Sulphur-containing resorcinol derivatives, methods for production thereof and cosmetic application

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where X=S, SO or SO2, and one of radicals R1 and R2 is a hydrogen atom and the other has a value given in the claim, which are used for depigmentation of the skin and/or hair and/or body hair and for skin disinfection, to cosmetic application of the disclosed compounds, and to compounds of formula (I), wherein R1 and R2 can also be a hydrogen atom at the same time. The invention also relates to a cosmetic composition and a pharmaceutical composition based on the disclosed compounds and to methods of producing said compounds.

EFFECT: improved properties.

19 cl, 2 tbl, 30 ex

 

The invention relates to novel analogues of resorcinarene, resorcinolarene and resorcinarene corresponding to General formula (I):

in which:

X=S, SO or SO2and

one of the radicals R1and R2represents a hydrogen atom, and the other radical:

- C1-C18normal or branched alkyl, optionally substituted by one or more than one halogen atom,

- C2-C18normal or branched alkenyl, in particular allyl group or a 3,3-dimethylallyl group, or geranyloxy group, or varnishlog group, optionally substituted by one or more than one halogen atom,

- aralkyl, in particular benzyl, optionally substituted by one or more than one group C1-C6alkoxy, or

- COR3or CONHR3but not both , where R3represents the radical:

- C1-C18normal or branched alkyl, optionally substituted by one or more than one halogen atom,

- C2-C18normal or branched alkenyl, optionally substituted by one or more than one halogen atom,

- aralkyl, in particular benzyl, optionally substituted by one or more than one group C1-C6alkoxy,

- aralkyl, optional someseni the one or more than one group C 1-C6alkoxy and/or IT group, or instead

- aryl radical, in particular phenyl, optionally substituted one or more than one group C1-C6alkoxy.

The term "alkyl" represents a normal or branched saturated aliphatic hydrocarbon chain and contains the specified number of carbon atoms.

The term "alkenyl" represents a normal or branched unsaturated aliphatic hydrocarbon chain and contains the specified number of carbon atoms, for example allyl group or a 3,3-dimethylallyl group, or geranyloxy group, or varnishlog group.

The term "alkoxy" represents a normal or branched hydrocarbon chain containing the specified number of carbon atoms and oxygen atom, such as methoxy group or ethoxypropan or propoxylate or butoxypropan.

The term "aryl" represents a monocyclic or bicyclic aromatic carbon ring, such as, for example, phenyl or naphthyl.

The term "aralkyl" denotes aryl, linked by alkyl, for example benzyl, ethylphenyl, propylphenyl. The term "aralkyl" denotes aryl associated with alkenyl, such as phenylacrylate, or (4-methoxyphenyl)acrylate, or (3,4-acid)acrylate.

The term "halogen" represents fluorine, chlorine, bromine or iodine.

The term"oleoyl" is a monovalent radical, formed from oleic acid in the loss of HE group.

The term "linoleoyl" is a monovalent radical formed from linoleic acid in the loss of HE group.

The term "alpha linoleoyl" is a monovalent radical formed from alpha-linoleic acid in the loss of HE group.

The term "gamma linoleoyl" is a monovalent radical formed from gamma-linoleic acid in the loss of HE group.

The term "coumaroyl" is a 4-hydroxycinnamic.

The term "caffeoyl" represents a 3,4-dihydroxycinnamic.

The term "verwaal" represents a 4-hydroxy-3-methoxycinnamyl.

The term "sinapol" represents a 4-hydroxy-3,5-dimethoxycinnamoyl.

Among the compounds of General formula (I) belonging to the present invention, especially an acceptable class of compounds correspond to compounds of General formula (I) in which X=S. similarly, the present invention particularly relates to compounds of General formula (I) in which X=S and R2=H.

Preferred compounds in accordance with the invention correspond to compounds of the formula (I) in which X=S, R2=H, and R1selected from the group consisting of: C1-C18normal or branched alkyl or C2-C18normal is whether branched alkenyl or COR 3and CONHR3.

In accordance with the form of implementation of the present invention compounds of General formula (I) are those compounds for which R1represents:

- C1-C8normal or branched alkyl and, in particular, C4-C8; or

- C2-C18normal or branched alkenyl selected from allyl group, or 3.3-dimethylethylene group, or gerbillinae group, or farnesenes group; or

- benzyl.

In accordance with the invention is especially appropriate class of compounds of General formula (I) corresponds to the compounds for which R3represents:

- C7-C15normal or branched alkyl and, in particular, C11-C15; or

- C10-C18normal or branched alkenyl, or

- benzyl; or

- aralkyl selected from phenylacrylate or (4-methoxyphenyl)acrylate or 3,4-acid)acrylate; or

is phenyl.

In accordance with the specific form of the invention, the compounds of General formula (I) are those compounds in which COR3represents:

- oleoyl or linoleoyl or alpha linoleoyl or gamma linoleoyl.

In accordance with another specific form of the invention, the compounds of General formula (I) are those with the organisations, in which COR3represents:

- cynnamoyl, substituted one or more than one group C1-C6alkoxy and/or IT group selected from kumarila or 4-methoxycinnamyl, or 3,4-dimethoxycinnamoyl or caffeoyl or perwaja or sinapore.

In accordance with the form of the invention, the compounds of General formula (I) can be selected from the following compounds:

- 4-(4-hydroxy-2-((2E,6E)-3,6,11-trimethyldodeca-2,6,10-5-trityloxy)phenylthio)benzene-1,3-diol,

- 4-(4-hydroxy-2-(3-methylbut-2-enyloxy)phenylthio)benzene-1,3-diol,

(E)-4-(2-(3,7-dimethylocta-2,6-vinyloxy)-4-hydroxyphenylazo)benzene-1,3-diol,

- 4-(2-butoxy-4-hydroxyphenylazo)benzene-1,3-diol,

- 4-(4-butoxy-2-hydroxyphenylazo)benzene-1,3-diol,

- 4-(4-hydroxy-2-(octyloxy)phenylthio)benzene-1,3-diol,

- 4-(2-hydroxy-4-(octyloxy)phenylthio)benzene-1,3-diol,

- 4-(2-(benzyloxy)-4-hydroxyphenylazo)benzene-1,3-diol,

- 4-(4-(benzyloxy)-2-hydroxyphenylazo)benzene-1,3-diol,

- 4-(4-hydroxy-2-(4-methoxybenzyloxy)phenylthio)benzene-1,3-diol,

- 4-(2-(decyloxy)-4-hydroxyphenylazo)benzene-1,3-diol,

- 4-(2-(hexadecylamine)-4-hydroxyphenylazo)benzene-1,3-diol,

- 2-(2,4-dihydroxyphenyl)-5-hydroxypentadecanoic,

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate,

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate,

- 4-(4 dihydroxyphenyl)-3-hydroxyphenylacetate,

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-phenylpropanoate,

- 4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl-3-phenylpropanoate,

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-methylbutanoate,

- 4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl-3-methylbutanoate,

- (9Z,12Z)-2-(2,4-dihydroxyphenyl)-5 - hydroxyphenylacetate-9,12-dienoate,

- (E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(4-methoxyphenyl)acrylate,

- (E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(3,4-acid)acrylate,

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenylethylamine,

- 2-(2,4-dihydroxydiphenylsulfone)-5-hydroxypentadecanoic,

- (9Z,12Z)-2-(2,4-dihydroxydiphenylsulfone)-5-hydroxyphenylacetate-9,12-dienoate,

- 4-(2-(decyloxy)-4-hydroxyphenylglycol)benzene-1,3-diol,

- 4-(2-(decyloxy)-4-hydroxyphenylethyl)benzene-1,3-diol.

The invention also relates to the cosmetic use of compounds of the formula (I'), which include, in addition, new analogues of the formula (I), resourceswhich, resorcinolarene and resorcinarene, and, in particular, to

their application for depigmentation of the skin, for use in the method of cosmetic treatment of aging skin. General formula (I'):

in which the radicals X, R1and R2have the meanings identical to those given above for formula (I), but where R1and R2could the t simultaneously represent a hydrogen atom.

The present invention relates to the cosmetic use of compounds of General formula (I') or formula (I) as an antioxidant active ingredient or as depigmenting active ingredient.

The object of the present invention is also the use of compounds of General formula (I) as medicaments, in particular as antibacterial active ingredient.

The invention also relates to pharmaceutical or cosmetic compositions containing at least one of the compounds of formula (I) or formula (I') in combination with at least one pharmaceutically or cosmetically acceptable excipients.

In the present invention, "pharmaceutically or cosmetically acceptable" is considered as denoting that it is useful for obtaining a pharmaceutical or cosmetic composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and which are acceptable for therapeutic or cosmetic use, in particular, by local application.

The object of the invention relates to cosmetic compositions, characterized in that the amount of the compounds of formula (I) or formula (I') ranges from 0.01% to 10% and preferably from 0.1% to 5 wt.% in relation to the total weight of the composition.

Now izaberete the s relates to a method for bleaching and/or whitening of the skin, and/or scalp and/or hair on the human head, comprising applying to the skin and/or hair and/or hair cosmetic composition containing at least one compound of formula (I) or formula (I').

The present invention relates to a method of cosmetic treatment and/or prevention of skin aging, comprising applying to the skin a cosmetic composition containing at least one compound of formula (I) or formula (I').

The object of the invention is also applicable to the method of synthesis of new compounds of the formula (I).

In accordance with another distinctive feature of the present invention, it also relates to a method for obtaining compounds of General formula (I), characterized in that 4,4'-ridibunda-1,3-diol or 4,4'-sulfanilic-1,3-benzodia subjected to interaction with the halide of formula II:

in which:

Hal represents a halogen atom, and R1has the same meaning as given above in relation to formula (I), with the exception of the hydrogen atom.

In accordance with another distinctive feature of the present invention, it also relates to a method for obtaining a derivative of resorcinol of the formula (I) in which X represents SO or SO2, characterized in that the compound of formula (I) in which X submitted is a sulfur atom, oxidized, in particular, an aqueous solution of hydrogen peroxide.

The present invention will be better understood in relation to the examples given below solely for illustrative purposes.

I. Synthesis of compounds according to the invention

1) Synthesis of analogues of resorcinarene

Example 1 (resorcinol):

- 4,4'-ridibunda-1,3-diol

1H NMR (400 MHz, DMSO-d6): δ: 6.19 (dd, 2H); 6.34 (d, 2H); 6.87 (d, 2H); 9.41 (broad s, 2H); 9.50 (broad s, 2H).

13C NMR (100 MHz, DMSO-d6): δ: 102.58; 107.52; 111.46; 133.90; 157.04; 158.37.

MS(IER-): 249.1 [M-N]-

A) Synthesis of ethers: Synthesis of ethers by combining resorcinarene with alkylhalogenide

To a suspension of 4,4'-ridibunda-1,3-diol (resorcinarene, 3 g, 12 mmol, 4 equiv.) and potassium carbonate (497 mg, 3.6 mmol, 1.2 EQ.) in 20 ml of anhydrous DMF (=dimethylformamide) in a nitrogen atmosphere add 856 mg farnesiana (3 mmol, 1 EQ.), the mixture is then stirred at 80°C for 6 hours. The reaction is monitored by TLC (=thin-layer chromatography).

After returning to room temperature the solvent is evaporated, then the residue is extracted with a mixture of ethyl acetate/water. The organic phase is washed twice with water, then saturated NaCl. After drying over magnesium sulfate receive solid material after evaporation of the solvent. This solid is washed DHM (=dichloro is an), then gather with obtaining 2 g of the original resorcinarene, which is not reacted.

Then the filtrate (DHM) is evaporated to obtain an oil, which was purified on silica gel with a mixture of heptane/ethyl acetate (95/5 to 50/50) or preparative HPLC. The product obtained in the form of a colorless oil, dried in vacuum over night. Then get 730 mg at exit 55%.

The structure was determined by proton NMR, carbon NMR, analysis NMFS (heteronuclear spin correlations with distant atoms), HMQC (heteronuclear multiquantum correlation) and NOESY (spectroscopy nuclear Overhauser effect).

Example 2:

- 4-(4-hydroxy-2-((2E,6E)-3,6,11-trimethyldodeca-2,6,10-trityloxy)phenylthio)benzene-1,3-diol

1H NMR (500 MHz, CDCl3): δ: 1.58 (s, 3H); 1.60 (s, 3H); 1.66 (s, 3H); 1.73 (s, 3H); 1.96 (m, 2H); 2.04 (m, 2H); 2.09 (m, 2H); 2.14 (m, 2H); 4.56 (d, J=6.4 Hz, 2H); 5.01 (s, 1H, HE steam S); 5.06 (s, 1H, HE steam S); 5.07 (m, 1H); 5.11 (m, 1H); 5.51 (t, 1H); 6.29 (d, J=8.5-2.4 Hz, 1H); 6.32 (d, J=8.2-2.7 Hz, 1H); 6.38 (d, J=2.4 Hz, 1H); 6.42 (d, J=2.7 Hz, 1H); 7.08 (d, J=8.5 Hz, 1H); 7.33 (s, 1H, HE ortho S); 7.38 (d, J=8.5 Hz, 1H).

13With NMR (125 MHz, CDCl3): δ: 16.04; 16.75; 17.69; 25.70; 26.20; 26.70; 39.54; 15 39.66; 65.99; 100.68; 102.31; 108.18; 108.33; 110.79; 115.32; 118.49; 123.62; 124.34; 131.38; 133.99; 135.50; 137.54; 142.24; 156.88; 158.09; 158.48; 158.73.

MS (ARS): 455.2 [M+H]+

Rf (1/1; Heptane/EtOAc): 0,75

Example 3:

- 4-(4-hydroxy-2-(3-methylbut-2-enyloxy)phenylthio)benzene-1,3-diol

From 1-bromo-3-methylbut-2-ene (=is alkylhalogenide)

1H NMR (400 MHz, CDCl3): δ: 1.76 (s, 3H); 1.82 (s, 3H); 4.56 (d, 2H); 5.07 (m, 2H, 2×OH couple S); 5.53 (t, 1H); 6.30-6.45 (m, 4H); 7.09 (d, 1H); 7.32 (s, 1H); 7.40 (d, 1H).

MS (chemical ionization at atmospheric pressure, APCI+): 319.0 [M+H]+

Example 4:

(E)-4-(2-(3,7-dimethylocta-2,6-vinyloxy)-4-hydroxyphenylazo)benzene-1,3-diol

From garnisheed.

1H NMR (400 MHz, CDCl3): δ: 1.62 (s, 3H); 1.68 (s, 3H); 1.75 (s, 3H); 2.13 (m, 2H); 4.59 (d, 2H); 4.80 (s, 1H); 4.85 (s, 1H); 5.11 (s, 1H); 5.53 (t, 1H); 6.30-6.45 (m, 4H); 7.09 (d, 1H); 7.32 (s, 1H); 7.41 (d, 1H).

MS (APCI+): 386.9 [M+H]+

Example 5:

- 4-(2-butoxy-4-hydroxyphenylazo)benzene-1,3-diol

1-bromobutane. The main product (590 mg)

1H NMR (400 MHz, CDCl3): δ: 1.01 (t, 3H); 1.53 (m, 2H); 1.88 (m, 2H); 4.02 (t, 2H); 4.78 (broad s, 2H, 2 HE a pair of S); 6.32 (m, 2H); 6.36 (s, 1H); 6.45 (s, 1H); 7.08 (d, 1H); 7.29 (s, 1H, HE ortho S); 7.40 (d, 1H).

MC (APCI+): 307,0 [M+H]+

Example 6:

- 4-(4-butoxy-2-hydroxyphenylazo)benzene-1,3-diol

1-bromobutane. The minor product (18 mg).

1H NMR (400 MHz, CDCl3): δ: 1.02 (t, 3H); 1.44 (m, 2H); 1.72 (m, 2H); 3.90 (t, 2H); 6.34 (d, 1 H); 6.41 (d, 1 H); 6.43 (s, 1 H); 6.49 (s, 1 H); 7.25 (m, 3H).

MC (APCI+): to 307.1 [M+H]+

Example 7:

- 4-(4-hydroxy-2-(octyloxy)phenylthio)benzene-1,3-diol 1-brometea. The main product (1.3 g).

1H NMR (400 MHz, CDCl3): δ: 0.91 (t, 3H); 1.30 (m, 8H) 1.47 (m, 2H); 1.88 (m, 2H); 3.99 (t, 2H); 4.90 (broad s, 2H); 6.30 (d, 1H); 6.35 (d, 1H); 6.36 (s, 1H); 6.45 (s, 1H); 7.07 (d, 1H); 7.32 (broad s, 1H); 7.41 (d, 1H).

MC (APCI+): 363,2 [M+H]+

Example 8:

- 4-(2-hydroxy-4-(octyloxy)phenylthio)benzene-1,3-diol 1-bromooctane. The minor product (100 mg).

1H NMR (400 MHz, CDCl3): δ: 0.87 (t, 3H); 1.27 (m, 8H); 1.41 (m, 2H); 1.72 (m, 2H); 3.90 (t, 2H); 6.34 (d, 1H); 6.41 (d, 1H); 6.44 (s, 1H); 6.48 (s, 1H); 7.25 (m, 3H).

MS (APCI+): 363,1 [M+H]+

Example 9:

- 4-(2-(benzyloxy)-4-hydroxyphenylazo)benzene-1,3-diol

From benzylbromide. The main product (600 mg).

1H NMR (400 MHz, CDCl3): δ: 4.80 (m broad, 2H); 5.14 (s, 2H); 6.34 (m, 2H); 6.44 (s, 2H); 7.02 (d, 1 H); 7.08 (s, 1 H); 7.34 - 7.41 (m, 6H).

MS (APCI+): 341,1 [M+H]+

Example 10:

- 4-(4-(benzyloxy)-2-hydroxyphenylazo)benzene-1,3-diol From benzylbromide. The minor product (28 mg).

1H NMR (400 MHz, CDCl3): δ: 5.00 (s, 2H); 6.34-6.57 (m, 4H); 7.28-7.39 (m, 7H).

MS (APCI+): 341,1 [M+H]+

Example 11:

-4-(4-hydroxy-2-(4-methoxybenzyloxy)phenylthio)benzene-1,3-diol 4-methoxybenzylamine. The main product (600 mg).

1H NMR (400 MHz, CDCl3): δ: 3.82 (s, 3H); 5.04 (s, 2H); 5.24 (m broad, 2H); 6.34 (m, 2H); 6.44 (m, 2H); 6.92 (d, 2H); 7.03 (d, 1H); 7.14 (broad s, 1H); 7.37 (m, 3H).

MS(ARS+): 371,0 [M+H]+

Example 12:

- 4-(2-(decyloxy)-4-hydroxyphenylazo)benzene-1,3-diol

The method of the example is 2, but with 2 equivalents of resorcinarene, 1 equivalent of 1-iododecane, 16 hours at room temperature. Product received in the form of a white solid after purification at exit 83%.

1H NMR (400 MHz, CDCl3): δ: 0.91 (t, 3H); 1.25 (m, 12H); 1.47 (m, 2H); 1.88 (m, 2H); 3.99 (t, 2H); 4.90 (broad s, 2H); 6.30 (d, 1H); 6.35 (d, 1H); 6.36 (s, 1H); 6.45 (s, 1H); 7.07 (d, 1H); 7.32 (broad s, 1H); 7.41 (d, 1H).

13With NMR (100 MHz, DMSO): δ: 13.89; 22.04; 25.39; 28.56; 28.65; 28.70; 28.89; 28.94; 31.24; 67.76; 100.18; 102,66; 107.47; 107.62; 107.98; 113.65; 130.42; 135.21; 156.83; 157.34; 158.20; 158.81.

MC(APCI+): to € 391.1 [M+H]+

Example 13:

- 4-(2-(hexadecylamine)-4-hydroxyphenylazo)benzene-1,3-diol

The same synthesis as SP02-131, from 1 iodohexane.

The product is obtained in the form of a white solid with yield of 84%.

1H NMR (400 MHz, CDCl3): δ: 0.88 (t, 3H); 1.2 (m, 24H); 1.47 (m, 2H); 1.84 (m, 2H); 3.92 (t, 2H); 5.31 (broad s, 2H); 6.27 (dd, 1H); 6.33 (s, 1H); 6.36 (d, 1H); 6.45 (s, 1H); 7.05 (d, 1H); 7.38 (broad s, 1H); 7.41 (d, 1H).

13C NMR (100 MHz, CDCl3): δ: 14.11; 22.68; 25.95; 28.89; 29.35; 29.56; 29.61; 29.66; 29.70; 31,91; 69.22; 100.39; 102,29; 108.19; 108.54; 110.89; 115.01; 133.93; 137.49; 156.88; 158.19; 158.40; 158.44.

MS (IER-): 473,2 [M-H]

C) Synthesis of esters

a) Path 1: the combination of resorcinarene

To a solution of 4,4'-ridibunda-1,3-diol (resorcinarene, 1 g, 4 mmol, 4 EQ.) triethylamine (177 μl, 1.2 mmol, 1.2 equiv.) in 20 ml of anhydrous THF (tetrahydrofuran) under nitrogen atmosphere was added kapl the m 219 mg laureillard (1 mmol, 1 EQ.), the mixture is then stirred at room temperature for 1 hour. The reaction is monitored by TLC.

After returning to room temperature the solvent is evaporated, then the residue is extracted with a mixture of ethyl acetate/water. The organic phase is washed twice with water, then saturated NaCl. After drying over magnesium sulfate, the solid obtained after evaporation of the solvent. This solid is washed DHM, then gather with the receipt of 510 mg of the original resorcinarene, which is not reacted.

Then the filtrate (DHM) is evaporated to obtain an oil, which was purified on silica gel with a mixture of cyclohexane/ethyl acetate (9/1) or preparative HPLC (high performance liquid chromatography). The product obtained in the form of a colorless oil, dried in vacuum over night. The product is solidified by cooling, then get 260 mg in the form of a white solid with yield of 60%.

Example 14:

- 2-(2,4-dihydroxyphenyl)-5-hydroxypentadecanoic

1H NMR (500 MHz, CDCl3): δ: 0.86 (t, J=7 Hz, 3H); 1.32 (m, 17H); 1.79 (q, J=7.6 Hz, 2H); 2.63 (t, J=7.5 Hz, 2H); 5.30 (s, 1H); 5.35 (s, 1H); 6.38 (dd, J=8.4 and 2.6 Hz, 1H); 6.45 (d, J=2.7 Hz, 1H); 6.48 (dd, J=8.5 and 2.7 Hz, 1H); 6.50 (d, J=2.4 Hz, 1H); 6.73 (d, J=8.5 Hz, 1 H); 6.76 (s, 1 H); 7.35 (d, J=8.5 Hz, 1 H).

13With NMR (125 MHz, CDCl3): δ: 14.12; 22.67; 24.83; 29.13; 29.22; 29.32; 29.44; 29.59; 31.89; 34.24; 103.01; 107.84; 108.72; 110.12; 14.67; 120.06; 130.45; 137.96; 148.93; 155.48; 158.48; 159.03; 172.98.

MC (APCI): 43371 [M+H]+

Rf (7/3; Heptane/EtOAc): 0,58

Example 15:

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenylarsonic

From octanoylthio.

1H NMR (400 MHz, CDCl3): δ: 0.82 (t, 3H); 1.29 (m, 8H); 1.63 (m, 2H); 2.35 (t, 2H); 6.41 (d, 1H); 6.49 (s, 1H); 6.56 (s, 1H); 6.57 (d, 1H); 6.81 (d, 1H); 7.39 (d, 1H 20).

MC(APCI+): 377,1 [M+H]+

Example 16:

- 4-(2,4-dihydroxyphenyl)-3-hydroxyphenylacetate

From octanoylthio.

1H NMR (400 MHz, CDCl3): δ: 0.88 (t, 3H); 1.33 (m, 8H); 1.72 (m, 2H); 2.3 (t, 2H); 6.36 (d, 1H); 6.41 (s, 1H); 6.58 (d, 1H); 6.71 (s, 1H); 7.31 (m, 2H).

MC(APCI+): 377,1 [M+H]+

Example 17:

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl 3-phenylpropanoate From hydrocinnamaldehyde.

1H NMR (400 MHz, CDCl3): δ: 2.98 (t Syst. AB, 2H); 3.13 (t Syst. AB, 2H); 5.40 (broad s, 2H); 6.41 (d, 1H); 6.46 (s, 1H); 6.48 (s, 1H); 6.54 (d, 1H); 6.79 (d, 1H); 7.22-7.38 (m, 6H).

MC (APCI+): 383,1 [M+H]+

Example 18:

- 4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl 3-phenylpropanoate From hydrocinnamaldehyde.

1H NMR (400 MHz, CDCl3): δ: 2.86 (t Syst. AB, 2H); 3.04 (t Syst. AB, 2H); 6.36 (d, 1H); 6.42 (s, 1H); 6.50 (d, 1H); 6.61 (s, 1H); 7.22-7.38 (m, 7H).

MC (APCI+): 383,1 [M+H]+

Example 19:

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl 3 methylbutanoate From isovaleraldehyde.

1H NMR (400 MHz, CDCl3): δ: 1.10 (d, 6H); 2.31 (m, 1H); 2.53 (d, 2H); 4.79 (broad s, 1H); 4.87 (broad s, 1H); 6.42 (d, 1H); 6.49 (s, 1H); 6.56 (s, 1H); 6.58 (d, 1H); 6.76 (s, 1H); 6.82 (d, 1H); 7.40 (d, 1H).

MC (APCI+): 335,0 [M+H]+

Example 20:

-4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl-3-methylbutanoate From isovaleraldehyde.

1H NMR (400 MHz, CDCl3): δ: 1.03 (d, 6H); 2.22 (m, 1H); 2.40 (d, 2H); 4.75 (broad s, 2H); 6.38 (d, 1H); 6.46 (s, 1H); 6.57 (d, 1H); 6.69 (s, 1H); 7.30 (m, 3H).

MS (APCI+): 335,1 [M+H]+

Example 21:

(9Z, E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate-9,12-dienoate

From linoleamide.

1H NMR (400 MHz, CDCl3): δ: 0.88 (t, 3H); 1.32 (m, 14N); 1.80 (m, 2H); 2.04 (m, 4H); 2.63 (t, 2H); 2.79 (t, 2H); 5.35 (m, 4H); 6.38 (d, 1H); 6.45 (s, 1H); 6.51 (m, 2H); 6.73 (d, 1H); 7.35 (d, 1H).

MS(IER):513,2[M+NG

Rf (1/1; Heptane/EtOAc): 0,75

b) Path 2: Mix by carbodiimide

To a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (960 mg, 5 mmol) and 4-DMAP (4-dimethylaminopyridine) (0.5 mmol) in 20 ml of anhydrous DMF in an atmosphere of N2add 620 mg of 4-methoxycatechol acid (3.5 mmol), the mixture is then stirred for 15 minutes. Add 3.5 g of 4,4'-ridibunda-1,3-diol (resorcinarene, 14 mmol, 4 equiv.) the mixture is then stirred at room temperature for 4 days.

The solvent is evaporated, then the residue purified on silica gel CHO3/Meon (95/5) to obtain the 320 mg of pure product in the form of a white solid after evaporation and drying in a vacuum oven. Yield: 22%.

Example 22:

- (E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(4-methoxyphenyl)acrylate

1H NMR (400 MHz, CDCl3): δ: 3.86 (s, 3H); 5.00 (broad s, 1H); 5.07 (broad s, 1H); 6.40 (dd, 1H); 6.48 (d, 1H); 6.60 (m, 2H); 6.64 (d, 1H); 6.85 (d, 1H); 6.95 (d, 2H); 7.40 (d, 1H); 7.58 (d, 2H); 7.91 (d, 1H).

MC (APCl+): 411,0 [M+H]+

Rf (1/1; Heptane/EtOAc):0,14

Example 23:

- (E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(3,4-acid)acrylate

From 3,4-dimethoxyphenol acid.

1H NMR (400 MHz, DMSO-d6): δ: 3.82 (s, 3H); 3.84 (s, 3H); 6.22 (d, 1H); 6.37 (d, 1H); 6.61 (s, 1H); 6.64 (d, 1H); 6.77 (d, 1H); 6.92 (m, 2H); 7.01 (d, 1H); 7.31 (d, 1H); 7.43 (s, 1H); 7.72 (d, 1H); 9.58 (m, 2H); 9.78 (m, 1H).

MS (IER+) 441,0 [M+H]+

Rf (95/5; DHM/Meon): 0,66

C. Synthesis of carbamates

To a solution of 4,4'-ridibunda-1,3-diol (resorcinarene, 5 g, 20 mmol, 4 equiv.) in 40 ml of anhydrous THF under nitrogen atmosphere is added dropwise to 0.88 ml activitiesat (5 mmol, 1 EQ.), the mixture is then stirred for 9 hours while boiling under reflux. The reaction is monitored by TLC.

After returning to room temperature the solvent is evaporated, then the residue is extracted with a mixture of ethyl acetate/water. The organic phase is washed twice with water, then saturated NaCl. After drying over magnesium sulfate, the solid obtained after evaporation of the solvent. This solid is washed DHM, the ATEM gather with obtaining the source resorcinarene, which is not reacted.

Then the filtrate (DHM) is evaporated to obtain an oil, which was purified on silica gel with a mixture of cyclohexane/ethyl acetate or preparative HPLC. The product obtained in the form of a colorless oil, dried in vacuum over night. Then get 540 mg in the form of a colorless oil in a yield of 27%.

Example 24:

- 2-(2,4-dihydroxyphenyl)-5-hydroxyphenylethylamine

1H NMR (400 MHz, CDCl3): δ: 0.86 (t, 3H); 1.26 (m, 8H); 1.35 (m, 2H); 1.59 (m, 2H); 3.32 (m, 2H); 5.30 (t, 1H); 5.93 (broad s, 1H); 6.23 (broad s, 1H); 6.35 (m, 2H); 6.41 (s, 1H); 6.52 (s, 1H); 6.63 (d, 1H); 7.32 (broad s, 1H); 7.35 (d, 1H).

MC (IER+): 406,1 [M+H]+

2) Synthesis of analogues of resorcinolarene

Example 25 (resorcinarene):

- 4.4 sulfonylamino-1,3-diol

1H NMR (400 MHz, DMSO-d6): δ: 6.32 (m, 4H); 7.10 (d, 2H); 9.82 (broad s, 2H); 10.13 (broad s, 2H).

MC (APCI): 267,0 [M+H]+

A) Synthesis of esters

A suspension of 4,4'-sulfanilic-1,3-bentolila (resorcinolarene, 2.66 g, 10 mmol, 4 equiv.) in 100 ml of anhydrous THF solubilizer in the hot condition and in nitrogen atmosphere, then after 5 minutes at room temperature add 420 μl of triethylamine (12 mmol, 1.2 EQ.). See rapid deposition, and then added dropwise 547 mg laureillard (2.5 mmol, 1 EQ.). The mixture is stirred for 2 hours at room temperature. the and the reaction monitored by TLC.

After returning to room temperature, the solid is filtered, then the filtrate is evaporated to obtain an oil, which was purified on silica gel with a mixture of heptane/ethyl acetate (80/20 to 50/50) or preparative HPLC. The product obtained in the form of white solid, dried in vacuum over night. Then get 511 mg at exit 46%.

Example 26:

-2-(2,4-dihydroxydiphenylsulfone)-5-hydroxypentadecanoic

1H NMR (400 MHz, DMSO-d6): δ: 0.86 (t, ZN); 1.24 (m, 16H); 1.53 (m, 2H); 2.45 (m, 2H); 6.28 (d, 1H); 6.33 (dd, 1H); 6.53 (s, 1H); 6.83 (dd, 1H); 7.12 (d, 1H); 7.43 (d, 1H); 9.88 (s1, 1H); 10.19 (s1, 1H); 10.27 (s1, 1H).

MC (APCI+): 449,2 [M+H]+

Rf (1/1; Heptane/EtOAc): 0,42

Example 27:

- (9Z,127)-2-(2,4-dihydroxydiphenylsulfone)-5-hydroxyphenylacetate-9,12-dienoate

From linoleamide.

1H NMR (400 MHz, DMSO-d6): δ: 0.84 (t, ZN); 1.29 (m, 14H); 1.55 (m, 2H); 2.00 (m, 4H); 2.42 (t, 2H); 2.76 (t, 2H); 5.33 (m, 4H); 6.28 (s, 1H); 6.35 (ds, 1H); 6.53 (s, 15 1H); 6.82 (d, 1H); 7.12 (d, 1H); 7.43 (d, 1H); 9.88 (s, 1H); 10.19 (s, 1H); 10.27 (s, 1H).

MC (IER): 529,2 [M+H]+

Rf (7/3; Heptane/EtOAc): 0.45

C) Synthesis of ethers by oxidation analogues resourceswhich

To a solution of example 12 (=4-(2-(decyloxy)-4-hydroxyphenylazo)benzene-1,3-diol) (320 mg) in 10 ml acetic acid is added 260 μl of a solution of 30% hydrogen peroxide (H2O (2.5 mmol, 3 equiv.) the mixture is then stirred for 3 hours at to matnog temperature.

Add 50 ml of water to precipitate the product. The obtained solid is collected, then dissolved in ethyl acetate, then this organic phase is washed with water, then saturated sodium chloride solution. After drying over MgSO4the solvent is evaporated to obtain a beige solid, which is dried overnight in a vacuum oven (50 mbar, 50°C). Obtain 310 mg of the product at the output 90%.

Example 28:

- 4-(2-(decyloxy)-4-hydroxyphenylglycol)benzene-1,3-diol

1H NMR (400 MHz, DMSO-d6): δ: 0.86 (t, 3H); 1.23 (m, 14H); 1.54 (m, 2H); 3.77-3.92 (m, 2H); 6.26 (d, 1H); 6.29 (s, 1H); 6.40 (d, 1H); 6.49 (dd, 1H); 6.98 (d, 1H); 6.76 (s, 1H); 7.28 (d, 1H); 9.80 (s, 1H); 9.98 (s, 1H); 10.06 (s, 1H).

13With NMR (100 MHz, DMSO-d6): δ: 13.89; 22.03; 25.14; 25.38; 28.29; 28.64; 28.66; 28.90; 28.93; 31.25; 67.86; 99.86; 102,38; 107.12; 107.49; 120.17; 121.72; 127.19; 127.68; 156.82; 157.07; 160.95; 161.18.

MS (IER+): 407,2 [M+H]+

Rf (1/1;Heptane/EtOAc): 0,12

3) Synthesis of analogues of resorcinarene

A) Synthesis of resorcinarene

To a solution of 4,4'-ridibunda-1,3-diol (resorcinarene, 10 mmol, 2.5 g) in a mixture of acetone/acetic acid (1/1, 60 ml) is added 5,12 ml of 30% solution of hydrogen peroxide (H2O (30 mmol), the mixture is then stirred for 72 hours at room temperature.

The solvent is evaporated, and the resulting solid is dissolved in ethyl acetate to obtain white solids. After filtration of the TV is Gogo matter, the filtrate is evaporated, then from this residue purified on silica gel to obtain 320 mg of a white solid.

Example 29:

- 4,4'-sulfonylamino-1,3-diol (resourceswhen)

1H NMR (400 MHz, DMSO-d6): δ: 6.24 (d, 2H); 6.33 (dd, 2H); 7.61 (d, 2H); 10.06 5 (s, 1H); 10.16 (s, 1H).

13With NMR (100 MHz, DMSO-d6): δ: 102.73; 106.41; 117.98; 131.54; 157.14; 162.86.

Rf(9/1; AXM/MeOH):0,6

C) Synthesis of analogues of resorcinarene by oxidation analogues resourceswhich to resorcinarene

To a solution of example 12 (=4-(2-(decyloxy)-4-hydroxyphenylazo)benzene-1,3-diol) (195 mg, 0.5 mmol) in 10 ml acetic acid is added to 2.8 ml of 30% solution of hydrogen peroxide (H2O (25 mmol, 50 equiv.) the mixture is then stirred for 48 hours at room temperature.

Add 50 ml of water to precipitate the product. The obtained solid is collected on a sinter, and then washed twice with water, then twice with n-pentane. Then the solid is dried overnight in a vacuum oven (50 mbar, 50°C) to obtain white solid. Obtain 135 mg of the product at the exit 64%.

Example 30:

- 4-(2-(decyloxy)-4-hydroxyphenylethyl)benzene-1,3-diol

1H NMR (400 MHz, DMSO-d6): δ: 0.87 (t1, ZN); 1.26 (m, 14H); 1.44 (ml, 2H); 3.77 (ml, 2H); 6.22 (s, 1H); 6.30 (d, 1H); 6.35 (s, 1H); 6.44 (d, 1H); 7.59 (d, 1H); 7.74 (d, 1H); 9.97 (s, 1H); 10.10 (s, 1H); 10.30 (s, 1H).

13C NMR (100 MHz, DMSO-d6: δ: 13.89; 22.02; 25.29; 28.25; 28.64; 28.75; 28.88; 28.92; 31.24; 67.96; 99.78; 102.66; 106.04; 106.28; 117.91; 119.88; 131.65; 131.82; 156.97; 157.69; 162.77; 163.15.

II the Results of biological tests

1) Protocols

A) Definition depigmentary activity in a cell-free test in vitro: test for inhibition of tyrosinase

- Principle:

This test is used to assess depigmenting activity of the tested molecules. Tyrosinase is the limiting enzyme in melanogenesis.

It belongs to the family of oxidoreductases. She, in particular, has the functions of monitormanagement (MRMO) and polyphenoloxidase (PPO).

This enzyme is synthesized at the level of melanocytes. It is activated during its migration in the direction of melanosomes to the keratinocytes. It converts tyrosine to DOPA, then dopamine, which leads in the end to the polymerization, i.e. the production of pigments (see chart below).

Tyrosinase
O2O2
SlowQuick Polyphenol oxidase
irosin Monophenol Dov monooxygenaseDopamine
MRMOPPO

The substrate L-tyrosine function monitormanagement converted to L-DOPA, which is converted by the function polyphenoloxidase tyrosinase in dopamine. The latter undergoes auto-oxidation to dopachrome, which is measured by spectrophotometry at 490 nm.

Rather, it is measured the total activity of tyrosinase (Mrod), because in the end analyze it diagram. Thus, the products are tested on Mermod (=measurement of the activity of PPO and MRMO), can combine the 2 inhibition functions

- unique inhibition functions MRMO in the strict sense (the conversion of tyrosine into DOPA) as a Supplement to the test PPO,

- can uniquely to inhibit PPO.

General experimental conditions:

Reader: the program Synergy HT: kinetics of tyrosinase 280-490: kinetics for 45 minutes, reading at t=10 minutes. Tests in 96 clear wells, phosphate buffer pH 6.8, enzymes: tyrosinase mushrooms - Sigma=T-3824, substrate: L-tyrosine - Sigma=T - 3754, positive control: kojic acid (KA) Peak=60890 (reference inhibitor)

- R is veresnya molecules to test:

Kojic acid: 9 μm<IC50<20 μm (PPO), 3 μm<IC50<7 μm (MRMO)

Vitamin C: 20 μm<IC50<40 μm (PPO)

Restored glutathione: 55% inhibition at 25 μm (PPO), an IC50 of 1-2 μm(MRMO)

Hydroquinone: IC50=3-4 μm (MRMO)

Arbutin: 57% inhibition at 88 microns (MRMO)

It is known that these exogenous molecules negatively regulate melaninogenica. Hydroquinone inhibits melanin synthesis by his prezentowania as a substrate of tyrosinase to distract her activity. Arbutin containing hydroquinone, acts in the same way. Kojic acid reduces the activity of tyrosinase by inhibition of increased pigmentation induced by UV light. Vitamin C will not inhibit tyrosinase, but will behave as a powerful reducing agent by preventing staining of melanin as a result of oxidation. Vitamin a reduces the expression of tyrosinase.

C) Quantitative analysis of melanin in cells B16-F10:

Principle:

In this test involved the measurement of melanin synthesis by colorimetric analysis on cell lines of melanoma mouse: line B16-F10. This test allows to evaluate depigmentosus the ability of the active ingredients.

Cells B16-F10 were cultured in 96-well tablets in DMEM with the addition of FTS (fetal calf serum) and incubated for 24 hours at 37°C, 5% CO 2. The cells are then stimulated with 0.1 μm of a-melanotropin (to stimulate the synthesis of melanin, the observed stimulation is approximately 150%) and processed within 72 hours of the tested active ingredients. Each concentration of active ingredient tested in at least three repetitions. Then the total melanin, and then intracellular melanin dissolved in buffer for lysis, analyze by reading the absorption at 405 nm. Total analyze proteins in the lysate and the results expressed in mg of melanin/mg protein. The percentage of activity is calculated as described below:

A negative value indicates inhibition, whereas a positive value indicates an induction of the synthesis of melanin.

General experimental conditions:

- Equipment:

CO2incubator cells (Heraeus), Oven, Centrifuge (Heraeus), exhaust system with laminar air flow, 96-well tablets with a transparent bottom - Falcon sterile conical tubes - Treff Lab, Polylabo, Mithras LB940 (Berthold Technologies)- 154/MIPA./003

- Biological equipment:

The cell line B16-F10 between P10 and P20 (melanocytes mouse) (ATS, CRL-6475)

- Reagents:

- DMEM without phenol red (GibcoBRL, 31053-028), the addition of 200 mm Glutamax-l (GibcoBRL, 35050-038), D-FSB (GibcoBRL, 14190-094), fetal calf serum (Invitrogen, 10270-098), Trypsin - EDTA (GibcoBRL, 25300-054), NaOH (Sigma, S8045-500G), DMSO (Sgma, 471267-1 L), NIe, Phe - melanotropin (Sigma, M-8764), melanin (Sigma, M-0418), BCA-Copper (Sigma, B9643 and S), BCA(Sigma,P0914).

C) Test for the study of antioxidant capacity using chemiluminescence (Photochem Analytik Jena)

- Principle:

This test is used to determine the antioxidant capacity of the molecules. It is a method that produces free radicals as a result of photochemical signal. The intensity of oxidation is 1000 times higher than those obtained in normal conditions.

Detection is performed using chemiluminescence. It provides an estimate of water-soluble and fat-soluble antioxidant molecules or extracts.

The results are expressed respectively as the equivalent amount of vitamin C or trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). The order of sensitivity is nanomolar.

Antioxidant activity were studied in this test is a specific ability to capture the superoxide anions by chemiluminescence.

Quantitative results are expressed in terms of trolox (standard), or "mcg product on 1 µg trolox". This means that the number of sample x, you need to get the activity equivalent to the activity defined for 1 μg of the standard. This number is an antioxidant with osobnosti relatively standard, that makes it possible not to take into account the tested concentration.

- The generation of oxygenated free radicals:

Superoxide radical: O20-generated by photochemical reactions:

L+hv (UV)+O2→ L*O2→L0++O20-

L*: luminal in the excited state

L0+: luminal radical

- Signal:

Part superoxide anions extinguished by antioxidants. The rest of the free radicals quantitatively determined using chemiluminescence.

L0++O20-→ N2+AR*2-→ AR2-+hv (luminescence)

AR*2-: aminophthalate in the excited state

NameConditionsPhotosensitivityAntioxidant
Net control100% generated O2+-
StandardsStandard range: from 1 to 3 nmol+Vitamin C or trolox
Test+/- generated O20- +The test molecule x

D) Test the protection of linoleic acid after UV stress

Target: protection of linoleic acid in the conditions of Fenton, UV irradiation

Linoleic acid belongs to the family of polyunsaturated fatty acids (Pufas). Sensitive to oxidation, linoleic acid is a favorable target for oxygenated free radicals (SRS) in biological environments. When biological membranes are exposed to oxidative stress, the most affected components are phospholipids comprising polyunsaturated fatty acids and cholesterol. Their decay leads to lipid peroxidation and, as a rule, to their destruction. Lipid peroxidation is autocatalytically process, which usually involved SRF. Lipid peroxidation is partly responsible for skin aging.

Used way to assess lipid peroxidation is based on a combination thiobarbituric acid (TBA) and secondary degradation products, resulting in colored compounds detectable with spectrofluorimetry. Significant secondary connection end of the collapse is malondialdehyde, MDA. MDA is carcinogenic and mutagenic aldehyde, it acts on proteins and DNA.

- Principle of the test:

The test sample is placed is in contact with linoleic acid in the ratio of the masses./mass. The sample undergoes irradiation MED (minimal erythema dose) in Fenton, namely in the presence of H2O2and iron II in the simulator solar radiation.

After irradiation, the reaction mixture was dissolved in methanol and derivateservlet at 90°C TBQ. A Chromogen, a complex of MDA-TBA, representative equimolar production of MDA, quantitatively determined with the aid of fluorimetry (excitation at 525 nm, emission at 549 nm).

The results are expressed in units of fluorescence depending on the control range of the MDA-TBA, then expressed as the concentration of the complex of MDA-TBA. Then determine the percentage of the original relationship MDA/linoleic acid (LA). Then determine the percentage of protection of linoleic acid.

(E) Determining the minimum inhibitory concentration (MIC):

This test is used to determine the antibacterial activity of the compounds. Tests carried out with 4 bacterial strains, using the principle of microdesmidae. MICK determine micromethods in a liquid medium. Serial dilutions in accordance with tested drugs in the culture medium (trypticase-soy broth) carried out on 96-well microplate in a final volume of 0.1 ml Wells seeded with 0.01 ml of the bacterial suspensions, titrated at about 107CFU/ml Microplates incubated in optimal condition is the conditions of growth and MICK read visually.

2) Results:

A) Definition depigmentary activity in a cell-free test in vitro: test for inhibition of tyrosinase

All results are grouped together in total table 1, are included in this proposal below.

- Refer to the results tyrosinase test:

Interesting activity +++Very good activity>80% analysis from 250 to 150 microns
Interesting activity ++Good activity>30% analysis from 250 to 150 microns

(B) Quantitative analysis of melanin in cells B16-F10:

The results are also grouped together in the total table 1 below.

Interpretation of results:

A negative value indicates inhibition, whereas a positive value indicates an induction of the synthesis of melanin.

It can be noted that most of the tested compounds shows good ability to inhibition of melanin synthesis. Thus, the invention relates to the cosmetic use for depigmentation of the skin of the compounds of General formula (I) or (I').

C) Test for the study of antioxidant capacity using

chemiluminescence (Photochem Analytic Jena)

The results is also grouped together in the total table 1 below. Most of the compounds have good antioxidant activity.

The scale for the interpretation of the results is shown below:

Drugság of sample per 1 µg troloxActivity
Vitamin C0,1-3,0Very good
OSH3,01-50Good
Cysteine50,1-1000Average
Albumin>1000Low
Lipoic acidNEGATIVENo

Most of the compounds shows results comparable with vitamin C. All compounds show results less than 1000 µg trolox (301 where µg is the lowest result obtained from resorcinarenes); they, therefore, have an interest antioxidant activity. The invention also relates to the cosmetic use for the prevention and/or treatment of skin aging compounds of General formula (I) or (I').

D) T is St protection of linoleic acid after UV stress

The results are also grouped together in the total table 1 below. Negative control is linoleic acid, which is not subjected to stress, UV radiation, and thus, chemically non-irradiated, (BUT). HE is representative for basal oxidation associated with the environment. It corresponds to the basal nonspecific production is very low (of the order of 10TH 7-7M).

Positive control is quercetin, which has almost complete protection at 1% and which protects partially (about 50%) at 0.1%.

Quantitative analysis of the product is expressed as the mass ratio./mass., in other words, in percent mass./mass. in relation to the total amount of linoleic acid. The maximum level of MDA was determined by conditions UV+H2O2+iron II (F).

The percentage protection of linoleic acid is a ratio of % of MDA in conditions of maximum stress without processing to % MDA under stress and spraying.

The molecule is considered significantly active, if its regarding the protection of linoleic acid above 20%. Thus, all the tested molecules are significantly active.

Table 1
ExampleRez is ltat depigmentary activity in gyrosensor test Results of activity of B16 -% if X mcmág of sample per 1 µg trolox% protection of linoleic acid under conditions of UV/Fenton
Example 1+++ 1 µm-50% (61 μm)2390%
Example 2++-50% (14 µm)the 9.792%
Example 3+++-41% (20 μm)the 4.787%
Example 4+++-35%(10 μm)5,289%
Example 5+++-27% (20 μm)2,889%
Example 6+++-30% (20 μm)14,9
Example 7+++-50% (10 μm) 3,492%
Example 8+++-40% (10 μm)18,897%
Example 9+++-31% (20 μm)3,285%
Example 10+++-20% (20 μm)2294%
Example 11+++-34% (20 μm)3,591%
Example 12+++3,496%
Example 13*the 5.795%
Example 14+++ 7 µM-50% (48 μm)4,8
Example 15++-20% (10 μm) 3075%
Example 16+++33,291%
Example 17+++-50% (92 μm)a 3.987%
Example 18+++-20% (50 μm)24,190%
Example 19+++-20% (50 μm)2,888%
Example 20+++-24% (50 μm)25,691%
Example 21+++ 11 µM-50% (32 μm)5,9
Example 22+++-2,597%
Example 23+++- 2,896%
Example 24+++-26% (50 μm)the 3.897%
Example 25+++ 12 mm-50% (73 µm)7379%
Example 26+++-6980%
Example 27+++-4078%
Example 28++-2894%
Example 29--30125%
Example 30--14734%

(E) Determining the minimum inhibitory concentration (MIC):

The results are grouped together in table 2. Connection consider the region is surrounding a very good antibacterial activity, when it has a MIC below 1 million-1. Antibacterial activity is considered good when MICK is from 1 million-1up to 100 million-1. Antibacterial activity is considered average when it is 100 million-1up to 1000 million-1.

Table 2
Bacterial strainsExample 5Example 7Example 12Example 13
Staphylococcus aureus IP4.83 ATS6 million-10.78 million-10.78 million-1190 million-1
Staphylococcus epidermidis IP of 6,8213 million-10,39 million-10,39 million-1156 million-1
P. acneslP53.117 ATCC69193 million-10,09 million-10,09 million-190 million-1
Escherichia coli IP53126ATCC8739-390 million-1 780 million-1-

The tested compounds exhibit significant antibacterial activity. In particular, examples 7 and 12 show a strong antibacterial activity against strains of Propionibacterium acnes.

III. The composition in accordance with the invention

Ingredients (trade name)Designation of INCIThe percentage of mass./mass.Function
I. Distilled waterWaterSQF 100%
Hydrolite 5Pentilenglikol3Humectant, preservative
EDTA 2NaThe disodium salt of EDTA0,1Complexing agent
Microcare PM4Phenoxyethanol - Paraben0,8Preservatives
Water solubleTrideceth-9 and PEG-51,5 Water softener
PCLEthylhexanoate
II. Pemulen TR-1Cross-linked polymer Acrylates/C10-30alkyl0,5Gelling agent, stabilizer
III. Stearin TRStearic acid2The emulsifier, the consistency factor
Liquid PCLCatherinethegreat and isopropylmyristate3The softener
DC200Dimethicone0,3The softener
Myritol 318Triglycerides of capric or Caprylic acid3The softener
Primol 352Liquid petrolatum2The softener
IV. Depigmentary active ingredient/td> The active ingredient
V. sodium HydroxideNaOH0,08The pH Adjuster

In such compositions, the percentage of active ingredient may vary from 0.01% to 10 wt.% and preferably from 0.1% to 5 wt.% with respect to the total weight of the composition.

The invention also relates to pharmaceutical or cosmetic compositions containing at least one of the compounds of formula (I) or formula (I') in combination with at least one pharmaceutically or cosmetically acceptable excipients.

In accordance with the specific form of the invention, the pharmaceutical or cosmetic compositions contain at least one of the compounds of formula (I) or formula (I') in combination with at least one pharmaceutically or cosmetically acceptable excipients and fat phase.

In accordance with the specific form of the invention, the pharmaceutical or cosmetic compositions contain at least one of the compounds of formula (I) or formula (I') in combination with at least one pharmaceutically or cosmetically acceptable excipients and softener.

The present invention relates to cosmetics the second composition for depigmenting the skin, and/or hair and/or hair, characterized in that it contains at least one compound of formula (I) or formula (I').

The invention also relates to cosmetic compositions against aging of the skin, characterized in that it contains at least one compound of formula (I) or formula (I').

The invention also extends to a pharmaceutical composition for disinfection of the skin, characterized in that it contains at least one compound of formula (I).

The composition in accordance with the invention may additionally contain conventional cosmetic adjuvants, in particular selected from fatty phase, organic solvents, thickeners, softeners, cloud emulsions, stabilizers, softeners, defoamers, hydrating agents, aromatic substances, preservatives, such as parabens, polymers, fillers, components with exfoliating action, bactericidal agents, odor absorbers, alkalizing or acidifying agents, surfactants, removers free radicals, antioxidants, vitamins E and C, α-hydroxyacids or thermal water, such as Avène thermal spring water, or any other ingredient, usually used in cosmetics, in particular, to obtain compositions of this type. The composition in accordance with what Subramaniam may further comprise a fatty phase. The fatty phase may consist of oil, or wax, or mixtures thereof, and also contains fatty acids, fatty alcohols and esters of fatty acids. Oil can be selected from vegetable, animal, mineral or synthetic oils and, in particular, vaseline oil, paraffin oil, silicone oils, volatile or non-volatile, such as Dimethicone; ISO, polyolefins, fluorinated and perfluorinated oils. Similarly, the waxes may be chosen from animal, fossil, vegetable or synthetic waxes such as bee wax, candelilla wax, Carnauba wax, Shea butter, petroleum wax or microcrystalline wax), paraffin and mixtures thereof. The composition in accordance with the invention may further comprise a polyol, miscible with water at room temperature (about 25°C), in particular selected from polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms and preferably having from 2 to 6 carbon atoms, such as glycerol; derivatives of glycols, such as propylene glycol, butyleneglycol pentilenglikol, hexyleneglycol, dipropyleneglycol, diethylene glycol; glycol ethers, such as C1-C4alkalemia esters of mono-, di-tripropyleneglycol, C1-C4alkalemia esters of mono-, di -, triethylene glycol; as well as them from the Yessei.

The composition in accordance with the invention may also contain thickeners or agents modifying rheological properties, such as, for example, nonionic ethoxylated hydrophobic modified urethanes, thickeners, representing polycarboxylic acids, such as copolymers of acrylates/steareth-20 and methacrylate, carbomer, vulcanized copolymers of acrylate and mixtures thereof.

The composition in accordance with the invention may also contain acids and bases, making it possible to adjust the pH range of the composition. the base can be inorganic (sodium hydroxide, potassium hydroxide, aqueous ammonia and so on), or organic, such as mono-, di - or triethanolamine, aminomethylpropanol, N-methylglucamine, basic amino acids such as arginine and lysine, and mixtures thereof.

The composition in accordance with the invention may also contain means of skin care. Examples of means of skin care include, but are not limited to, anionic, cationic and nonionic emulsifiers such as sodium lauryl sulfate, dioctylsulfosuccinate sodium, sodium stearate, ester sorbitan; ethoxylated fatty acids; ethoxylated fatty alcohols, such as Trideceth-9 and PEG-5 ethylhexanoate; stearic acid; and other emulsifier and tool care, well-known specialists in the field of those who IKI; as well as mixtures thereof.

The composition in accordance with the invention may in addition contain other active ingredients, leading to a complementary effect.

The composition in accordance with the invention can be provided in any form suitable for topical application, in particular on the skin and/or hair. In particular, they may take the form of emulsions obtained by dispersing an oil phase in the aqueous phase, such as emulsion, oil-in-water or water-in-oil or multiple emulsion, or in the form of a gel or liquid, paste or solid anhydrous product, or in the form of a dispersion in the presence of Sterol. The composition in accordance with the invention may also be less liquid and may be in the form of a white or colored cream, ointment, milk, lotion, serum, paste, mask, powder, solid stick or optional aerosol foam or spray.

1. The compound of General formula (I)

in which:
X=S, SO or SO2and
one of the radicals R1and R2represents a hydrogen atom, and the other radical:
- C1-C18normal or branched alkyl, optionally substituted by one or more than one halogen atom,
- C2-C18normal or branched alkenyl, optionally substituted by one or more than one halogen atom, Il the
- aralkyl, optionally substituted by one or more than one group C1-C6alkoxy, or
- COR3or CONHR3but not both , where R3represents the radical:
- C1-C18normal or branched alkyl, optionally substituted by one or more than one halogen atom,
- C2-C18normal or branched alkenyl, optionally substituted by one or more than one halogen atom,
- aralkyl, optionally substituted by one or more than one group C1-C6alkoxy,
- aralkyl, optionally substituted by one or more than one group With1-C6alkoxy and/or one or more than one IT group, or instead aryl radical, optionally substituted by one or more than one group With1-C6alkoxy.

2. Connection on p. 1, characterized in that X=S.

3. Connection on p. 1, characterized in that X=S and R2=H.

4. Connection on p. 1, characterized in that X=S, R2=N and R1selected from the group consisting of:1-C18normal or branched alkyl, C2-C18normal or branched alkenyl and COR3or CONHR3as defined in paragraph 1.

5. Connection on p. 1, characterized in that R1is:
- C1-C8n is rmally or branched alkyl and in particular, C4-C8; or
- C2-C18normal or branched alkenyl selected from allyl group, or 3.3-dimethylethylene group, or gerbillinae group, or farnesenes group; or
- benzyl.

6. Connection on p. 1, characterized in that R3is:
- C7-C15normal or branched alkyl and, in particular, With11-C15; or
- C10-C18normal or branched alkenyl; or
- benzyl; or
- aralkyl selected from phenylacrylate or (4-methoxyphenyl)acrylate or 3,4-acid)acrylate; or
is phenyl.

7. Connection on p. 1, characterized in that it is selected from the following compounds:
- 4-(4-hydroxy-2-((2E,6E)-3,6,11-trimethyldodeca-2,6,10-trityloxy)-phenylthio)benzene-1,3-diol,
- 4-(4-hydroxy-2-(3-methylbut-2-enyloxy)phenylthio)benzene-1,3-diol,
(E)-4-(2-(3,7-dimethylocta-2,6-vinyloxy)-4-hydroxyphenylazo)benzene-1,3-diol,
-4-(2-butoxy-4-hydroxyphenylazo)benzene-1,3-diol,
-4-(4-butoxy-2-hydroxyphenylazo)benzene-1,3-diol,
-4-(4-hydroxy-2-(octyloxy)phenylthio)benzene-1,3-diol,
-4-(2-hydroxy-4-(octyloxy)phenylthio)benzene-1,3-diol,
-4-(2-(benzyloxy)-4-hydroxyphenylazo)benzene-1,3-diol,
-4-(4-(benzyloxy)-2-hydroxyphenylazo)benzene-1,3-diol,
-4-(4-hydroxy-2-(methoxybenzyloxy)phenylthio)benzene-1,3-diol,
-4-(2-(deciles is)-4-hydroxyphenylazo)benzene-1,3-diol,
-4-(2-(hexadecylamine)-4-hydroxyphenylazo)benzene-1,3-diol,
-2-(2,4-dihydroxyphenyl)-5-hydroxypentadecanoic,
-2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate,
-4-(2,4-dihydroxyphenyl)-3-hydroxyphenylacetate,
-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-phenylpropanoate,
-4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl-3-phenylpropanoate,
-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-methylbutanoate,
-4-(2,4-dihydroxyphenyl)-3-hydroxyphenyl-3-methylbutanoate,
-(9Z,12Z)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate-9,12-dienoate,
-(E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(4-methoxyphenyl)acrylate,
-(E)-2-(2,4-dihydroxyphenyl)-5-hydroxyphenyl-3-(3,4-acid)acrylate,
-2-(2,4-dihydroxyphenyl)-5-hydroxyphenylethylamine,
-2-(2,4-dihydroxydiphenylsulfone)-5-hydroxypentadecanoic,
-(9Z,12Z)-2-(2,4-dihydroxydiphenylsulfone)-5-hydroxyphenylacetate-9,12-dienoate,
-4-(2-(decyloxy)-4-hydroxyphenylglycol)benzene-1,3-diol,
-4-(2-(decyloxy)-4-hydroxyphenylethyl)benzene-1,3-diol,
-2-(2,4-dihydroxyphenyl)-5-hydroxyphenylacetate.

8. The compound of formula (I) according to any one of paragraphs.1-7, characterized in that it is used as an antibacterial active ingredient.

9. Cosmetic use of compounds of formula (I')

in which the radicals X, R1 and R2have the meanings identical to those listed in paragraph 1 in relation to formula (I), but where R1and R2can also simultaneously be a hydrogen atom.

10. Application under item 9 as depigmenting active ingredient.

11. Application under item 9 as an antioxidant active ingredient.

12. Cosmetic composition, characterized in that it contains as active ingredient at least one compound of formula (I) or formula (I') as defined in any of paragraphs. 1-9, in combination with a cosmetically acceptable excipient.

13. Cosmetic composition according to p. 12, characterized in that the amount of the compounds of formula (I) or formula (I') is from 0.01 to 10 wt.% of the total weight of the composition.

14. Cosmetic composition for depigmentation of the skin and/or hair and/or scalp under item 12 or 13, characterized in that it contains at least one compound of formula (I) or formula (I').

15. Cosmetic composition for anti-aging skin under item 12 or 13, characterized in that it contains at least one compound of formula (I) or formula (I').

16. Pharmaceutical composition for disinfection of the skin, characterized in that it contains at least one compound of formula (I).

17. The pharmaceutical composition according to p. 16, Hara is terisolasi fact, the amount of the compounds of formula (I) is from 0.01 to 10 wt.% of the total weight of the composition.

18. The method of obtaining compounds of General formula (I) in which X=S or SO, according to any one of paragraphs. 1-7, characterized in that 4,4'-ridibunda-1,3-diol or 4,4'-sulfanilic-1,3-benzodia subjected to interaction with the halide of formula II

in which:
Hal represents a halogen atom and R1has the same meaning as provided for in paragraph 1, with the exception of the hydrogen atom.

19. The method of obtaining the derivative of resorcinol of the formula (I) in which X represents SO or SO2, characterized in that the compound of formula (I) in which X represents a sulfur atom, a oxidized, in particular, an aqueous solution of hydrogen peroxide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel thio compounds which can be used as antioxidants for rubber, and a method for production thereof. The novel thio compound is obtained by reacting an alkylation product, obtained from p-cresol and dicyclopentadiene, with mercaptan and paraformaldehyde.

EFFECT: unlike existing antioxidants such as 2,6-di-tert-butyl-4-methylphenol, which are harmful to the human body due to high volatility, the novel thio compounds disclosed herein are characterised by low volatility and do not have any harmful effect on the human body.

15 cl, 6 dwg, 5 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-[3-[(2-methoxyphenyl)sulfanyl]-2-methylpropyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-amine of general formula (1) , involving condensation of intermediate compounds of formulae (2) and (3), where R denotes methyl or preferably 4-methylphenyl. The invention also relates to novel compounds of formulae (3), which are used as intermediate compounds in synthesis of formula (1) compounds.

EFFECT: novel method of producing the said compound is safe and cheap.

7 cl, 2 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns carboxylic acid compounds of the formula (I) , where R1 is hydrogen or C1-4alkyl; m is 2 or 3; n is 0-2; R2 is phenyl, naphtyl, benzofuran, benzothiophene; Q is -CH2-O-Cyc1, -CH2-Cyc2, -L-Cyc3, each of R3a and R3b radicals is independently a hydrogen, alkyl, or the R3a and R3b radicals together form tetrahydro-2H-pyran; pharmaceutically acceptable salts, method of obtaining them, and pharmaceutical agent including this compound as active component. Compound of the formula (I) displays antagonistic effect on PGE2 receptor, especially EP3 receptor, which is its subtype, and is applied in prevention and/or treatment of itching, pain, urination disorder or diseases caused by stress.

EFFECT: increased efficiency of compounds.

11 cl, 37 ex, 5 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tocopherol, tocotrienol and other derivatives of chroman of the general formula (1): wherein X is taken among the group comprising oxygen and nitrogen atoms; Y is taken among the group comprising oxygen, nitrogen and sulfur atoms wherein if Y represents oxygen or nitrogen atom then n = 1 and if Y represents sulfur atom then n = 0; R1 represents residue of carboxylic acid, carboxamide, ester, alcohol, amine or sulfate; R2 represents methyl; R3 represents methyl; R4 represents methyl; R5 is taken among the group comprising alkyl, alkenyl, alkynyl, carboxyl and ester residue wherein if Y represents nitrogen atom then indicated nitrogen atom is replaced with group R6 wherein R6 represents hydrogen atom or methyl wherein if X represents oxygen atom, Y represents oxygen atom and R5 represents phytyl then R1 doesn't mean butanoic acid. Also, invention relates to a pharmaceutical composition based on these compounds, a method for treatment of cellular-proliferative disease and a method for induction of cells apoptosis. Invention provides preparing new compounds possessing the proliferative effect.

EFFECT: valuable medicinal properties of compounds.

36 cl, 4 tbl, 19 dwg, 19 ex

The invention relates to new derivatives of tocopherol, tocotrienol and other derivative Romana and the side chains of the formula 1:,

where X represents oxygen; R1represents a group-C1-10alkylene-COOH, -C1-4alkylene-CONH2, -C1-4alkylene-COO-C1-4alkyl, -C1-4alkylene-CON(C1-4alkylene-COOH)2- 1-4alkylene-OH, -CH2(CH2)2-NH3-CI or-C1-4alkylen-OSO3NH(C1-4alkyl)3; R2and R3represent hydrogen or methyl; R4represents methyl; and R5represents a group-C7-17alkyl, -COOH, -C7-16-olefinic group containing from 3 to 5 ethylene linkages, -C=C-COO-C1-4alkyl or-C1-4alkylene-COO-C1-4alkyl; provided that R1may not represent any group-FROM2-4alkylene-COOH or-C1-4alkylene-CONH2or-C1-4alkylen HE, when each of R2, R3and R4represents methyl, and R5represents-C16alkyl, as well as to a method of treating cellular proliferative diseases and method of induction of apoptosis cells

The invention relates to methods of producing mercaptans, specifically to receive mercaptans containing in its structure a fragment of 2-tert.-butyl - or 2,6 di-tert.-butylphenol formula I:

(I)

Ia R=C4H9-tert; n=0

IB R=C4H9-tert; n=3

IF R=H; n=0,

used in the synthesis of antioxidants, modifiers, polymers, and also serve as the source in getting medicines (EP 482342, 1992; U.S. Patent 5326907, 1994 and 5147893, 1992, C 07 C 69/738; EP 190685, 1986)

The invention relates to 4,4'-(oxybis(n-ferentia))littleitaly formula I, which can be used as a component of the binder for polymer composites - aminoethoxyethanol

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to organic chemistry, namely to a compound of formula I and to their pharmaceutically acceptable salt or their ester, wherein W means C(H)2, C(H)2-C(H)2 or C(H)(CH3); X is specified in a group consisting of: (1) O, (2) N(H), (4) S, (5) S(O) and (6) S(O)2; Y means carbon or nitrogen; R1 is specified in a group consisting of: (1) hydrogen, (2) halogen, (3) methyl optionally substituted by fluorine, (4) C1-7alkoxygroup optionally substituted by fluorine, (5) cyano group and (6) C1-7alkylsulphonyl; R2 means hydrogen, fluorine, chlorine or C1-7alkoxygroup; R3 means hydrogen, fluorine, chlorine, bromine or methyl; R4 is specified in a group consisting of: (1) hydrogen, (2) halogen, (3) C1-7alkyl optionally substituted by fluorine, (4) C3-7cycloalkyl, and (5) ethenyl; R5 and R6 are independently from each other specified in a group consisting of: (1) hydrogen, (2) halogen, (3) C1-7alkyl, (4) cyanogroup and (5) C3-7cycloalkyl; R7 means cyano group or S(O)2-R8, wherein R8 is specified in a group consisting of: (1) C1-7alkyl, (2) C3-7cycloalkyl, (4) C1-7alkylamino group, (5) C1-7dialkylamino group, (6) lower heterocycloalkyl optionally substituted by halogen, C1-7alkyl, or C1-7alkoxycarbonyl and (7) 2-oxa-6-azaspiro[3.3]hept-6-yl, wherein lower heterocycloalkyl means a saturated or partially unsaturated non-aromatic ring fragment containing 3 to 7 atoms bound together to form a ring structure, wherein one, two or three ring atoms are heteroatoms, whereas the rest ring atoms are carbon atoms; and pharmaceutically acceptable esters represent methyl and ethyl acid esters of formula I acceptable as prodrugs. The invention also refers to a pharmaceutical composition based on the compound of formula .

EFFECT: prepared are new compounds possessing the CRTH2 receptor antagonist or partial agonist activity.

23 cl, 90 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formulas I, II, III, IV, V, VIII or to their pharmaceutically acceptable salts, wherein: Z represents , or phenyl; D represents or ; X represents N(R9), O, S, S(=O) or S(O)2; each Y independently represents O or S; G represents or ; the other radical values are described in the patent claim. The invention also refers to pharmaceutical compositions based on the above compounds.

EFFECT: there are prepared new compounds and based compositions which can find application for treating malaria or eliminating or inhibiting the growth of Plasmodium species.

30 cl, 3 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4,4'-bis(4-aminophenoxy)diphenylsulphone of formula I:

.

The method involves reaction of 4,4'-dichlorodiphenylsulphone II with a sodium salt of n-aminophenol III. The reaction is carried out in aprotic nonpolar solvents of the aromatic series in the presence of phase-transfer catalysts - pyridinium salts Q+Hlg- (where Q=Alk2NPyAlk'; Hig=Cl, Br), with reactants in the ratio II:III:NaOH:Q+Hlg=1.0:2.0:(2.0-2.01):0.01 mol, while stirring, at temperature 160-170°C and holding for 4-6 hours. The n-aminophenol III is added to a mixture of solvents containing aqueous sodium hydroxide solution and toluene, mixed with a water separator while boiling, collecting water in form of an azeotrope with toluene and distilling toluene. 4,4'-dichlorodiphenylsulphone and a catalyst are added to the obtained reaction mass and the mother solution is recycled after extracting the product.

EFFECT: novel method of obtaining said composition with high output at low technological and material expenses.

1 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to high-molecular weight compounds, particularly aromatic oligoesters of general formula , where n=1-20. The invention also relates to a method of producing said oligoesters, which involves reaction at the first step of 1,1-dichloro-2,2-di(n-oxyphenyl)ethylene with 4,4'-dichlorodiphenyl ketone in an aprotic dipolar solvent (dimethylsulphoxide) at 140°C in an atmosphere of an inert gas for 1 hour, and then at the second step, 4,4'-dichlorodiphenyl sulphone is added to the formed dimer and the reaction takes place at temperature 160°C for 3 hours.

EFFECT: disclosed oligoesters can be used as oligomers for producing polycondensation polymers.

FIELD: chemistry.

SUBSTANCE: invention relates to an amine compound of formula (I), pharmaceutically acceptable addition salts, hydrates or solvates thereof, having immunodepressive effect , where R - H or P(=O)(OH)2; X - O or S; Y denotes -CH2CH2- or -CH=CH-; Z denotes C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene; R1 denotes CF3, R2 denotes C1-4-alkyl, substituted with OH or halogen; R3 and R4 independently denotes H < or C1-4-alkyl; A denotes optionally substituted C6-10-aryl, heteroaryl containing 5-10 ring atoms, where 1 or 2 atoms are selected from N, O and S, C3-7-cycloalkyl optionally condensed with optionally substituted benzene, or heterocycloalkyl containing 5-7 ring atoms, where 1 or 2 atoms are selected from N and O, where said substitutes are selected from C1-4-alkylthio, C1-4-alkylsulphanyl, C1-4-alkylsulphonyl, C2-5-alkylcarbonyl, halogen, cyano, nitro, C3-7-cycloalkyl, C6-10-aryl, C7-14-aralkyloxy, C6-10-aryloxy, optionally substituted with oxo or halogen, C2-3-alkyleneoxy, C3-4-alkylene or C1-2-alkylenedioxy, optionally substituted with halogen C1-4-alkyl or C1-4-alkoxy.

EFFECT: novel compound which is effective in reducing the level of lymphocytes in peripheral blood, suppresses tissue breakdown and exhibiting less side effects, such as bradycardia, is disclosed.

20 cl, 237 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

,

in which A and D are independently selected from hydrogen, halogen, nitrile, C1-3alkyl, C1-3alkoxy; X is a halogen or C1-3alkyl; Y is a bond; Z is phenyl or naphthyl; R1 and R2 together can form a 3-8-member ring, possibly containing one or more atoms selected from O, S and NR3. Described also are intermediate compounds.

EFFECT: disclosed compounds are used to treat respiratory disorders.

19 cl, 23 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to high-molecular compounds, particularly to aromatic oligoesters, which can be used as oligomers for producing polycondensation polymer. Description is given of aromatic oligoesters of formula:

, where n ranges from 1 to 20. Description is also given of a two-step method of producing said oligomers, in which at the first step, 4,4'-dioxydiphenylpropane is reacted with 4,4'-dichlorodiphenyl ketone in an aprotic dipolar solvent - dimethylsulphoxide at 140°C in an atmosphere of inert gas for 1 hour. At the second step, 4,4-dichlorodiphenyl sulfone is added to the formed dimer, and the reaction is carried out at 160°C for 3 hours.

EFFECT: use of proposed oligoesters allows for obtaining a block of copolyesters with high value of intrinsic viscosity and molecular weight, thermal stability and good deformation-strength properties.

2 cl, 4 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the method for modulation of the CRTh2-receptor activity with usage of the compounds of formula (I) or their pharmaceutically acceptable salts where: W is O, S(O)n (where n is equal 0, 1 or 2), NR15, CR1OR2 or CR1R2; X is hydrogen, halogen or C1-6 alkyl which can be substituted with one or more halogen atom; Y is hydrogen, halogen; Z is phenyl, pyridyl, pyrimidyl or quinolyl possibly substituted with one or more substituting group independently selected from following groups: halogen, CN, nitro, SO2R9, SO2NR10R11, CONR10R11, NHSO2R9 or C1-3 alkyl substituted with one or more halogen atom; R1 and R2 are independently hydrogen atom or C1-6 alkyl; R9 is C1-6 alkyl; R10 and R11 are independently hydrogen atom or C1-6 alkyl; R15 is hydrogen atom or C1-6 alkyl.

EFFECT: improvement of the method.

19 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a composition of oral care agents involving silicone dioxide particles in an amount of 5 to 50 wt % of the composition weight, wherein the silicone dioxide particles have an oil absorption value to 100 cm3/100 g, a sphericity coefficient (S80) of more than 0.9 and the Brass-Einlener abrasive wear of less than 8.0 mg loss/100,000 revolutions, wherein at least 80% particles of silicone dioxide are shaped from rounded to round.

EFFECT: improving the composition.

13 cl, 6 ex, 13 dwg, 10 tbl

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