification, any of the compounds defined above, that is, those compounds that respond to the general formula (I), can also be referred to herein as "compound or compounds of the invention".
The term "alkyl" refers to a linear, unbranched saturated hydrocarbon chain having 1 to 4 carbon atoms, such as, for example, methyl, ethyl, n-propyl or n-butyl. The alkyl groups may be optionally substituted by one or more substituents such as alkynyl, alkenyl, halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro or mercapto. Preferably the alkyl group is methyl.
The term "aryl" refers in the present invention to an aromatic carbocyclic chain, having from 5 to 18 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings. Preferably the group aryl has 5 to 7 carbon atoms An example, not limiting, of aryl is a phenyl, benzyl, naphthyl, diphenyl, indenyl, phenanthryl or anthracil group, aryl radicals may be optionally substituted by one or more substituents that may be selected from alkyl, alkoxy or hydroxyl More preferably the aryl group is a phenyl or benzyl group, optionally substituted by at least one OH group.
In a preferred embodiment, R2 to R11 independently represent hydrogen, -OH or -O (C1-C4) alkyl, more preferably R2 to R11 independently represent hydrogen, -OH or -OCH3.
In another preferred embodiment, at least one radical R2 to R6 is a group -OH and at least one radical R7 to R11 is a group -OH, preferably at least one radical R2 to R6 is a group -OH and at least two radical R7 to R11 is a group -OH.
In another preferred embodiment, R6 and R11 are hydrogen.
In another preferred embodiment, R 1 is hydrogen or aryl optionally substituted by at least one -OH group, preferably the aryl group is a phenyl or benzyl group optionally substituted by at least one -OH group.
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In another preferred embodiment, n is 0 and / or m is 0.
In another preferred embodiment, X is CH2 and in another preferred embodiment X is NR12, preferably R12 is hydrogen or aryl optionally substituted by at least one -OH group, more preferably R12 is hydrogen.
More preferably, the compound of formula (I) is selected from:
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -N- (2,5-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
N- (2,5-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 4’-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N- (3,4-dihydroxyphenyl) acetamide,
2- (3 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N, N-bis (4-hydroxyphenyl) acetamide,
N- (2 ’, 5’-dihydroxybenzyl) -2- (2’ ’, 5’ - dihydroxyphenyl) -N- (4-Hydroxyphenyl) acetamide,
N- (2,4-Dihydroxyphenyl) -N ’- (2’, 5’-dihydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) - N- (3 ’, 4’-dihydroxyphenyl) urea, N- (3,4-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N, N-bis (4-Hydroxyphenyl) urea,
N, N-bis (2,5-Dihydroxyphenyl) urea,
N, N-bis (4-Hydroxyphenyl) -N '- (4-hydroxyphenyl) urea and N- (2', 5'-Dihydroxybenzyl) - N '- (2' ', 5' '- dihydroxyphenyl) -N- (4-hydroxyphenyl) urea.
Taking into account the antioxidant activity of the compounds of the invention, in a preferred embodiment, the invention relates to the use of a compound of formula (I), as defined above or any of its salts, as preservatives or additives for Fabrication of compositions in any industry, such as for the cosmetic, pharmaceutical, food or chemical industry. These compositions may comprise the compounds of formula (I) incorporated into sustained release systems.
Another aspect of the present invention relates to the use of a compound of general formula (I) described above as a food supplement.
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Another aspect of the present invention relates to the cosmetic use of a compound of general formula (I) described above against skin aging.
Another aspect of the present invention relates to the use of a compound of general formula (I) described above for the preparation of a medicament, more preferably for the prevention or treatment of diseases related to oxidative stress, selected from among cardiovascular diseases. (as for example and not limited to hypertension), metabolic syndrome (such as and not limited to obesity or diabetes), inflammation, neurodegenerative diseases and cancer.
Another aspect of the present invention relates to a compound of formula (II) or any of its salts
image2
where:
R1 represents hydrogen or optionally substituted aryl;
R2 to R5 and R7 to R10 independently represent hydrogen, -OH, -O (C1-C4) alkyl or (C1-C4) alkyl; m is 0 or 1 ;, preferably m is 0;
with the proviso that at least three radicals selected from R2 to R5 and R7 to R10 are a -OH group,
and with the proviso that the following compounds:
N- (2,5-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
N- (2,5-Dihydroxyphenyl) -3- (2 ’, 5’-dihydroxyphenyl) propanamide,
N- (3,4-Dihydroxyphenyl) -2- (3 ’, 4’-dihydroxyphenyl) acetamide,
N- (3,4-Dihydroxyphenyl) -3- (3 ’, 4’-dihydroxyphenyl) propanamide, and
N- (4-hydroxy-3,5-dimethylphenyl) -3- (3 ’, 4’-dihydroxyphenyl) propanamide,
They are excluded.
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In a preferred embodiment of the compounds of general formula (II), R2 to R5 and R7 to R10 independently represent hydrogen, -OH or -Oalkyl (C1-C4), more preferably R2 to R5 and R7 to R10 represent independently hydrogen, -OH or -OCH3.
In another preferred embodiment of the compounds of general formula (II), R 1 is hydrogen or aryl optionally substituted by at least one -OH group, and more preferably the aryl group is a phenyl or benzyl group optionally substituted by at least one -OH group .
In another preferred embodiment, the compounds of formula (II) are selected from:
W- (2,4-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -W- (2,5-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -W- (4-hydroxyphenyl) acetamide,
W- (2,4-Dihydroxyphenyl) -2- (2 ’, 4’-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -W- (3,4-dihydroxyphenyl) acetamide,
2- (3 ’, 4’-Dihydroxyphenyl) -W- (4-hydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -W- (4-hydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -W, W-bis (4-hydroxyphenyl) acetamide and
W- (2 ’, 5’-dihydroxybenzyl) -2- (2’ ’, 5’ - dihydroxyphenyl) -W- (4-Hydroxyphenyl) acetamide.
Another aspect of the present invention relates to a compound of formula (III) or any of its salts
image3
where:
R1 and R12 represents optionally substituted hydrogen or aryl;
R2 to R5 and R7 to R10 independently represent hydrogen, -OH, .......
- (C1-C4) alkyl or (C1-C4) alkyl;
with the proviso that at least three radicals selected from R2 to R5 and R7 to R10 are a -OH group,
and with the condition that the following compounds:
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N- (2,4-Dihydroxyphenyl) -N ’- (4’-hydroxyphenyl) urea,
N, N-bis (2,3-Dihydroxyphenyl) urea and N, N-bis (3,4-Dihydroxyphenyl) urea, are excluded.
In a preferred embodiment of the compound of general formula (III), R2 to R5 and R7 to R10 independently represent hydrogen, -OH or -O-alkyl (C1-C4), more preferably R2 to R5 and R7 to R10 independently represent hydrogen, -OH or -OCH3.
In another preferred embodiment of the compound of general formula (III), R1 and / or R12 is hydrogen or aryl, optionally substituted by at least one -OH group. In another preferred embodiment, R1 and R12 are hydrogen. In yet another embodiment, R1 is aryl optionally substituted by at least one -OH group and R12 is hydrogen. Preferably the aryl group is a phenyl or benzyl group optionally substituted by at least one -OH group.
In another preferred embodiment the compound of general formula (III) is selected from:
N- (2,4-Dihydroxyphenyl) -N- (2 ’, 5’-dihydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) - N- (3 ’, 4’-dihydroxyphenyl) urea, N- (3,4-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N, N-bis (2,5-Dihydroxyphenyl) urea,
N, N-bis (4-Hydroxyphenyl) -N '- (4-hydroxyphenyl) urea and N- (2', 5'-Dihydroxybenzyl) - N '- (2' ', 5' '- dihydroxyphenyl) -N- (4-hydroxyphenyl) urea.
Another aspect of the present invention relates to a composition comprising at least one compound of formula (II) or of formula (III) as described above.
The composition of the present invention can be a pharmaceutical, cosmetic, chemical composition (for example polymeric compositions, rubbers, lubricants or fuels) or food.
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In a particular embodiment the composition is a pharmaceutical composition that also comprises a pharmaceutically acceptable vehicle.
The term "vehicle" refers to a diluent, adjuvant or excipient with which the active substance is administered. Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferably, water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol are used as vehicles, particularly for injectable solutions.
The compounds of the invention, of formula (II) or of formula (III), can also be incorporated into sustained release systems, preferably pharmaceutical or cosmetic.
The term "sustained release" is used in the conventional sense referring to a vehicle system of a compound that provides for the gradual release of said compound over a period of time and preferably, but not necessarily, with relatively constant levels of release of the compound. over a period of time. Examples of vehiculization or sustained-release systems include, without limitation, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milliparriculas, microparriculas, nanoparriculas and nanoparriculas solid lipid, nanostructured lipid supports, sponges, cyclodextrins, vesicles, micelles, mixed micelles, micelles of surfactants, mixed phospholipid-surfactant micelles, microspheres, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, as well as in microemulsions and nanoemulsions, which can be added to achieve greater penetration of the active ingredient and / or improve its properties, in particular its pharmacokinetic and pharmacodynamic properties thereof. Preferred carrier or sustained release systems are liposomes, mixed micelles phospholipid tesioactive and microemulsions, more preferably water-in-oil microemulsions with internal reverse micelle structure.
Sustained release systems can be prepared by methods known in the state of the art, and the compositions containing them can be administered, for example, by oral, topical or transdermal administration, including
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adhesive patches, non-adhesive patches, occlusive patches and microelectric patches.
The compounds of the present invention can also be adsorbed on solid organic polymers or solid mineral supports such as for example and without limitation talc, bentonite, silica, starch or maltodextrin among others.
Compositions containing the compounds of the invention can also be incorporated into tissues, non-woven fabrics and sanitary products that are in direct contact with the skin, so that they release the compounds of the invention well by biodegradation of the anchoring system to tissue, non-woven fabric or medical device or by their friction with the body, body moisture, skin pH or body temperature. Also, non-woven fabrics and fabrics can be used for making garments that are in direct contact with the body. Examples of fabrics, non-woven fabrics, garments, sanitary products and means of immobilization of the compounds thereto, among which are the vehiculization systems and / or the sustained release systems described above, can be found described in the literature. and are known in the state of the art [Schaab CK (1986) HAPPI May 1986; Nelson G. (2002) Int. J. Pharm. 242: 55-62; “Biofunctional Textiles and the Skin” (2006) Curr. Probl. Dermatol v.33, Hipler U.C. and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcom R.K. et al. (2004) J. Cont. Release 97: 313-320]. Fabrics, non-woven fabrics, garments and sanitary products preferred are bandages, gauze, T-shirts, socks, socks, underwear, girdles, gloves, honeycombs, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches , microelectric patches and / or facial masks.
The compounds and pharmaceutical compositions of this invention can be used alone or together with other drugs or active ingredients to provide a combination therapy. The other drugs or active ingredients may be part of the same pharmaceutical composition, or be provided as a separate pharmaceutical composition, for administration at the same time or at a different time. Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
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For pharmaceutical, food or cosmetic use, the salts mentioned above will be physiologically and pharmaceutically, food or cosmetically acceptable salts.
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 characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
EXAMPLES
The invention will be illustrated below by tests carried out by the inventors, which show the effectiveness of the product of the invention.
Synthesis of compounds 1 to 10
h3co
image4
Scheme 1
The amide derivatives 22-31 were prepared by reacting the aniline conveniently substituted with the corresponding phenylacetic acid in DCM, using as coupling agents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) and 1-hydroxybenzotriazole (HOBt), in the presence of N, N-diisopropylethylamine (DIEA) as a base (Scheme 1) and according to the following procedure:
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General Procedure A. Preparation of methoxylated amides. To a solution of the conveniently substituted aniline or benzylamine (1.52 mmol) in CH2Cl2 (15 mL), the corresponding phenylacetic acid (1.52 mmol), HOBt (0.22 g, 1.68 mmol) are added, DIEA (0.198 g, 1.52 mmol). The solution is cooled in an ice bath, and EDCHCl (0.35 g, 1.83 mmol) is added. The ice bath is maintained for 2 hours and then allowed to reach room temperature. After 12 hours of stirring at room temperature, extractions with 10% citric acid and 10% NaCO3H are performed. The organic phase is washed with water and saturated NaCl solution. Dry over MgSO4 and evaporate the solvent to dryness. The resulting residue is crystallized from MeOH.
Subsequent treatment with BBr3 led to the corresponding hydroxylated amides, compounds 1 to 10 by the following procedure:
General Procedure B. Deprotection of methoxyl groups. To a solution of the corresponding substituted methoxy product (1 equivalent) in dry CH2Cl2, previously cooled to 0 ° C, and under an argon atmosphere, a 1M solution of BBr3 in CH2Cl2 (2 equivalents per heteroatom) is slowly added. The reaction mixture is maintained with stirring at room temperature until total deprotection of the methoxyl groups (HPLC-MS). Then H2O and CH2Cl2 are added and the precipitate formed is filtered off and washed with H2O and CH2Cl2. If it does not precipitate, AcOEt is added, the phases are separated and dried over Na2SO4. When the purity is not high enough, it is purified on a chromatograph column.
HPLC-MS analyzes for all compounds were performed on a Waters 2695 device, with a Sunfire C18 reverse phase column (4.6 * 50 mm, 3.5 pm) and connected to a Waters Micromass ZQ spectrometer. The flow used was 1 mL / min and as eluents mixtures of 0.1% solution of HCOOH in CH3CN (A) and 0.1% solution of HCOOH in H2O (B) were used.
EXAMPLE 1
N- (2,4-Dimethoxyphenyl) -2- (2 ’, 5’-dimethoxyphenyl) acetamide (22)
image5
image6
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General Procedure A. Gray crystalline solid. Rdto. 81% (Mp. 10:3-105°C, MeOH). HPLC (Sunfire): t R = 8.93 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.60 (s, 2H, CH2), 3.70 (s, 3H, OMe), 3.72 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.80 (s, 3H, OMe), 6.46 (dd, 1H, J = 8.8, 2.6 Hz, 4'-H), 6.60 (d, 1H, J =
2.6 Hz, 6'-H), 6.81 (dd, 1H, J = 8.9, 3.0 Hz, 5-H), 6.87 (d, 1H, J = 3.0 Hz, 3-H), 6.93 (d, 1H, J = 8.9 Hz, 6-H), 7.80 (d, 1H, J = 8.8 Hz, 3'-H), 8.84 (s, 1H, NH) ppm. 13C-NMR (100 MHz, DMSO-cfe) 5: 38.3 (CH2), 55.3 (OMe), 55.4 (OMe), 55.8 (OMe), 55.9 (OMe), 98.7 (C-3), 104.0 (C-5 ), 111.7 (C-3 '), 112.3 (C-4'), 116.9 (C-6 '), 120.7 (C-6), 122.1 (C-1), 125.1 (C-1'), 150.4 ( C), 151.1 (C), 153.0 (C), 156.3 (C), 168.4 (CO) ppm. MS (ES +): m / z 332.4 (M + H) +, 354.5 (M + Na) +.
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide (1)
image7
OH
General Procedure B. Reddish solid. Rdto. 41% Precipitated with Et2O. (Mp .: 178-178 ° C). HPLC: t R = 6.06 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-d6) 5: 3.51 (s, 2H, CH2), 6.15 (dd, 1H, J = 8.6, 2.5 Hz, 4'-H), 6.29 (d, 1H, J = 2.6 Hz, 6'-H), 6.48 (dd, 1H, J = 8.5, 2.9 Hz, 5-H), 6.59 (d, 1H, J = 2.9 Hz, 3-H), 6.63 (d, 1H, J = 8.5 Hz, 6-H), 7.47 (d, 1H, J = 8.6 Hz, 3'-H), 8.67 (s, 1H, NH), 9.01 (s, 1H, OH), 9.03 (s, 1H, OH ), 9.08 (s, 1H, OH), 9.64 (s, 1H, OH) ppm. 13C-NMR (75 MHz, DMSO-cfe) 5: 38.2 (CH2), 102.9 (C-3), 105.6 (C-5), 114.2 (C-6 '), 115.8 (C-4'), 117.2 ( C-1), 118.3 (C-3 '), 122.5 (C-1'), 122.8 (C-6), 147.7 (C), 148.7 (C), 149.8 (C), 154.5 (C),
169.5 (CO) ppm. MS (ES +): m / z 276.4 (M + H) +.
EXAMPLE 2
2- (2 ’, 4’-Dimethoxyphenyl) -N- (2,5-dimethoxyphenyl) acetamide (23)
image8
OMe
General Procedure A. Gray crystalline solid. Rdto. 77% (P.:117-119°C, MeOH). HPLC: t R = 9.48 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-cfe) 5: 3.58 (s, 2H, CH2), 3.65 (s, 3H, OMe), 3.76 (s, 6H, OMe), 3.82 (s, 3H, OMe), 6.51 (dd, 1H, J = 8.3, 2.4 Hz, 4'-H), 6.57 (dd, 1H, J = 8.9, 3.0 Hz, 5-H), 6.60 (d,
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1H, J = 2.4 Hz, 6'-H), 6.92 (d, 1H, J = 8.9 Hz, 6-H), 7.14 (d, 1H, J = 8.3 Hz, 3'-H), 7.78 (d, 1H, J = 3.0 Hz, 3-H), 8.81 (s, 1H, NH) ppm. 13C-NMR: (75 MHz, DMSO-cfe) 5: 38.2 (CH2), 55.2 (OMe), 55.3 (OMe), 55.6 (OMe), 56.3 (OMe), 98.4 (C-3), 104.8 (C- 5),
106.6 (C-1), 107.3 (C-6 '), 111.6 (C-4'), 115.8 (C-5 '), 128.4 (C-1'), 131.3 (C-6), 142.4 (C) , 153.0 (C), 157.6 (C), 159.8 (C), 169.4 (CO) ppm. MS (ES +): m / z 332.4 (M + H) +,
354.5 (M + Na) +.
2- (2 ’, 4’-Dihydroxyphenyl) -N- (2,5-dihydroxyphenyl) acetamide (2)
image9
H
N
image10
General Procedure B. Reddish solid. Rdto. 44% Precipitated with Et2O. (Mp .: 77-79 ° C). HPLC: t R = 2.50 min (gradient of 15 to 95% of A in B in 10 min). 1 H-NMR
(300 MHz, DMSO-cfe) 5: 1.91 (s, 2H, CH2), 6.19 (dd, 1H, J = 8.2, 2.3 Hz, 4'-H), 6.27 (dd, 1H, J = 8.5, 2.9 Hz , 5-H), 6.33 (d, 1H, J = 2.3 Hz, 6'-H), 6.58 (d, 1H, J = 8.5 Hz, 6- H), 6.93 (d, 1H, J = 8.2 Hz, 3'-H), 7.49, (d, 1H, J = 2.9 Hz, 3-H), 8.70 (Sa, 1H, OH), 8.78 (s, 1H, NH) 9.03 (Sa, 1H, OH), 9.19 (Sa, 1H, OH), 9.61 (Sa, 1H, OH) ppm. 13C-NMR (75 MHz, DMSO-d6) 5: 38.3 (CH2), 102.9 (C-3), 106.4 (C-6 ’), 107.3 (C-5), 109.8 (C-1),
112.4 (C-4 ’), 115.4 (C-3’), 127.1 (C-1 ’), 131.4 (C-6), 138.8 (C), 149.8 (C), 156.0 (C),
157.5 (C), 170.0 (CO) ppm. MS (ES +): m / z 276.4 (M + H) +.
EXAMPLE 3
2- (2 ’, 5’-Dimethoxyphenyl) -N- (4-methoxyphenyl) acetamide (24)
OMe
MeO
image11
OMe
General Procedure A. White crystalline solid. Rdto. fifty%. (Mp .: 145-146°C, MeOH). HPLC: t R = 4.29 min (gradient of 15 to 95% of A in B in 5 min). 1 H-NMR
(300 MHz, CDCl3) 5: 3.70 (s, 2H, CH2), 3.79 (s, 3H, OMe), 3.80 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.85 (m, 3H, 3.4, 4'-H), 6.91 (m, 2H, 3-H, 5-H), 7.37 (d, 2H, J = 8.6 Hz, 2- H, 6-H), 7.76 (sa, 1H , NH) ppm. 13C-NMR: (75 MHz, CDCh) 5: 40.2 (CH2), 55.5 (OMe), 55.8 (OMe), 56.2 (OMe), 112.1 (C-2 '), 113.6 (C-4'), 114.1 ( C-3, C-5), 117.1 (C-6 '),
121.6 (C-2, C-6), 124.2 (C-1 ’), 131.4 (C-1), 151.2 (C), 154.0 (C), 156.3 (C), 169.6 (CO) ppm. MS (ES +): m / z 302.28 (M + H) +.
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2- (2 ’, 5’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide (3)
image12
image13
General Procedure B. Freeze-dried white solid. Purified column, AcOEt-Hex (1: 2 to 3: 1). Rdto. 79% (Mp .: 185-187°C d). HPLC: t R = 2.17 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.46 (s, 2H, CH2), 6.45 (dd, 1H, J = 8.3, 2.9 Hz, 4'-H), 6.58 (d, 1H, J = 2.8 Hz, 6'-H), 6.59 (d, 1H, J = 8.6 Hz, 3'-H), 6.68
(d, 2H, J = 8.8 Hz, 3-H, 5-H), 7.37 (d, 1H, J = 8.6 Hz, 2-H, 6-H), 8.63 (Sa, 1H, OH), 8.84 ( Sa, 1H, OH), 9.16 (Sa, 1H, NH), 9.80 (s, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-da) 5:
38.0 (CH2), 113.9 (C-4 '), 115.0 (C-3, C-5), 115.6 (C-3'), 117.1 (C-6 '), 120.9 (C-2, C-6) , 123.2 (C-1 '), 130.9 (C-1), 147.7 (C), 149.7 (C), 153.24 (C), 169.0 (CO) ppm. MS (ES +): m / z 260.33 (M + H) +.
EXAMPLE 4
N- (2,5-Dimethoxyphenyl) -2- (2 ’, 5’-dimethoxyphenyl) acetamide (25)
OMe
image14
H
N
image15
OMe OMe
General Procedure A. White crystalline solid. Rdto. 65% (Mp .: 109-111 ° C, MeOH). HPLC: t R = 4.82 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (300 MHz, CDCl3) 5: 3.74 (s, 2H, CH2), 3.79 (s, 6H, OMe), 3.80 (s, 3H, OMe), 3.92 (s,
3H, OMe), 6.55 (dd, 1H, J = 8.3, 3.1 Hz, 4-H), 6.77 (d, 1H, J = 8.9 Hz, 3'-H), 6.88 (M, 3H, 3.4 ' , 6'-H), 8.15 (d, 1H, J = 3.1 Hz, 6-H), 8.55 (sa, 1H, NH) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 40.8 (CH2), 55.9 (OMe), 56.9 (OMe), 56.5 (OMe), 105.8 (C-6), 108.4 (C-3), 111.0 (C- 4), 111.5 (C-3 '), 113.6 (C-4'), 117.0 (C-6 '), 124.4 (C-1'), 128.9 (C-1), 142.1 (C), 151.1 (C ), 153.9 (C), 154.0 (C), 169.3 (CO) ppm. MS (ES +): m / z 332.35 (M + H) +.
N- (2,5-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide (4)
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image16
General Procedure B. Lyophilized solid rosacea. Purified in column, AcOEt-Hex (1: 1 to 4: 1). Rdto. 79% (P.F.:204-207°C d). HPLC: t R = 2.24 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.53 (s, 2H, CH2), 6.28
(dd, 1H, J = 8.6, 2.9 Hz, 4-H), 6.49 (dd, 1H, J = 8.6, 2.9 Hz, 4'-H), 6.60 (m, 2H, 3'-H, 6'- H), 8.65 (d, 1H, J = 8.6 Hz, 3-H), 7.48 (d, 1H, J = 2.9 Hz, 6-H), 8.71 (s, 1H, OH), 8.73 (s, 1H, OH), 8.95 (s, 1H, NH), 0.03 (s, 1H, OH), 9.07 (sa, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 39.8 (CH2), 107.6 (C-6), 110.0 (C-3), 114.4 (C-4), 115.5 (C-4 ’),
115.7 (C-3 ’), 117.2 (C-6’), 122.5 (C-1 ’), 127.0 (C-1), 138.3 (C), 147.6 (C), 149.8 (C),
149.8 (C), 169.5 (CO) ppm. MS (ES +): m / z 276.27 (M + H) +.
EXAMPLE 5
N- (2,4-Dimethoxyphenyl) -2- (2 ’, 4’-dimethoxyphenyl) acetamide (26)
image17
OMe
image18
H
N
OMe
image19
image20
General Procedure A. Brown crystalline solid. Crude purified chromatograph column, EtOAc-Hex (1: 3 to 2: 1). Rdto. 74% (Mp .: 125-126°C, MeOH). HPLC: t R = 4.70 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (300 MHz, CDCl3) 5: 3.62 (s, 2H, CH2), 3.76 (s, 6H, OMe), 3.80 (s, 3H, OMe), 3.87 (s, 3H, OMe), 6.35-6.56
(m, 4H, 3-, 5-, 3 - ', 5'-H), 7.24 (d, 1H, J = 7.9 Hz, 6'-H), 8.11 (sa, 1H, NH), 8.22 (d , 1H, J = 8.3 Hz, 6-H) ppm. 13C-NMR: (75 MHz, CDCh) 5: 39.6 (CH2), 55.5 (OMe), 55.5 (OMe), 55.6 (OMe), 55.8 (OMe), 98.7 (C-3), 98.8 (C-3 ' ), 103.8 (C-5 '), 104.7 (C-5), 116.2 (C-6), 120.4 (C6'), 121.8 (C-1 '), 131.7 (C-1), 149.2 (C), 156.1 (C), 158.0 (C), 160.5 (C),
169.5 (CO) ppm. MS (ES +): m / z 331.93 (M + H) +.
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 4’-dihydroxyphenyl) acetamide (5)
image21
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30
General Procedure B. Freeze-dried white solid. Purified column, AcOEt-Hex (1: 1 to 4: 1). Rdto. 94% (Mp .: 75-78 ° Cd, MeOH). HPLC: t R = 2.24 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.43 (s, 2H, CH2), 6.13 (dd, 1H, J = 8.7, 2.6, 4'-H), 6.16 (dd, 1H, J = 8.1, 2.4, 4-H), 6.25 (d, 1H, J = 2.6 Hz, 6'-H), 6.29 (d, 1H, J = 2.4 Hz, 6-H), 6.90 (d, 1H, J = 8.2 Hz , 3'-H), 7.48 (d, 1H, J = 8.7 Hz, 3-H), 8.84 (sa, 1H, NH), 9.12 (sa, 2H, OH), 9.51 (sa, 2H, OH) ppm . 13C-NMR: (75 MHz, DMSO-d6) 5: 37.8 (CH2), 102.6 (C-3 '), 102.9 (C-3), 105. 7 (C-5), 106.4 (C-5') , 112.7 (C-6), 118.5 (C6 '), 122.2 (C-1'), 131.3 (C-1), 148.4 (C), 154.4 (C), 156.1 (C), 157.4 (C),
170.0 (CO) ppm. MS (ES +): m / z 276.34 (M + H) +.
EXAMPLE 6
2- (2 ’, 5’-Dimethoxyphenyl) -N- (3,4-dimethoxyphenyl) acetamide (27)
MeO
image22
General Procedure A. White crystalline solid. Rdto. 73.5% (Mp: 140-142°C, MeOH). HPLC (Sunfire): tR = 4.09 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (300 MHz, CDCl3) 5: 3.71 (s, 2H, CH2), 3.76 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.87 (s , 3H, OMe), 6.70-7.34 (m, 6H, Ar-H), 7.71 (sa, 1H, NH) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 40.3 (CH2), 55.8 (OMe), 56.0 (OMe), 56.2 (OMe), 105.0 (C-2), 111.4 (C-5), 111.6 (C- 3 '), 112.1 (C-4'), 113.6 (C-6), 117.2 (C6 '), 124.5 (C-1'),
132.0 (C-1), 145.8 (C), 149.1 (C), 151.2 (C), 154.1 (C), 169.2 (CO) ppm. MS (ES +): m / z 332.28 (M + H) +.
2- (2 ’, 5’-Dihydroxyphenyl) -N- (3,4-dihydroxyphenyl) acetamide (6)
OH
OH
General Procedure B. Column, 50 to 65% gradient of AcOEt in hexane. Lyophilized pinkish solid. Rdto. 56% (Mp .: 180 ° Cd). HPLC: t R = 4.02 min (gradient of 2 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-da) 5: 3.34 (s, 2H, CH2), 6.45 (dd, 1H, J = 8.5, 2.9, 5'-H), 6.57 (d, 1H, J = 2.9, 6'-H), 6.59 (d, 1H, J = 8.5 Hz, 5-H), 6.62 (d, 1H, J = 8.5 Hz, 4'-H), 6.79 (dd, 1H, J = 8.5, 2.4 Hz, 6-H), 7.14 (d, 1H, J = 2.4
image23
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Hz, 2-H), 8.57 (s, 1H, OH), 8.62 (s, 1H, OH), 8.85 (s, 1H, NH), 8.92 (s, 1H, OH), 9.69 (s, 1H, OH ) ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 38.2 (CH2), 107.9 (C-2), 110.4 (C-6), 113.9 (C-4 '), 115.2 (C-5), 115.6 ( C-3 '), 117.1 (C6'), 123.2 (C-1 '), 131.3 (C-1), 141.2 (C), 144.9 (C), 147.7 (C), 149.7 (C), 169.0 (CO ) ppm. MS (ES +): m / z 276.27 (M + H) +.
EXAMPLE 7
2- (3 ’, 4’-Dimethoxyphenyl) -N- (4-methoxyphenyl) acetamide (28)
MeO
image24
image25
OMe
OMe
General Procedure A. White crystalline solid. Rdto. 81% (Mp: 143-146°C, MeOH). HPLC (Sunfire): tR = 3.90 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, CDCh) 5: 3.66 (s, 2H, CH2), 3.77 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.90 (s, 3H, OMe), 6.28 (d , 2H, J = 8.9 Hz, 3-H, 5-H), 6.83-6.90 (m, 3H, 2'-H, 5'-H, 6'- H), 7.04 (sa, 1H, NH), 7.31 (d, 2H, J = 8.9 Hz, 2-H, 6-H) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 44.3 (CH2), 55.5 (OMe), 56.0 (OMe), 111.8 (C-2 '), 112.7 (C-5'), 114.2 (C-3, C -5), 121.8 (C-2, C-6, C6 '), 127.2 (C-1'), 130.9 (C-1), 148.6 (C), 149.5 (C), 156.6 (C),
169.4 (CO) ppm. MS (ES +): m / z 302.21 (M + H) +.
2- (3 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide (7)
image26
General Procedure B. Column, 50 to 75% gradient of AcOEt in hexane. Solid white. Rdto. 75% (P.f.:192-194°C). HPLC: t R = 2.09 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-da) 5: 3.36 (s, 2H, CH2), 6.54
(dd, 1H, J = 8.0, 2.1, 6'-H), 6.64 (d, 1H, J = 8.0, 3'-H), 6.66 (d, 2H, J = 8.9 Hz, 3-H, 5- H), 6.72 (d, 1H, J = 2.1 Hz, 2'-H), 7.35 (d, 2H, J = 8.9 Hz, 2-H, 6-H), 8.70 (s, 1H, OH), 8.81 (sa, 1H, OH), 9.14 (s, 1H, NH), 9.76 (sa, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 43.0 (CH2), 115.3 (C-3, C-5), 115.6 (C-2 '), 116.6 (C-5'), 120.0 (C- 6 '),
121.1 (C-2, C-6), 127.3 (C-1 ’), 131.3 (C-1), 144.2 (C), 145.3 (C), 153.5 (C), 169.2 (CO) ppm. MS (ES +): m / z 260.33 (M + H) +.
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EXAMPLE 8
2- (2 ’, 4’-Dimethoxyphenyl) -N- (4-methoxyphenyl) acetamide (29)
image27
General Procedure A. White crystalline solid. Rdto. 76% (Mp .: 126-128°C, MeOH). HPLC (Sunfire): t R = 4.35 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, CDCl3) 5: 3.62 (s, 2H, CH2), 3.76 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.51 (m , 2H, 4'-H, 5'-H), 6.80 (d, 2H, J = 8.9 Hz, 3-H, 5-H), 7.19 (d, 1H, J = 8.0 Hz, 3'-H) , 7.32 (d, 2H, J = 8.9 Hz, 2-H, 6-H), 7.43 (sa, 1H, NH) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 39.2 (CH2), 55.5 (OMe), 55.6 (OMe), 55.7 (OMe), 99.1 (C-3 '), 105.2 (C-5'), 114.1 ( C-3, C-5), 115.9 (C-1 '), 121.6 (C-2, C-6), 131.4 (C-1), 131.8 (C-6'), 156.3 (C), 158.2 ( C), 160.7 (C), 169.7 (CO) ppm. MS (ES +): m / z 302.35 (M + H) +.
2- (2 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide (8)
image28
General Procedure B. Column, gradient of 25 to 65% AcOEt in hexane. Solid white. Rdto. 80% Precipitated with Et20. (P.:186-189°C). HPLC: t R = 2.43 min (gradient of 15 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.45 (s, 2H, CH2), 6.17 (dd, 1H, J = 8.2, 2.4, 5'-H), 6.27 (d, 1H, J = 2.4, 3'-H), 6.67 (d, 2H, J =
8.8 Hz, 3-H, 5-H), 6.88 (d, 1H, J = 8.2 Hz, 6'-H), 7.36 (d, 2H, J = 8.8 Hz, 2-H, 6-H), 9.07 (s, 1H, NH), 9.14 (s, 1H, OH), 9.39 (sa, 1H, OH), 9.69 (sa, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-da) 5: 37.4 (CH2), 102.5 (C-3), 106.1 (C-5 '), 113.1 (C-1'), 115.0 (C-3, C- 5), 120.9 (C-2, C-6), 131.0 (C-1), 131.1 (C-6 '), 153.2 (C), 156.1 (C), 157.1 (C),
169.6 (CO) ppm. MS (ES +): m / z 260.33 (M + H) +.
EXAMPLE 9
2- (2 ’, 5’-Dimethoxyphenyl) -N, N-bis (4-methoxyphenyl) acetamide (30)
image29
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General Procedure A. Sirupe transparent. Rdto. 28% HPLC (Sunfire): t R = 7.62 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, CDCl3) 5: 3.42 (s, 2H, CH2), 3.67 (s, 3H, OMe), 3.68 (s, 3H, OMe), 3.73 (s, 6H, OMe), 6.72-7.30 (m, 11H, Ar-H) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 37.0 (CH2), 55.6 (OMe), 55.7 (OMe), 55.9 (OMe), 56.0 (OMe), 11.3 (C-2 '), 112.7 (C-4 '), 114.2 (C-3, C-5), 114.8 (C3' ', C5' '),
116.8 (C-6 '), 125.7 (C1'), 127.4 (C-2, C-6), 129.8 (C2 '', C6 ''), 136.4 (C-1 ', C1' '), 151.7 ( C), 153.6 (C), 157.5 (C), 158.9 (C), 171.7 (CO) ppm. MS (ES +): m / z 408.39 (M + H) +. 2- (2 ’, 5’-Dihydroxyphenyl) -N, N-bis (4-hydroxyphenyl) acetamide (9)
OH
image30
General Procedure B. Column, gradient of 35 to 65% AcOEt in hexane. Lyophilized white solid. Rdto. 72% Precipitated with Et2O. (P.f.:124-126°C). HPLC: t R = 4.57 min (gradient from 2 to 95% of A in B in 5min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.26 (s, 2H, CH2), 6.34 (dd, 1H, J = 8.5, 2.9, 4'-H), 6.27 (d, 1H, J = 2.9, 6'-H), 6.43 (d, 1H, J = 8.5 Hz, 3'-H), 6.62 (d, 2H, J = 8.1 Hz, 3-H, 5-H), 6.68 (d, 2H, J = 8.2 Hz, 3 '' - H, 5 '' - H), 6.98 (d, 2H, J = 8.2 Hz, 2 '' - H, 6 '' - H), 7.10 (d, 2H, J = 8.1 Hz, 2-H, 6-H), 8.51 (s, 1H, OH), 8.57 (s, 1H, OH), 9.33 (sa, 1H, OH), 9.57 (sa, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-da) 5: 35.7 (CH2), 113.6 (C-3 '', C-5 ''), 115.2 (C-4 '), 115.3 (C-3, C- 5),
115.9 (C-3 ', C-6'), 117.2 (C-2 '', C-6 ''), 123.4 (C-2, C-6), 127.8 (C-1 '), 129.4 (C -one''),
134.9 (C-1), 147.6 (C), 149.5 (C), 155.4 (C), 156.6 (C), 170.9 (CO) ppm. MS (ES +): m / z 352.29 (M + H) +.
EXAMPLE 10
N- (2 ’, 5’-Dimethoxybenzyl) -2- (2”, 5 ”-dimethoxyphenyl) -N- (4-methoxyphenyl) acetamide (31)
image31
General Procedure A. Column, gradient of 15 to 25% AcOEt in hexane. Crystallization of MeOH. White crystalline solid. Rdto. 74% (Mp .: 127-129°C, MeOH).
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HPLC (Sunfire): tR = 8.02 min (gradient of 15 to 95% of A in B in 10 min). 1 H-NMR
(300 MHz, CDCls) 5: 3.35 (s, 2H, CH2), 3.58 (s, 3H, OMe), 3.65 (s, 3H, OMe), 3.67 (s,
3H, OMe), 3.68 (s, 3H, OMe), 3.73 (s, 3H, OMe), 6.73-6.86 (m, 6H, Ar-H), 6.91 (d, 2H, J = 9.0 Hz, 3-H , 5-H), 7.13 (d, 2H, J = 8.9 Hz, 2-H, 6-H) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 36.0 (CH2), 47.7 (N-CH2), 55.5 (OMe), 55.8 (OMe), 55.85 (OMe), 55.9 (OMe), 56.0 (OMe), 111.2 (C-2 ''), 111.6 (C-2 '), 112.5 (C-4' '), 112.8 (C-4'), 114.2 (C-3, C-5), 115.9 (C-6 ' '), 116.8 (C-6'), 126.0 (C-1 '), 127.2 (C-1' '), 129.5 (C-2, C-6), 135.8 (C-1), 151.6 (C) , 151.8 (C), 153.5 (C), 153.7 (C), 158.8 (C), 171.7 (CO) ppm. MS (ES +): m / z 452.33 (M + H) +.
N- (2 ’, 5’-dihydroxybenzyl) -2- (2”, 5 ”-dihydroxyphenyl) -N- (4-Hydroxyphenyl) acetamide (10)
Oh
image32
General Procedure B. Column, gradient of 35 to 65% AcOEt in hexane. Solid white. Rdto. 81% Precipitated with Et2O. (P.f.:114-116°C). HPLC: t R = 4.64 min (gradient of 2 to 95% of A in B in 5 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.25 (s,
2H, CH2), 4.66 (s, 2H, N-CH2), 6.41-6.46 (m, 3H, 4'-H, 4 '' - H, 6 '' - H), 6.49 (d, 1H, J = 2.9, 6'-H), 6.52 (d, 1H, J = 8.2 Hz, 3'-H), 6.54 (d, 1H, J = 8.5 Hz, 3 '' - H), 6.74 (d, 2H, J = 8.7 Hz, 3-H, 5-H), 7.01 (d, 2H, J = 8.7 Hz, (d, 2H, J = 8.1 Hz, 2-H, 6-H), 8.56 (s, 1H, OH ), 8.60 (s, 1H, OH), 8.68 (s, 1H, OH), 8.73 (sa, 1H, OH), 9.63 (sa, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-d6 ) 5: 35.0 (CH2), 48.2 (N-CH2), 113.8 (C-4``), 114.6 (C-6 ''),
115.4 (C-3 ''), 115.8 (C-3, C-5), 115.9 (C-4 '), 117.4 (C-3', C-6 '), 123.1 (C-1'), 123.7 (C-1 ''), 129.1 (C-2, C-6), 133.7 (C-1), 147.4 (C), 147.7 (C), 149.5 (C), 149.6 (C), 156.7 (C) , 171.7 (CO) ppm. MS (ES +): m / z 382.29 (M + H) +.
Synthesis of compounds 11 to 18:
image33
R
NCO HN
H3CO + OCH3
image34
THF, t.a.
H3CO
image35
Rl H
Y
OR
image36
OCH3
32-39
BBr3 / CH2Cl2 ta, Ar
Scheme 2
HO
image37
R1 H N N
OR
image38
OH
11-18
The synthesis of the methoxylated urea derivatives 32-39 was carried out by reaction 5 of the corresponding methoxyanilines with the appropriate methoxy-substituted isocyanates in tetrahydrofuran (THF) at room temperature (t.a.) (Scheme 2) and according to the following procedure:
General Procedure C. Preparation of methoxylated ureas. At a solution of the conveniently substituted aniline or benzylamine (1.2 mmol) in dry THF (20 mL) the corresponding phenyl isocyanate (1.0 mmol) is added. After stirring for 15 hours at room temperature, THF is evaporated and the residue is treated with CH2Cl2. The organic phase is washed with water and saturated NaCl solution, dried over MgSO4 and the solvent is evaporated to dryness. The resulting residue is purified by column chromatography or crystallization.
fifteen
Subsequent treatment of the above methoxy derivatives with BBr3 led to hydroxylated ureas 11-18 according to procedure B (General Procedure B) described for the synthesis of compounds 1 to 10.
20 EXAMPLE 11
N- (2,4-Dimethoxyphenyl) -N ’- (2’, 5’-dimethoxyphenyl) urea (32)
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OMe
image39
Y
OR
H
N
OMe
image40
OMe
General procedure C. White solid. Crude purified by column chromatography, EtOAc-Hex (1: 3 to 2: 1). Rdto. 55% (Mp .: 150-152°C, MeOH). HPLC: t R = 8.96 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-cf6) 5: 3.67 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.80 (s, 3H, OMe), 3.84 (s, 3H, OMe), 6.45 -6.47 (m, 2H, 4'-H, 5-H), 6.60 (d, 1H, J = 2.7 Hz, 3-H), 6.89 (d, 1H, J = 8.8 Hz, 3'-H), 7.83 (d,
1H, J = 3.0 Hz, 6’-H), 7.85 (d, 1H, J = 8.8 Hz, 6-H), 8.70 (s, 1H, NH), 8.73 (s, 1H, NH) ppm. 13C-NMR (100 MHz, DMSO-cfe) 5: 55.2 (OMe), 55.3 (OMe), 55.7 (OMe), 56.3 (OMe), 98.7 (C-3), 104.0 (C-6 '), 105.1 ( C-5), 105.5 (C-4 '), 111.4 (C-3'), 120.9 (C-1),
121.7 (C-6), 130.0. (C-1 ’), 142.1 (C), 149.9 (CO), 152.8 (C), 153.3 (C), 155.2 (C) ppm. MS (ES +): 333.3 (M + H) +.
N- (2,4-Dihydroxyphenyl) -N ’- (2’, 5’-dihydroxyphenyl) urea (11)
image41
OH
General Procedure B. White solid. Rdto 95%. (Mp> 155 ° Cd). HPLC: t R = 5.97 min (gradient from 2 to 40% of A in B in 15 min). 1H-NMR (500 MHz, DMSO-d6)
5: 6.16 (dd, 1H, J = 8.6.3.0 Hz, 4'-H), 6.18 (dd, 1H, J = 8.5, 2.9 Hz, 5-H), 6.31 (d, 1H, J = 2.7 Hz, 3-H), 6.58 (d, 1H, J = 8.5 Hz, 3'-H), 7.43 (d, 1H, J = 8.7 Hz, 6-H), 7.46 (d, 1H, J = 2.9 Hz, 6 '-H), 8.45 (s, 1H, NH), 8.47 (s, 1H, NH), 8.59 (sa, 1H, OH), 8.93 (sa, 1H, OH), 9.00 (s, 1H, OH), 9.58 (s, 1H, OH) ppm. 13C-NMR (125 MHz, DMSO-cfe) 5:
102.7 (C-3), 105.6 (C-6 '), 106.7 (C-4'), 107.6 (C-5), 115.0 (C-3 '), 119.0 (C-1), 122.3 (C6), 128.6 (C-1 '), 138.4 (C), 148.5 (C), 149.9 (CO), 153.4 (C), 153.6 (C) ppm. MS (ES +): m / z 277.3 (M + H) +.
EXAMPLE 12
N- (2,5-Dimethoxyphenyl) -N ’- (4’-methoxyphenyl) urea (33)
OMe
image42
image43
image44
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General procedure C. White needles. Rdto. 85% (P.:162-164°C, Cl2CH2). HPLC: t R = 8.62 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-d6) 5: 3.68 (s, 3H, OMe), 3.71 (s, 3H, OMe), 3.81 (s, 3H, OMe), 6.46 (dd, 1H, J = 8.8 and 3.0 Hz, 4-H), 6.86-6.91 (m, 3H, 3'-H, 5'-H, 3-H), 7.37 (d, 2H, J = 8.6 Hz, 2'-H, 6 '-H), 7.37 (d, 1H, J = 2.9 Hz, 6-H), 8.16 (s, 1H, NH), 9.16 (s, 1H, NH) ppm. 13C-NMR (75 MHz, DMSO-d6) 5: 55.2 (OMe), 55.3 (OMe), 56.3 (OMe), 105.1 (C-6), 105.2 (C-4),
111.4 (C-3), 114.1 (C-3 ’, C-5’), 119.8 (C-2 ’, C-6’), 129.8 (C-1), 132.8. (C-1 ’), 141.8 (C), 152.5 (CO), 153.4 (C), 154.5 (C) ppm. MS (ES +): 303.3 (M + H) +. N- (2,5-Dihydroxyphenyl) -N ’- (4’-hydroxyphenyl) urea (12)
image45
General Procedure B. White solid. Rdto. 56% (Mp .: 180-182°C, MeOH). HPLC: t R = 2.49 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-da) 5: 6.15 (dd, 1H, J = 8.4, 2.8 Hz, 4-H), 6.59 (d, 1H, J = 8.5 Hz, 3-H), 6.67 (d , 2H, J = 8.8 Hz, 3'-H, 5'-H), 7.20 (d, 2H, J = 8.8 Hz, 2'-H, 6'-H), 7.58 (d, 1H, J = 2.8 Hz, 6-H), 7.94 (d, 1H, NH), 8.60 (s, 1H, NH), 8.97 (s, H, OH), 9.03 (s, 1H, OH), 9.1 (s, 1H, OH ) ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 106.2 (C-6), 107.3 (C-4), 114.8 (C-3),
115.3 (C-3 ', C-5'), 120.1 (C-2 ', C-6'), 128.7 (C-1), 131.5 (C-1 '), 137.9 (C), 150.0 (C) ,
152.4 (CO), 152.7 (C), ppm. MS (ES +): m / z 261.28 (M + H) +.
EXAMPLE 13
N- (2,5-Dimethoxyphenyl) -N ’- (3’, 4’-dimethoxyphenyl) urea (34)
image46
General procedure C. White needles. Rdto. 69% (Mp .: 159-161 ° C,
Cl2CH2 / MeOH). HPLC: t R = 8.82 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-d6) 5: 3.68 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.80 (s, 3H, OMe), 3.84 (s, 3H, OMe), 6.44 -6.49 (m, 2H, 4-H, 6'-H), 6.60 (d, 1H, J = 2.5 Hz, 2'-H), 6.89 (d, 1H, J = 8.9 Hz, 3-H), 7.84-7.88 (m, 2H, 6-H, 5'-H), 8.69 (s, 1H, NH), 8.72 (s,
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30
1H, NH) ppm. 13C-NMR (75 MHz, DMSO-cfe) 5: 55.2 (OMe), 55.3 (OMe), 55.7 (OMe), 56.3 (OMe), 98.8 (C-2 '), 104.1 (C-6), 105.2 ( C-4), 105.5 (C-5 '), 111.5 (C-3), 120.9 (C-6), 121.7 (C-1), 130.0. (C-1 ’), 142.1 (C), 149.9 (C), 152.8 (C), 153.3 (CO), 155.2 (C) ppm. MS (ES +): 333.4 (M + H) +.
N- (2,5-Dihydroxyphenyl) - N ’- (3’, 4’-dihydroxyphenyl) urea (13)
image47
General Procedure B. White prisms. Rdto. 68% (P.:141-143°C,
MeOH / Ci2CH2). HPLC: t R = 1.73 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-d6) 5: 6.1-6.2 (m, 2H, 4.6'-H), 6.31 (d, 1H, J = 2.6, 2'-H), 6.58 (d, 1H , J = 8.5 Hz, 3-H), 7.43 (d, 1H, J = 8.7 Hz, 5'-H), 7.46 (d, 1H, J = 2.9 Hz, 6-H), 8.44 (s, 1H, NH), 8.47 (s, 1H, OH), 8.59 (s, 1H, OH), 8.94 (s, 1H, OH), 9.01 (s, 1H, OH), 9.59 (s, 1H, NH) ppm. 13C-NMR: (75 MHz, DMSO-da) 5: 102.8 (C-6), 105.6 (C-2 ’),
106.8 (C-4), 107. 7 (C-5 '), 115.1 (C-3), 119.0 (C-6'), 122.4 (C-1), 128.6 (C-1 '), 138.4 (C ), 148.6 (C), 149.9 (C), 153.4 (C), 153.6 (CO) ppm. MS (ES +): m / z 277.29 (M + H) +.
EXAMPLE 14
N- (3,4-Dimethoxyphenyl) -N ’- (4’-methoxyphenyl) urea (35)
MeO
image48
OMe
OMe
General procedure C. White scales. Rdto. 42% (Mp .: 185-187°C, EtOH). HPLC: t R = 8.35 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-d6) 5: 3.71 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.85 (s, 3H, OMe), 6.47 (dd, 1H, J
= 8.7, 2.4 Hz, 6-H), 6.61 (d, 1H, J = 2.4 Hz, 2-H), 6.86 (d, 1H, J = 8.7 Hz, 3'-H, 5'-H), 7.34 (d, 1H, J = 8.6 Hz, 2'-H, 6'-H), 7.88 (s, 1H, NH), 7.93 (d, 1H, J = 8.8 Hz, 5-H), 8.95 (s, 1H, NH) ppm. 13C-NMR (75 MHz, DMSO-d6) 5: 55.2 (OMe), 55.3 (OMe), 55.8 (OMe), 98.8 (C-2), 104.1 (C-5), 114.0 (C-3 ', C -5 '), 119.5 (C-2', C-6 '), 119.6 (C-6), 122.1 (C-1), 133.1 (C-1), 149.1 (C), 152.8 (C), 154.3 (CO), 154.8 (C) ppm. MS (ES +): 303.99 (M + H) +.
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N- (3,4-Dihydroxyphenyl) -N ’- (4’-hydroxyphenyl) urea (14)
image49
General Procedure B. White solid. Rdto. 60% (Mp .: 184-187 ° C, MeOH / Cl2CH2). HPLC: t R = 2.12 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-d6) 5: 6.14 (dd, 1H, J = 8.7, 2.6 Hz, 6-H), 6.32 (d, 1H, J = 2.6 Hz, 2-H), 6.66 (d ,
1H, J = 8.8 Hz, 3'-H, 5'-H), 7.18 (d, 1H, J = 8.8 Hz, 2'-H, 6'-H), 7.59 (d, 1H, J = 8.7 Hz , 5-H), 7.68 (d, 1H, OH), 8.72 (s, 1H, OH), 8.87 (s, 1H, NH), 8.99 (s, 1H, NH), 9.69 (s, 1H, OH) ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 102.5 (C-2), 105.5 (C-5), 115.2 (C- 3 ', 5'), 119.61 (C-6), 120.0 (C- 2 ', C-6'), 120.6 (C-1), 131.7 (C1 '), 147.2 (C), 152.2 (C), 152.7 (CO), 153.2 (C) ppm. MS (ES +): m / z 261.31 (M + H) +.
EXAMPLE 15
N, N’-bis (4-Methoxyphenyl) urea (36)
image50
image51
or

General procedure C. White needles. Rdto. 80% (Mp .: 237-239 ° C, EtOH; mp Lit = 236-238 ° C). HPLC: t R = 7.88 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-cfe) 5: 3.71 (s, 6H, OMe), 6.86 (d, 4H, J = 8.8, 3-H, 5-H), 7.35
(d, 4H, J = 8.8 Hz, 2-H, 6-H), 8.36 (s, 1H, NH) ppm. 13C-NMR (75 MHz, DMSO-cfe) 5: 55.1 (OMe), 113.9 (C-3, C-5), 119.9 (C-2, C-6), 132.9 (C-1), 153.0 (CO ), 154.3 (C-4) ppm. MS (ES +): 273.10 (M + H) +. (Iqbal, A. F. M. et al, Helv. Chim. Acta (1976) 59 (2),
655-656).
N, N’-bis (4-Hydroxyphenyl) urea (15)
H H
-l L
HO
OH
image52
General Procedure B. White prisms. Rdto. 84% (Mp .: 245° Cd, MeOH; mp Lit = 240 ° Cd). HPLC: t R = 2.59 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-da) 5: 6.66 (d, 4H, J = 8.8, 3-H, 5-H), 7.18 (d, 4H, J = 8.8 Hz, 2-H, 6- H ), 8.16 (s, 2H, NH), 8.99 (s, 2H, OH), ppm. 13C-NMR: (75 MHz, DMSO-d6) 5: 115.2
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(C-3, C-5), 120.3 (C-2, C-6), 131.5 (C-1), 152.3 (C-4), 153.1 (CO), ppm. MS (ES +): m / z 245.30 (M + H) +. (Franz, R. A. et al., J. Org. Chem. (1961) 26, 3309-3312).
EXAMPLE 16
N, N’-bis (2,5-Dimethoxyphenyl) urea (37)
image53
H H
Y
image54
image55
General procedure C. White needles. Rdto. 84% (Mp .: 207-209°C, MeOH; mp Lit = 209 ° C). HPLC: t R = 9.04 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (300 MHz, DMSO-cfe) 5: 3.69 (s, 6H, OMe), 3.80 (s, 6H, OMe), 6.49 (dd, 2H, J = 8.8,
3.0 Hz, 4-H), 6.90 (d, 2H, J = 8.9 Hz, 3-H), 7.84 (d, 2H, J = 2.9 Hz, 6-H), 8.96 (d, 2H, NH) ppm. 13C-NMR (75 MHz, DMSO-cfe) 5: 55.3 (OMe), 56.3 (OMe), 105.5 (C-6), 106.0 (C-4), 111.54 (C-3), 129.7 (C-1) , 142.4 (C-2), 152.6 (CO), 153.3 (C-5) ppm. MS (ES +):
333.0 (M + H) +. (Zhou, S. et al, J. Chem. Res. (2013) 37 (5), 315-319). N, N’-bis (2,5- Dihydroxyphenyl) urea (16)
image56
H H
Y
image57
image58
General Procedure B. Purified by column chromatography, EtOAc-Hex (1: 3 to 4: 1). Freeze dried solid. Rdto. twenty%. (P.10.109°Cd). HPLC: t R = 1.76 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (500 MHz, DMSO-da) 5: 6.19 (dd, 2H, J = 8.5,
2.9 Hz, 4-H), 6.59 (d, 2H, J = 8.5 Hz, 3-H), 7.47 (d, 2H, J = 2.9 Hz, 6-H), 8.6 (s, 1H, NH), 8.74 (s, 2H, OH), 8.99 (s, 2H, OH) ppm. 13C-NMR: (125 MHz, DMSO-d6) 5: 107.2 (C-6), 108.0 (C-4), 115.1 (C-3), 128.4 (C1), 138.7 (C-2), 149.9 (C -5), 153.0 (CO) ppm. MS (ES +): m / z 277.39 (M + H) +.
EXAMPLE 17
N, N-bis (4-Methoxyphenyl) -N ’- (4’-methoxyphenyl) urea (38)
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OMe
image59
General Procedure C. White solid. Rdto. 63% (Mp .: 153-156 ° C, MeOH). HPLC (Sunfire): t R = 7.24 min (gradient of 15 to 95% of A in B in 10 min). 1 H-NMR (400
MHz, CDCl3) 5: 3.77 (s, 3H, OMe), 3.81 (s, 6H, OMe), 6.31 (sa, 1H, NH), 6.81 (d, 2H, J
= 9.0 Hz, 3'-H, 5'-H), 6.91 (d, 4H, J = 8.8 Hz, 3-H, 5-H), 7.25 (d, 2H, J = 9.0 Hz, 2'-H , 6'- H), 7.27 (d, 4H, J = 8.8 Hz, 2-H, 6-H) ppm. 13C-NMR: (75 MHz, CDCl3) 5: 55.6 (OMe),
114.2 (C-3 ', C-5'), 114.9 (C-3, C-5), 121.3 (C-2 ', C-6'), 128.8 (C-2, C-6), 131.9 ( C), 135.5 (C), 154.4 (C), 155.8 (CO), 158.1 (C) ppm. MS (ES +): m / z 379.05 (M + H) +. N, N-bis (4-Hydroxyphenyl) -N ’- (4’-hydroxyphenyl) urea (17)
image60
HO ^ ^ OH
General Procedure B. Column, gradient of 35 to 75% AcOEt in hexane. Lyophilized pinkish solid. Rdto. 68% (Mp: 186-187°C). HPLC: t R = 7.15 min (gradient from 2 to 95% of A in B in 5min). 1H-NMR (400 MHz, DMSO-d6) 5: 6.60 (d, 2H, J = 8.9,
3'-H, 5'-H), 6.72 (d, 4H, J = 8.8, 3-H, 5-H), 7.05 (d, 4H, J = 8.7 Hz, 2-H, 6-H), 7.12 (d, 2H, J = 8.9 Hz, 2'-H, 6'-H), 7.41 (s, 1H, NH), 9.02 (s, 1H, OH), 9.43 (s, 2H, OH) ppm. 13C-NMR: (75 MHz, CDCh) 5: 114.7 (C-3 ', C-5'), 115.7 (C-3, C-5), 122.3 (C-2 ', C-6'), 128.7 (C-2, C-6), 131.2 (C), 134.9 (C), 152.8 (C), 154.6 (CO), 155.4 (C) ppm. MS (ES +): m / z 337.32 (M + H) +.
EXAMPLE 18
N- (2 ’, 5’-Dimethoxybenzyl) -N’ - (2 ”, 5” -dimethoxyphenyl) -N- (4-methoxyphenyl) urea (39)
image61
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General procedure C, using 1.5 mmol of amine. Purification by column chromatography, EtOAc-Hex (1: 3 to 3: 1). White prisms. Rdto. 17% (P.:91-94°C, Cl2CH2 / cyclohexane). HPLC: t R = 7.33 min (gradient from 30 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-d6) 5: 3.53 (s, 3H, OMe), 3.61 (s, 3H, OMe), 3.66 (s, 3H, OMe), 3.67 (s, 3H, OMe), 3.77 (s, 3H, OMe), 4.81 (s, 2H, N-CH2), 6.46 (dd, 1H, J = 8.8, 3.0 Hz, 4 '' - H), 6.77 (dd, 1H, J = 8.9, 2.9 Hz, 4'-H), 6.78 (d, 1H, 3'-H), 6.84-6.86 (m, 2H, 3 '' - H, 6'-H), 7.00 (d, 2H, J = 8.8 Hz , 3-H, 5-H), 7.11 (s, 1H, NH), 7.26 (d, 2H, J = 8.8 Hz, 2-H, 6-H), 7.77 (d, 1H, J = 3.0 Hz, 6 '' - H) ppm. 13C-NMR (100 MHz, DMSO-d6) 5: 47.25 (CH2), 55.2 (OMe), 55.3 (OMe), 55.4 (OMe), 55.7 (OMe), 56.5 (OMe), 104.6 (C-6 '' ), 105.6 (C-4 ''), 111.6 (C-4 '), 111.7 (C-3'), 112.0 (C-3 ''), 114.9 (C-6 '), 115.0 (C-3, 5), 127.0 (C), 129.3 (C-2, C-6), 129.5. (C), 133.5 (C), 141.6 (C), 150.9 (C), 153.0 (CO), 153.4 (C), 153.7 (C), 158.5 (C) ppm. MS (ES +): 453.1 (M + H) +. N- (2 ’, 5’-Dihydroxybenzyl) - N’ - (2 ”, 5” -dihydroxyphenyl) -N- (4-hydroxyphenyl) urea (18)
image62
General Procedure B. Purification by column chromatography, EtOAc-Hex (1: 3 to 4: 1). Solid white. Rdto. 10% (P.f.:114-115°Cd, MeOH). HPLC: t R = 5.40 min (gradient of 15 to 95% of A in B in 10 min). 1H-NMR (400 MHz, DMSO-d6) 5: 4.67 (s, 2H, N-CH2), 6.14 (dd, 1H, J = 8.5, 2.8, 4 '' - H), 6.43-6.48 (m, 2H , 4'-H, 3'-H), 6.56 (d, 1H, J = 8.6 Hz, 3 '' - H), 6.59 (d, 1H, J = 2.8 Hz, 6'-H), 6.80 (d , 1H, J = 8.7 Hz, 3-H, 5-H), 7.05 (s, 1H, NH), 7.10 (d, 1H, J = 8.7 Hz, 2-H, 6-H), 7.57 (d, 1H, J = 2.8 Hz, 6 '' - H), 8.62 (sa, 1H, OH), 8.65 (sa, 1H, OH), 8.78 (sa, 1H, OH), 8.88 (sa, 1H, OH), 9.72 (sa, 1H, OH) ppm. 13C-NMR: (100 MHz, DMSO-da) 5: 47.9 (N-CH2), 105.6 (C-6 ''), 107.6 (C-6 '), 114.4 (C-4' '), 114.5 (C -4 '), 115.3 (C-3' '), 115. 9 (C-3'), 116.5 (C-3, C-5), 124.7 (C),
128.2 (C), 129.5 (C-2, C-6), 132.0 (C), 137.5 (C), 147.2 (C), 149.7 (C), 150.0 (C), 154.4 (CO), 156.9 (C) ppm. MS (ES +): m / z 383.25 (M + H) +.
Comparison with other compounds derived from amides:
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image63
19: R = fBu; n = 1 20: R = H; n = 1 21: R = fBu; n = 0 22: R = H; n = 0
Scheme 3
image64
As a comparison and following the procedures for compounds 1 to 10 previously described, the amide derivatives 19 and 21, described in US2006 / 0233741A1, were also prepared. During the deprotection reaction, mono-tert-butyl derivatives 20 and 22, respectively, not described were also obtained.
EXAMPLE 19
3- (3 ’, 5’-Di-ferc-butylphenyl-4’-hydroxy) -N- (4-methoxybenzyl) propanamide (40)
tBu
XjLh.
image65
General Procedure A. White solid. Rdto. 59% Mp .: 126-128°C (EtAcO). HPLC: t R = 7.61 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, CDCfe) 5: 1.41 (s, 18H, CH3-tBu), 2.49 (dd, 2H, CH2, J = 8.7 and 7.0 Hz), 2.90 (dd, 2H, CH2, J = 8.7 and
7.0 Hz), 3.78 (s, 3H, OCH3), 4.35 (d, 2H, CH2N, J = 5.5 Hz), 5.10 (s, 1H, OH), 5.60 (sa, 1H, NH), 6.84 (d, 2H , 3,5-H, J = 8.7 Hz), 7.00 (s, 2H, 1'-H, 6'-H), 7.10 (d, 2H, 2-H, 6-H, J = 8.8 Hz). 13C-NMR (100 MHz, CDCfe) 5: 30.45 (6C, CH-tBu), 31.94 (CH2), 34.45 (2C, C-tBu), 39.23 (CH2), 43.25 (CH2), 55.42 (OCH3), 114.21 (2C, C-3, C-5), 124.98
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(2C, C-2 ', C-6'), 129.22 (2C, C-2, C-6), 130.39 (C), 131.43 (C), 136.11 (2C, C-tBu), 152.31 (C- OH), 159.10 (C-OH), 172.28 (CO). MS (ESI +): m / z 398.0 (M + H) +, 420.28 (M + Na) +.
3- (3 ’, 5’-Di-tert-butylphenyl-4’-hydroxy) -N- (4-hydroxybenzyl) propanamide (19)
“Om
General Procedure B. Starting from 39 (0.2g, 0.5 mmol) and using 2 equiv BBr3, this product is obtained together with 13% of 19. White solid, 0.90 g (47%). Mp .: 162-163 ° C (EtAcO / hexane). HPLC: t R = 6.25 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, DMSO-cfe) 5: 1.35 (s, 18H, CH3-tBu), 2.35 (t, 2H, CH2, J = 7.7 Hz), 2.71 (t, 2H, CH2, J = 7.7 Hz ), 4.13 (d, 2H, CH2N, J = 5.7 Hz), 6.67 (d, 2H, 3.5-H, J = 8.5 Hz), 6.70 (s, 1H, OH), 6.91 (s, 2H, 2 '-H, 6'-H), 6.98 (d, 2H, 2-H, 6-H, J = 8.5 Hz), 8.18 (t, 1H, NH, J = 5.8 Hz), 9.26 (s, 1H, OH). 13C-NMR (100 MHz, CDCfe) 5: 30.45 (CH3-tBu), 31.24 (CH2), 34.47 (C-tBu), 37.54 (CH2), 41.64 (CH2), 114.98 (2C, 3.5-C) , 124.22 (2C, C-2 ', C-6'), 128.56 (2C, C-2, C-6), 129.62 (C), 132.21 (C), 139.05 (2C, C-tBu), 151.90 ( C-OH), 156.18 (C-OH), 171.40 (CO). MS (ESI +): m / z 384.0 (M + H) +. EXAMPLE 20
image66
3- (3’-ferc-Butylphenyl-4’-hydroxy) -N- (4-hydroxybenzyl) propanamide (20)
tBu
image67
General Procedure B. Starting from 39 (0.2g, 0.5 mmol) and using 8 equiv BBr3, this product is obtained together with 39% of 18. White solid, 0.16 g (55%). P.f. 150-151 ° C (Cl2CH2 / MeOH). HPLC: t R = 4.18 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, DMSO-cfe) 5: 1.32 (s, 18H, CH3-tBu), 2.34 (t, 2H, CH2, J = 7.6 Hz), 2.70 (t, 2H, CH2, J = 7.5 Hz ), 4.11 (d, 2H, CH2N, J = 5.5 Hz), 6.64-6.68 (m, 3H, 3- H, 5-H, 5'-H), 6.81 (m, 1H, 6'-H), 6.95-6.97 (m, 3H, 2-H, 6-H, 2'-H), 8.16 (t, 1H, NH, J =
5.2 Hz), 9.08 (s, 1H, OH), 9.26 (s, 1H, OH). 13C-NMR (100 MHz, CDCh) 5: 29.42 (CH3-tBu), 30.80 (CH2), 34.21 (C-tBu), 37.62 (CH2), 41.57 (CH2), 114.97 (2C, C-3, C- 5), 115.91 (C-5 '), 126.26 (2C, C-2', C-6 '), 128.52 (2C, C-2, C-6), 129.66 (C), 130.97 (C), 134.82 (C-tBu), 153.92 (C-OH), 156.16 (C-OH), 171.36 (CO). MS (ESI +): m / z 328.0 (M + H) +.
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EXAMPLE 21
3- (3 ’, 5’-Di-ferc-butylphenyl-4’-hydroxy) -N- (4-methoxyphenyl) propanamide (41)
tBu
Oh
image68
General Procedure A. White solid. Rdto. 68% P.f. 172-174 ° C (EtAcO); m.p. Lit. = 170-175 ° C. HPLC: t R = 7.96 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, DMSO-d6) 5: 1.42 (s, 18H, CH3-tBu) 2.61 (t, 2H, CH2, J = 7.7 Hz), 2.97 (t, 2H, CH2, J = 7.7 Hz) , 3.78 (s, 3H, OCH3), 5.10 (s, 1H, OH), 6.83 (d, 2H, 3-H, 5-H, J = 8.9 Hz), 6.94 (sa, 1H, NH) 7.04 (s , 2H, 2'-H, 6'-H), 7.33 (d, 2H, 2-H, 6-H, J = 9.0 Hz), 9.26 (s, 1H, OH). MS (ESI +): m / z 384.32 (M + H) +. (US 2006/0233741 A1). 3- (3 ’, 5’-Di-ferc-butylphenyl-4’-hydroxy) -N- (4-hydroxyphenyl) propanamide (21)
image69
General Procedure B. Starting from 40 (0.2g, 0.5 mmol) and using 6 equiv of BBr3, this product is obtained together with 50% of 21. White solid, 0.05 g (26%). P.f. 240-242 ° C (EtAcO / hexane). HPLC: t R = 6.47 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, DMSO-cfe) 5: 1.34 (s, 18H, H-tBu) 2.49 (t, 2H, CH2, J = 7.2 Hz),
2.77 (t, 2H, CH2, J = 7.6 Hz), 6.67 (d, 2H, 3-H, 5-HJ = 8.9 Hz), 6.71 (s, 1H, OH), 6.94 (s, 1H, 2'- H, 6'-H), 7.35 (d, 2H, 2-H, 6-H, J = 8.9 Hz), 9.15 (s, 1H, NH), 9.64 (s, 1H, OH). 13C-NMR (100 MHz, CDCh) 5: 30.45 (CH3-tBu), 31.20 (CH2), 34.49 (C-tBu), 38.46 (CH2), 114.99 (2C, C-3, C-5), 120.83 ( 2C, C-2 ', C-6'), 124.24 (2C, C-2, C-6), 131.01 (C), 132.15 (C), 139.14 (2C, C-tBu), 151.96 (C-OH ), 153.11 (C-OH), 170.03 (CO). MS (ESI +): m / z 370.33 (M + H) +. (WO 2006/060800 A1)
EXAMPLE 22
3- (3’-ferc-Butylphenyl-4’-hydroxy) -N- (4-hydroxyphenyl) propanamide (22)
image70
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General Procedure B. Starting from 40 (0.2g, 0.5 mmol) and using 6 equiv BBr3, it is obtained together with 26% of 20. White solid, 0.08 g (50%). P.f. 96-8 ° C (Cl2CH2 / Hexane). HPLC (Sunfire): tR = 4.32 min (10 min gradient: 30 to 95% of A in B). 1H-NMR (400 MHz, DMSO-d6) 5: 1.34 (s, 18H, H-tBu), 2.48. (t, 2H, CH2, J = 7.6 Hz), 2.76 (t, 2H, CH2, J = 7.7 Hz), 6.64-6.68 (m, 3H, 3-H, 5-H, 5'-H), 6.84 (dd, 1H, 6'-H, J = 8.1, 2.0 Hz), 6.99 (d, 1H, 2'-H, J = 2.0 Hz,), 7.33 (m, 3H, H-2, H-6, H-6 '), 8.16 (t, 1H, NH, J = 5.2 MHz), 9.09 (s, 1H, OH), 9.14 (s, 1H, OH), 9.61 (s, 1H, OH). 13C-NMR (100 MHz, CDCl3) 5: 29.40 (CH3-tBu), 30.72 (CH2), 34.21 (C-tBu), 38.53 (CH2), 114.99 (2C, C-3, C-5), 115.97 ( 2C, C-2 ', C-6') 120.84 (2C, C-2, C-6), 126.20 (C), 126.26 (C), 130.91 (C), 131.00 (C), 134.87 (C-tBu ), 153.11 (C-OH), 153.94 (C-OH), 169.94 (CO). MS (ESI +): m / z 314.38 (M + H) +.
Antioxidant Activity
To determine the antioxidant activity, the ORAC (Oxygen Radical Absorbance Capacity) assay was used and fluorescell was used as oxidizable substrate. This test was carried out according to the method described by Ou et al. J. Agric. Food Chem. 49 (2001) 4619-4626, modified by Davalos et al. J. Agric. Food Chem. 52 (2004) 48-54.
This test measures the ability of the antioxidants present in a sample to neutralize peroxyl radicals, which originate from the thermal decomposition of 2,2'-azo-bis- (2-methylpropionamidine) dihydrochloride (AAPH) (Sigma- Aldrich) and that causes the oxidation of the fluorescell that acts as a substrate (Scheme 4). 6-Hydroxy-2,5,7,8-tetramethylchromano-2-carboxylic acid (Trolox) (Sigma-Aldrich), a soluble analogue of vitamin E., was used as the reference antioxidant.
The AAPH, the trolox and the samples were diluted in phosphate buffer (75 mM, pH 7.4). The trolox was diluted to obtain different concentrations (0.2 - 2 nmol) with which a reference calibration curve was constructed. AAPH and trolox solutions were prepared daily. A stock solution of fluorescell (1.17 mM) was also prepared in the same buffer, which was stored in the dark at 4 ° C for 4 weeks. The reaction was carried out in a final volume of 200 μl (20 μl of the corresponding sample, 120 μl of fluorescell and 60 μl of AAPH).
Fluorescence was measured using a fluorimeter (SpectraMax M2; Molecular Devices, California, USA), the excitation wavelength being 485 nm and the emission wavelength 520 nm. Black multi-well polystyrene plates (Nunc, Denmark) were used, and the fluorescence measurement was performed at 40 ° C every minute, for 95 minutes. The 5 fluorescence measurements were normalized with respect to the target (non-antioxidant). From the standardized curves, the area under the fluorescence descent curve (AUC) was calculated using the following formula:
i = 80
AUC = 1+ I fifteen
i = 1
Where fo is the initial fluorescence reading at 0 minutes and fi is the reading of 10 fluorescence after i minutes.
All samples were prepared in triplicate and at least three independent tests were carried out for each sample. ORAC values were expressed as pmol of trolox equivalents / pmol of pure compound, using the standard curve calculated for each test (Table 1).
image71
Scheme 4. Simplified scheme of the process of oxidation of fluorescell by peroxyl radicals produced by the thermal decomposition of 2,2'-azo-bis- (2-methylpropionamidine) dihydrochloride (AAPH). Taken from Ou et al., 2001.
Table 1. Antioxidant activity of compounds 1 to 22
 Compound  pure compound trolox / pmol pmoles
 one  11.0 ± 0.4
 2  8.1 ± 0.1
 3  19.2 ± 0.2
 4  14.4 ± 0.2
 5  5.2 ± 0.4
 6  9.4 ± 0.4
 7  19.2 ± 0.4
 8  19.3 ± 0.5
 9  29.5 ± 0.5
 10  27.6 ± 0.5
 eleven  6.6 ± 0.1
 12  12.5 ± 0.7
 13  7.8 ± 0.3
 14  9.6 ± 0.1
 fifteen  26.1 ± 0.3
 16  11.9 ± 0.4
 18  15.3 ± 0.7
 19  0.08 ± 0.003
 twenty  2.2 ± 0.2
 twenty-one  0.6 ± 0.04
 22  2.0 ± 0.2

权利要求:
Claims (29)
[1]
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1. Use of a compound of general formula (I)
R3
R4
4
image 1
3
Ri
■ 8
R,
■ 9
R5
R10
eleven
(I)
where:
X represents CH2 or NR12;
R1 and R12 independently represent hydrogen or optionally substituted aryl;
R2 to R11 independently represent hydrogen, -OH, -O (C1-C4) alkyl or (C1-C4) alkyl;
n and m are each, independently 0 or 1; or any of its salts,
with the proviso that at least one radical R2 to R11 is a group -OH, as an antioxidant.
[2]
2. Use according to claim 1, wherein R2 to R11 represent
independently hydrogen, -OH or -O (C1-C4) alkyl.
[3]
3. Use according to claim 2, wherein R2 to R11 represent
independently hydrogen, -OH or -OCH3.
[4]
4. Use according to any one of claims 1 to 3, wherein at least one radical R2 to R6 is a group -OH and at least one radical R7 to R11 is a group -OH, preferably at least one radical R2 to R6 is a group -OH and at least two radical R7 to R11 is a -OH group.
[5]
5. Use according to any one of claims 1 to 4, wherein R6 and R11 are hydrogen.
[6]
6. Use according to any one of claims 1 to 5, wherein R1 is hydrogen or aryl optionally substituted by at least one -OH group.
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[7]
7. Use according to any one of claim 6, wherein the aryl is a phenyl or benzyl group optionally substituted by at least one -OH group.
[8]
8. Use according to any one of claims 1 to 7, wherein n is 0 and / or m is 0.
[9]
9. Use according to any of claims 1 to 8, wherein X is CH2.
[10]
10. Use according to any one of claims 1 to 8, wherein X is NR12 and R12 is
hydrogen or aryl optionally substituted by at least one -OH group,
preferably R12 is hydrogen.
[11]
11. Use according to any of claims 1 to 10, wherein the compound is selected from:
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -N- (2,5-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
N- (2,5-Dihydroxyphenyl) -2- (2 ’, 5’-dihydroxyphenyl) acetamide,
N- (2,4-Dihydroxyphenyl) -2- (2 ’, 4’-dihydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N- (3,4-dihydroxyphenyl) acetamide,
2- (3 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
2- (2 ’, 4’-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide,
2- (2 ’, 5’-Dihydroxyphenyl) -N, N-bis (4-hydroxyphenyl) acetamide,
N- (2 ’, 5’-dihydroxybenzyl) -2- (2’ ’, 5’ - dihydroxyphenyl) -N- (4-Hydroxyphenyl) acetamide,
N- (2,4-Dihydroxyphenyl) -N ’- (2’, 5’-dihydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) - N- (3 ’, 4’-dihydroxyphenyl) urea, N- (3,4-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N, N’-bis (4-Hydroxyphenyl) urea,
N, N’-bis (2,5-Dihydroxyphenyl) urea,
N, N-bis (4-Hydroxyphenyl) -N '- (4-hydroxyphenyl) urea and N- (2', 5'-Dihydroxybenzyl) - N '- (2' ', 5' '- dihydroxyphenyl) -N- (4-hydroxyphenyl) urea.
[12]
12. Use according to any of claims 1 to 11, as an additive or preservative.
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[13]
13. Use according to claim 12, for the manufacture of a cosmetic, pharmaceutical, food or chemical composition.
[14]
14. Cosmetic use of a compound of general formula (I) described according to any of claims 1 to 11 against skin aging.
[15]
15. Use of a compound of general formula (I) described according to any of claims 1 to 11, as a food supplement.
[16]
16. Use of a compound of general formula (I) described according to any one of claims 1 to 11 for the preparation of a medicament.
[17]
17. Use of a compound of general formula (I) described according to any of claims 1 to 11 for the preparation of a medicament for the prevention or treatment of diseases related to oxidative stress selected from cardiovascular diseases, metabolic syndrome, inflammation , neurodegenerative diseases and cancer.
[18]
18. General formula compound (II)
image2
where:
R1 represents hydrogen or optionally substituted aryl;
R2 to R5 and R7 to R10 independently represent hydrogen, -OH, -O (C1-C4) alkyl or (C1-C4) alkyl; m is 0 or 1;
or any of its salts,
with the proviso that at least three radicals selected from R2 to R5 and R7 to R10 are a -OH group,
and with the proviso that the following compounds:
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N- (2,5-Dihydroxyphenyl) -2- (2 ', 5'-dihydroxyphenyl) acetamide, N- (2,5-Dihydroxyphenyl) -3- (2', 5'-dihydroxyphenyl) propanamide, N- (3 , 4-Dihydroxyphenyl) -2- (3 ', 4'-dihydroxyphenyl) acetamide, N- (3,4-Dihydroxyphenyl) -3- (3', 4'-dihydroxyphenyl) propanamide, and N- (4-hydroxy- 3,5-dimethylphenyl) -3- (3 ', 4'-dihydroxyphenyl) propanamide, are excluded.
[19]
19. Compound of formula (III)
image3
where:
R1 and R12 represents optionally substituted hydrogen or aryl;
R2 to R5 and R7 to R10 independently represent hydrogen, -OH, -O (C1-C4) alkyl or (C1-C4) alkyl; or any of its salts,
with the proviso that at least three radicals selected from R2 to R5 and R7 to R10 are a -OH group,
and with the proviso that the following compounds: N- (2,4-Dihydroxyphenyl) -N ’- (4’-hydroxyphenyl) urea,
N, N-bis (2,3-Dihydroxyphenyl) urea and N, N-bis (3,4-Dihydroxyphenyl) urea, are excluded.
[20]
20. Compound of general formula (II) according to claim 18 or of general formula (III) according to claim 19, wherein R2 to R5 and R7 to R10 independently represent hydrogen, -OH or -O-alkyl (C1-C4).
[21]
21. Compound according to claim 20, wherein R2 to R5 and R7 to R10 independently represent hydrogen, -OH or -OCH3.
[22]
22. Compound according to any of claims 18 to 21, wherein R1 is hydrogen or aryl optionally substituted by at least one -OH group.
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[23]
23. Compound according to claim 22, wherein the aryl is a phenyl or benzyl group optionally substituted by at least one -OH group.
[24]
24. Compound according to claim 18 selected from: N- (2,4-Dihydroxyphenyl) -2- (2 ', 5'-dihydroxyphenyl) acetamide, 2- (2', 4'-Dihydroxyphenyl) -N- (2 , 5-dihydroxyphenyl) acetamide, 2- (2 ', 5'-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide, N- (2,4-Dihydroxyphenyl) -2- (2', 4'-dihydroxyphenyl) acetamide , 2- (2 ', 5'-Dihydroxyphenyl) -N- (3,4-dihydroxyphenyl) acetamide, 2- (3', 4'-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide, 2- (2 ' , 4'-Dihydroxyphenyl) -N- (4-hydroxyphenyl) acetamide, 2- (2 ', 5'-Dihydroxyphenyl) -N, N-bis (4-hydroxyphenyl) acetamide and N- (2', 5'-dihydroxybenzyl) ) -2- (2``, 5 '' - dihydroxyphenyl) -N- (4-Hydroxyphenyl) acetamide.
[25]
25. Compound according to claim 19 selected from: N- (2,4-Dihydroxyphenyl) -N- (2 ', 5'-dihydroxyphenyl) urea, N- (2,5-Dihydroxyphenyl) -N- (4'- hydroxyphenyl) urea,
N- (2,5-Dihydroxyphenyl) - N- (3 ’, 4’-dihydroxyphenyl) urea, N- (3,4-Dihydroxyphenyl) -N- (4’-hydroxyphenyl) urea,
N, N’-bis (2,5-Dihydroxyphenyl) urea,
N, N-bis (4-Hydroxyphenyl) -N '- (4-hydroxyphenyl) urea and N- (2', 5'-Dihydroxybenzyl) - N '- (2' ', 5' '- dihydroxyphenyl) -N- (4-hydroxyphenyl) urea.
[26]
26. Composition comprising a compound as described in any of claims 18 to 25.
[27]
27. Composition according to claim 26, wherein said composition is pharmaceutical, cosmetic, chemical or food.
[28]
28. Composition according to any of claims 26 or 27, wherein the composition is in the form of sustained release.
[29]
29. Pharmaceutical composition comprising a compound described according to any one of claims 18 to 25 together with a pharmaceutically acceptable carrier.

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WO2017168024A1|2017-10-05|

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ES2639762B1|2018-09-11|

引用文献:

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CA2197364A1|1996-02-15|1997-08-16|Toshikazu Suzuki|Phenol compound and process for preparing the same|

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