Polyunsaturated fatty acid and diol ester as anti-acne medication

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of the following formula , in which n equals integer number from 1 to 15, m equals 0, 1, 2 or 3, and R represents hydrocarbon chain of polyunsaturated fatty acid, selected from omega-3 and omega-6 polyunsaturated fatty acids, and to method of obtaining them.

EFFECT: development of pharmaceutical or cosmetic composition based on said compounds and to method of acne or seborrheic dermatitis treatment for cosmetic purposes.

16 cl, 4 dwg, 2 tbl, 3 ex

 

The present invention relates to esters alcantera and polyunsaturated fatty acids, specifically omega-3 or omega-6 fatty acids, as well as to pharmaceutical and cosmetic compositions containing the above-mentioned, the method of production/manufacture of the above and to the application of the above, in particular for the treatment of acne or seborrheic dermatitis.

Arcangioli are compounds that are used in many fields, as for example, in cosmetic products and the agri-food industry. In particular, we can note their use as a preservative due to its bacteriostatic properties. So, arcangioli introduced into the composition as a means of controlling bacterial and fungal colonization and to protect many cosmetic products and products agri-food industry (Faergemann J, Fredriksson T. Sabouraudia: 1980, 18, 287-293). These diols have a broad spectrum of activity and are particularly effective against fungi and gram-positive bacteria (Harb NA, Toama MA. Drug Cosmet. Ind.: 1976, 118, 40). Moreover, almost no acquired resistance in microorganisms makes arcangioli important tools in the development antiresistance strategies, in particular, against Staphylococcus aureus (Faergemann J, Hedner T, Larsson P: 2005, 85, 203-205; WO 2004/112765). And finally, they are very good tolerability deletezone their frequent use and doses exceeding a few percent.

1,2-Arcangioli, in particular, possess bacteriostatic activity and are widely used as preservatives (JP-A-51091327) or in the treatment of many pathologies such as acne, etiology which microbial component plays a key role (US 6123953). Also describes other applications of 1,2-alkanediols, as for example, the protective properties against odors of the body, due to their antiseptic (US 5516510; WO 2003/000220) or antifungal (WO 2003/069994) actions. Similarly describes the combination of 1,2-alkanediols with other compounds, and the result is a synergistic antimicrobial effect. Thus, in this context, the claimed combination for control of microorganisms as sources of body smells (US 2005/228032) or microorganisms involved in the formation of acne lesions (US 2007/265352, EP 1598064).

Polyunsaturated fatty acids (PUFA) are divided into two categories: omega-3 (ω-3) and omega-6 (ω-6). In addition to its metabolic effects, they are able to modify the expression of genes encoding intracellular proteins. This effect of PUFA on the genes apparently through a nuclear receptor called PPAR (receptors activated proliferation peroxisome). PPAR belong to the family of nuclear receptors for steroid hormones. They form heterodimer with retinoid X receptor (RXR) retinoic acid is you and modulate gene expression. Thus, the ω-3 PUFA may be negative regulators of the inflammatory response by inhibiting the activation path of NF-KB (nuclear factor kV) by induction of expression of KV, which is the main inhibitor of NF-kV-path (Ren J and Chung SH. J. Agric. Food Chem., 2007, 55: 5073-80). Moreover, ω-3 PUFA exert an inhibitory effect on the synthesis of arachidonic acid in favor of synthesis docosahexaenoic and eicosapentaenoic acids (Calder PC. Lipids, 2001, 36, 1007-24).

When acne is a favorable environment for colonization by Propionibacterium acnes (P. acnes) is the excess sebum in the funnel follicle. Thus, it is possible to establish a correlation between the degree of colonization of P. acnes pilosebaceous channel and the formation of microcomedones. Moreover, it is shown that such colonization is more apparent in subjects with acne compared with healthy subjects (Brown S, Shalita A. Acne vulgaris. Lancet, 1998, 351: 1871-6).

Through natural receptors of the immune system P. acnes induce the production of NF-KB-dependent Pro-inflammatory cytokines, such as IL-8 (interleukin-8). Then these mediators are influenced, in particular, the migration of polynuclear neutrophils to the site of inflammation, where their mission is to destroy the bacteria. This inflammatory response is a normal and necessary for elimination of the pathogen in infected tissue. However, excessive and incontro the dummy activation leads to inflammatory lesions of acne. It has been shown that the level of IL-8 correlates with the number of neutrophils mobilized in inflammatory acne lesion (Abd EI All HS et al., Diagn. Pathol., 2007, 2: 4).

Bacterial colonization in patients with acne most often associated with the appearance of inflammatory lesions of acne: for example, in follicular channels with a high degree of colonization detected a greater number of polynuclear neutrophils and higher levels of IL-8 compared with the follicular channels with a low degree of colonization in subjects without acne. Apparently, the levels of these inflammatory markers correlate with bacterial "load". However, many questions remain unanswered, such as the cause of colonization and the sequence of stages leading to the formation of lesions. In any case, the role of bacterial colonization as a factor in the progression of this disease is considered to be proved.

Present treatment of acne in extent from low to medium or acne in a state of inflammation is a local application of antibacterial active agents, anti-colonization, in particular P. acnes, in combination with anti-inflammatory drugs (Shalita A., J. Eur. Acad. Dermatol. Venereal., 2001, 15: 43).

Treatment is usually initiated after the appearance of a number of inflammatory lesions of acne.

One g is avnah problems anti-acne therapy is finding the adapted treatment, which is a treatment commensurate with the severity of acne, which begin as early as possible, which operates at the initial stage of colonization against the development of inflammatory lesions of acne.

Thus, the inventors have described that all of a sudden esters alcantera and polyunsaturated fatty acids, specifically omega-3 or omega-6 polyunsaturated fatty acids have antibacterial and anti-inflammatory action at the initial stage of colonization by the bacteria P. acnes in the follicular canal, and this action is in addition to the just proportion of colonization.

Indeed, it turns out that esters alcantera and PUFA are recognized and specifically split under the action of bacterial (P. acnes) lipase, facilitating thus, by cleavage of the ester bonds, releasing two active agents with complementary activities, namely, antibacterial diol, able to control the colonization of the bacteria P. acnes, anti-inflammatory PUFA, which blocks the recruitment of neutrophils and thus the inflammatory cascade characteristic of acne. Thus, the release of these two active agents induces an adapted response that is a response commensurate with the colonization of the bacteria P. acnes at the initial stage of colonization, and so the m image blocks the development of this pathology, responsible for the inflammatory lesions of acne. In addition, since the bacteria P. acnes are present in subjects without lesions of acne, these esters also help to prevent exacerbation of lesion of acne by affecting the formation of comedone and by inhibiting the inflammatory cascade characteristic of acne.

Such esters have already been described in the literature (WO 98/18751; Sugiura et al., J. Biol. Chem., 1999, 274(5), 2794-2801), but not their biological properties.

Thus, the present invention relates to a compound of the following General formula (I):

where

- n is an integer from 1 to 15, preferably from 1 to 10,

- m is 0, 1, 2 or 3, and

- R represents a hydrocarbon chain polyunsaturated fatty acid selected from omega-3 and omega-6 polyunsaturated fatty acids.

In the context of the present invention "polyunsaturated fatty acid" refers to a linear carboxylic acid (R1CO2H)containing 10-28, preferably 16 to 24, more preferably 18 to 22 carbon atoms (including the carbon atom of the functional group of carboxylic acid) and containing at least 2, preferably 2 to 6 double bonds C=C, the double bond preferably have the CIS-configuration.

In the context of the present invention "hydrocarbon chain polyunsaturated fatty acids" Rel is referring to the hydrocarbon chain (R1), associated with the acid functional group of polyunsaturated fatty acids (R1CO2H). Thus, R1 is a linear hydrocarbon chain containing from 9 to 27, preferably 15 to 23, more preferably 17 to 21 carbon atom and containing at least 2, preferably 2 to 6 double bonds C=C, the double bond preferably have the CIS-configuration. So, in the case of linoleic acid of the following formula:

consider the hydrocarbon chain is the following chain:

In the context of the present invention, "omega-3 fatty acid" refers to a polyunsaturated fatty acid such as defined above, where the first double bond in the chain corresponds to the third carbon-carbon connection, measured from the end opposite to the functional group of carboxylic acid, as illustrated below in the case of α-linolenic acid:

These omega-3 fatty acids can be, in particular, α-linolenic acid, stereonova acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid and tetracosapentaenoic acid, and preferably α-linolenate the acid or stereonova acid, with anti-inflammatory properties.

In the context of the present invention "omega-6 fatty acid" refers to a polyunsaturated fatty acid such as defined above, where the first double bond in the chain corresponds to the sixth carbon-carbon connection, measured from the end opposite to the functional group of carboxylic acid, as illustrated in the case of linoleic acid below:

These omega-6 fatty acids can be, in particular, linoleic acid, γ-linolenic acid, eicosadienoic acid, di-Homo-γ-linolenic acid, arachidonic acid, docosatetraenoic acid, docosapentaenoic acid, Agranova acid and calendula acid, and preferably linoleic acid, having the properties regulate oil secretions.

In particular, n may be equal to 1, 2, 3, 4 or 5, preferably 5. Preferably, n is not less than (≥) 3, and preferably n is not less than 5.

Preferably, m is 0 or 1.

Preferably, the sum n+m is equal to not less than 3 and preferably n+m is equal to not less than 5.

Preferably, the term "hydrocarbon chain" refers to a polyunsaturated fatty acid selected from α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic key is lots docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosapentaenoic acid, linoleic acid, γ-linolenic acid, eicosadienoic acid, di-Homo-γ-linolenic acid, arachidonic acid, docosatetraenoic acid, docosapentaenoic acid, atenolol acid and calendulas acid. Preferably, the polyunsaturated fatty acid is selected from α-linolenic acid, stearidonic acid and linoleic acid, more preferably of α-linolenic acid and linoleic acid.

In particular, the compounds according to the invention can be selected from the following molecules:

The present invention also relates to the compound of formula (I)defined above, for the application of the foregoing compounds as medicines, in particular intended for the treatment of acne or seborrheic dermatitis.

The present invention also relates to the use of compounds of formula (I)defined above, for the manufacture of a medicinal product, in particular intended for the treatment of acne or seborrheic dermatitis.

The present invention also relates to a method Les is possible acne or seborrheic dermatitis, including the introduction of an effective amount of the compounds of formula (I)defined above, to a subject in need of it.

The present invention also relates to pharmaceutical or cosmetic compositions containing at least one compound of formula (I)defined above, in combination with at least one pharmaceutically or cosmetically acceptable excipients, in particular adapted to the introduction by penetration through the skin.

In the present invention, the term "pharmaceutically or cosmetically acceptable" refers to what is useful in the manufacture of pharmaceutical or cosmetic compositions, and is generally safe, non-toxic and neither biologically nor otherwise undesirable way, and is acceptable for therapeutic or cosmetic use, in particular by local application.

Pharmaceutical or cosmetic compositions according to the invention can be offered in the forms normally used for topical application, which are, in particular, lotions, foams, gels, dispersions, emulsions, shampoos, sprays, serums, masks, lotions or creams, together with excipients, which contribute, in particular, the penetration through the skin to improve the properties and availability of the current beginning. Before occhialino, these compositions are presented in the form of cream.

These compositions usually contain in addition to one or more compounds of the present invention are physiologically acceptable medium, usually water-based or solvent-based, for example on the basis of alcohols, ethers or glycols. These compositions can also contain surface-active agents, exfoliating agents, preservatives, stabilizers, emulsifiers, thickeners, gelling agents, moisturizers, softeners, minerals, essential oils, fragrances, dyes, giving a matte tools, chemical or mineral filters, moisturisers or thermal water, etc.

These compositions can also contain other active start, causing complement or possibly a synergistic effect.

Preferably, the compositions of the present invention will contain from 0.01% to 10% by weight, preferably from 0.1% to 1% by weight, of one or more compounds of the formula (I) based on the total weight of the composition.

More specifically, these compositions are intended for the treatment of acne or seborrheic dermatitis.

The present invention also relates to a method of cosmetic treatment of acne or seborrheic dermatitis, comprising applying to the skin a cosmetic composition, such as opisanie.

The present invention also relates to a method for obtaining compounds of formula (I)defined above, through a combination of polyunsaturated fatty acid selected from omega-3 and omega-6 fatty acids, in which the functional group of carboxylic acid is in the free or activated form, and a diol of the following formula (II):

where n is an integer from 1 to 15, preferably from 1 to 10, and m is 0, 1, 2, or 3.

In particular, n may be equal to 1, 2, 3, 4 or 5, preferably 5. Preferably, n is at least 3, and preferably n is at least 5.

Preferably, m is 0 or 1.

Preferably, the sum n+m is at least 3, and preferably n+m is equal to at least 5.

In the context of the present invention the term "free form" means that the functional group of carboxylic acid PUFA are not protected and thus represents a group of CO2H. Thus, PUFA presents form R1CO2H, as defined previously.

In the context of the present invention "activated form" refers to a functional group of carboxylic acid, which is modified so that it becomes more active in respect of nucleophiles. These activated forms well known to experts in the art and may be in private is the acid chloride of acid (COCl). Thus, activated PUFA in the form of a carboxylic acid has the formula R1COCl.

According to the first specific embodiment of the invention, the polyunsaturated fatty acid is used in its free acid form. In this case, the reaction mix will be carried out in the presence of the agent combinations, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (HATU), possibly in combination with an auxiliary agent combinations, such as N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazol (HOOBt), 1-hydroxy-7-asobancaria (HOAt), dimethylaminopyridine (DMAP) or N-hydroxysulfate-succinimide (sulfo-NHS). Preferably, the combination is carried out in the presence of carbodiimide (in particular, DIC, DCC or EDC) and dimethylaminopyridine. Preferably, the combination is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or diisopropylcarbodiimide and dimethylaminopyridine.

According to the second specific embodiment of the invention polyunsaturated fatty key is use a lot in its activated form, and more specifically in the form of a carboxylic acid. In this case, the reaction mix will preferably be carried out in the presence of pyridine and dimethylaminopyridine.

The present invention will be better understood in the light of non-limiting examples below.

Description of the DRAWINGS

Figure 1. Detection of lipase P. acnes (33 kDa) in the inflammatory lesions of acne (M corresponds to the size of the markers; And complies with inflammatory acne lesions; b corresponds to the comedones without inflammation).

Figure 2. The study of the hydrolysis of esters according to the invention under the action of the recombinant lipase P. acnes after 2 h of incubation. In the form of light-gray column presents the results obtained using 3-hydroxybutyl-α-linolenate, in the form of dark-gray column presents the results obtained using 2-hydroxyphenyl-α-linolenate, in a black column presents the results obtained using 2-hydroxyacyl-α-linolenate, in the form of a white column presents the results obtained using 3-hydroxyaryl-α-linolenate, and as a hatched column presents the results obtained using glycerol-trilinoleate.

Figure 3. The activity of the PUFA in relation to the release of interleukin 8 Nasat-human keratinocytes stimulated by PMA/A (phorbol-12-myristate-13-acetate and calcium ionophores) (proinflammatory what gentami).

Figa, 4B and 4C. The effect of PUFA on the production of eicosanoids (CYCLO: metabolites of cyclooxygenase, LIPOX: lipoxygenase metabolites, AA: arachidonic acid) in inflammatory response induced by PMA/A. Column white colors correspond to control the reaction medium without PUFA); column light gray correspond to the activity of the PUFA concentration of 2.3 μg/ml; column dark gray correspond to the activity of the PUFA concentration of 11.5 mg/ml; and column of the black color corresponds to the activity of PUFA at a concentration of 23 μg/ml of Data on Figa belong to α-linolenic acid, the data on FIGU belong to stearidonic acid, and the data on Pigs related to linoleic acid.

USED ABBREVIATIONS:

APCI chemical ionization at atmospheric pressure;

MIC, minimum inhibitory concentration;

DPM the number of disintegrations per minute;

ESI, electrospray ionization;

HPLC high performance liquid chromatography;

NMR nuclear magnetic resonance;

Rf factor (retention) relative to the front;

MS mass spectrum;

CFU colony forming unit.

EXAMPLE 1. The synthesis of compounds according to the invention

1.1. General method a: from unsaturated fatty acids

Prepare a solution of unsaturated fatty acid in 20 ml of anhydrous CH2Cl2in the atmosphere circulating N2. Then directly after the amount of carbodiimide agent (combination) (1.1 EQ.) and dimethylaminopyridine (0.5 EQ.). After mixing environment at room temperature for 5-10 minutes add diol (5 EQ.). Wednesday intensively stirred for 18 hours in an atmosphere of N2in the absence of light. The organic phase is then extracted with CH2Cl2, then washed with saturated NaCl solution, dried over MgSO4filter and concentrate.

The crude product is a yellow oil, which was purified column chromatography on an open column using silica gel (⌀: 22×3.5 cm) and CHCl3as a solvent.

The following three products received in accordance with the method And using diisopropylcarbodiimide as agent combinations.

3-Hydroxybutyl-(9Z,12Z,15Z)-octadeca-9,12,15-trienoic (C22H38O3) (3-hydroxybutyl-α-linolenate)

Conditions of purification: gradient elution: CHCl3/AcOEt: 95/5, then CHCl3/AcOEt: 9/1.

Semi-transparent oil (yield: 69%).

Rf (CHCl3/AcOEt:9/1)=0,5.

NMR (1H, CDCl3) δ (m-1): 0.98 (t, 3H, CH3 (a)); 1.22 (d, 3H, CH3 (v)); 1.31 (m, 8H, CH2 - (o, n, m, l)); 1.6 (m, 2H, CH2 (p)); 1.8 (m, 2H, CH2 (t)); 2.1 (m, 4H, CH2 (2k, b)); 2.3 (t, 2H, CH2 (q)); 2.8 (m, 4H, CH2 (h, e)); 3.85 (m, 1H, CH(u)); 4.1-4.3 (m, 2H, CH2 (s)); 5.4 (m, 6H, CH(C, d, f, g, i, j)).

NMR (13With, CDCl3) δ (m-1): 14.24 (CH3 (a)); 20.46 (With the 2 (b)); 23.42 (CH3 (v)); 25.01 (CH2 (p)); 25.5 (CH2 (e)); 25.59 (CH2 (h)); 27.16 (CH2 (k)); 29.06 (CH2 - (o, n)); 29.07 (CH2 (m)); 29.53 (CH2 (l)); 34.3 (CH2 (q)); 38.1 (CH2 (t)); At 61.51 (CH2 (s)); 64.89 (CH(u)); 127.08 (CH(C)); 127.6 (CH(j)); 128.22 (CH(f)), 128.26 (CH(g)); 130.22 (CH(i)); 131.93 (CH(d)); 174.2 (C=O(r)).

MS: ESI+[M+H]+=351,2 (100%); [M+Na]+=373,3 (48%).

APCI+ [M+H]+=351,2 (calculated M=350,2).

2-Hydroxyphenyl-(9Z,12Z,15Z)-octadeca-9,12,15-trienoic (C23H40About3) (2-hydroxyphenyl-α-linolenate)

Cleaning requirements: CHCl3/AcOEt: 98/2.

Semi-transparent oil (yield: 45%).

Rf (CHCl3/AcOEt: 97/3)=0,58.

NMR (1H, CDCl3) δ (m-1): 1 (m, 6H, CH3 (w, a)); 1.25 (m, 10H, CH2 - (o, n, m, l, v)); 1.5 (m, 4H, CH2(p, u)); 1.65 (m, 4H, CH2(b, k)); 2.1 (m, 2H, CH2 (e)); 2.4 (t, 2H, CH2 (q)); 2.8 (m, 2H, CH2 (h)); 3.9 (m, 1H, CH(t)); 4.1-4.3 (m, 2H, CH2 (s)); 5.4 (m, 6H, CH(d, d, f, g, i, j)).

NMR (13C, CDCl3) δ (m-1): 14.2 (CH3 (a, w)); 18.6 (CH2 (v, b)); 25.5 (CH2(p)); 25.5 (CH2 (p)); 27.16 (CH2 (e)); 28.9 (CH2 (h)); 29.1 (CH2 (k)); 29.4 (CH2 - (o, n)); 29.5 (CH2 (m)); 34.17 (CH2 (q)); 35.41 (CH2 (u)); 68.53 (CH(t)); 69.76 (CH2 (s)); 128.22 (CH(C)); 129.58 (CH(j)); 130.22 (CH(f)) CH(g)); 130.81 (CH(i)); 131.93 (CH(d)); 17.05 (C=O (r)).

MS: APCI+ [M+H]+=365,1 (calculated M=364,3).

3 Hydroxyaryl-(9Z,12Z,15Z)-octadeca-9,12,15-trienoic (C27H48About3) (3 hydroxyaryl-α-linolenate)

Cleaning requirements: CHCl3/AcOEt: 96/4.

Semi-transparent oil (yield 73%).

Rf (CHCl3/AcOEt: 97/3)=0,64.

NMR (1H, CDCl3) δ (m-1): 0.95 (m, 3H, CH3 (AA)); 1 (m, 3H, CH3 (a)); 1.4 (m, 16H, CH2 - (o, n, m, l, w, x, y, z)); 1.5 (m, 2H, CH2 (v)); 1.6-1.8 (m, 4H, CH2 (R, o)); 2 (m, 4H, CH2 (k, b)); 2.3 (t, 2H, CH2 (q)); 2.8 (m, 4H, CH2 (h, e)); 3.7 (m, 1H, CH(u)); 4.1-4.3 (m, 2H, CH2 (s)); 5.4 (m, 6H, CH(d, d, f, g, l, j)).

NMR (13C, CDCl3) δ (m-1): 14 (CH3 (a, AA)); 20.4 (CH2 (b)); 22.5 (CH2 (z)); 25.09 (CH2 (p)); 25.26 (CH2 (w)); At 25.58 (CH2 (e, h)); 27.17 (CH2 (k)); 29.06-29.3 (CH2 (x, o, n, m, l)); 31.7 (CH2 (y)); 34.5 (CH2 (q)); 37.45 (CH2 (t)); 37.58 (CH2 (v)); 61.59 (CH2 (s)); 68.72 (CH(u)); 127.08 (CH(c)); 127.71 (CH(j)); 128.21 (CH(f)); 128.26 (CH(g)); 130.22 (CH(i)); 131.94 (CH(d)); 174.9 (C=O(r)).

MS: ESI+ [M+H]+=421,1 (100%); [M+Na]+=443,1 (92%).

The following product was obtained according to method a using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as agent combinations.

2-Hydroxyacyl-(9Z,12Z,15Z)-octadeca-9,12,15-trienoic (C26H46About3) (2-hydroxyacyl-α-linolen is t)

Cleaning requirements: CHCl3/AcOEt: 98/2.

Semi-transparent oil (yield 37%).

Rf (CHCl3/AcOEt: 98/2)=0,72.

NMR (1H, CDCl3) δ (m-1): 0.88 (m, 3H, CH3 (z)); 0.97 (t, 3H, CH3 (a)); 1.31 (m, 16H, CH2 - (o, n, m, l, v, w, x, y)); 1.47 (m, 2H, CH2 (u)); 1.65 (m, 2H, CH2 (p)); 2.02 (m, 4H, CH2 (b, k)); 2.4 (t, 2H, CH2 (q)); 2.8 (m, 4H, CH2 (e, h)); 3.9 (m, 1H, CH(t)); 4.1-4.3 (m, 2H, CH2 (s)); 5.4 (m, 6H, CH(e, d, f, g, i, j)).

NMR (13With, CDCl3) δ (m-1): 14.2 (CH3 (a, w)); 18.6 (CH2 (v, b)); 22.7 (CH2 (y)); 25.5 (CH2 (p)); 25.5 (CH2 (p)); 27.16 (CH2 (e)); 28.9 (CH2 (h)); 29.1 (CH2 (k)); 29.4 (CH2 - (o, n)); 29.5 (CH2 (m)); 29.9 (CH2 (w)); 31.7 (CH2 (x)); 34.17 (CH2 (q)); 35.41 (CH2 (u)); 68.53 (CH(t)); 69.76 (CH2 (s)); 128.22 (CH(C)); 129.58 (CH(j)); 130.22 (CH(f)CH(g)); 130.81 (CH(i)); 131.93 (CH (d)); 174.05 (C=O(r)).

MS: APCI+ [M+H]+=407,3 (calculated M=406,34).

1.2. A common way To: from carboxylic polyunsaturated fatty acids

Linoleoyl (6,7×10-3mol) and dimethylaminopyridine (DMAP) (0.1 EQ.) add in the atmosphere circulating nitrogen to a solution of diol (5 EQ.) in pyridine (20 ml). After intensive stirring for 18 hours in an atmosphere of N2at room temperature and in the absence of light volume of the reaction medium is reduced by drying

The organic phase is then extracted with AcOEt, then washed with H2O and NH4+Cl-, dried over MgSO4filter and concentrate.

The crude product is a brown oil, which was purified column chromatography on an open column using silica gel (⌀: 22×3.5 cm) and CHCl3as a solvent.

The following product was obtained according to method B, using pentilenglikol as diol.

2-Hydroxyphenyl-(9Z,12Z)-octadeca-9,12-dienoate (C23H42O3) (2-hydroxyphenyl-linoleate)

Cleaning requirements: CHCl3/AcOEt: 98/2.

Translucent oil.

Rf (CHCl3/AcOEt: 98/2)=0,54.

NMR (1H, CDCl3) δ (m-1): 0.9 (m, 6H, CH3 (a, w)) 1.3 (m, 16H, CH2 - (o, n, m, l, b, C, d, v)); 1.45 (m, 2H, CH2 (u)); 1.65 (m, 2H, CH2 (p)); 2 (m, 4H, CH2 (k, e)); 2.3 (t, 2H, CH2 (q)); 2.8 (m, 2H, CH2 (h)); 3.8 (m, 1H, CH(t)); 4.1-4.3 (m, 2H, CH2 (s)); 5.4 (m, 4H, CH(f, g, i, j)).

NMR (13With, CDCl3) δ (m-1): 14.2 (CH3 (a, w)); 18.6 (CH2 (v)); 22.6 (CH2 (b)); 25 (CH2 (p)); 25.6 (CH2 (h)); 27.2 (CH2 (e, h)); 29 (CH2 (on)); 29.1 (CH2 (n)); 29.3 (CH2 (d)); 29.4 (CH2 (m)); 29.6 (CH2 (l)); 31.4 (CH2 (C)); 34.1 (CH2 (q)); 36.2 (CH2 (u)); 69 (CH2 (s)); 70 (CH(t)); 127.78 (CH(g)); 127.91 (CH(i)); 129.94 (CH(f)); 130.22 (C (j)); 174.05 (C=O(r)).

MS: ESI+ [M+H]+=367,3 (100%); [M+Na]+=389,3 (80%).

EXAMPLE 2. The composition according to the invention

The composition according to the invention in the form of a cream of the following composition (amounts given in% by weight based on the total weight of the composition):

NumberConnectionFunction
3GlycerinHumidifier
0,1The disodium salt of EDTA*Exfoliating substance
0,35PhenoxyethanolPreservative
1Polyacrylate-13; polyisobutene; Polysorbate 20; water (mixture sold by SEPPIC under the trade name Sepiplus® 400)Gelling agent and stabilizer
4Literallayout; stearate PEG-100 (polyethylene glycol 100) (mixture sold by SEPPIC under the trade name Simulsol® 165)Emulsifier
1Cetyl alcohol The consistency index
5CyclopentasiloxaneEmollient
3Glyceryl-tri-2-ethylhexanoateEmollient
2DisabilitantEmollient
1Ester diol and PUFA according to the inventionRemedy for acne
0,27ChlorphenesinPreservative
2PolymethylmethacrylateGives matte powder
0,1PerfumePerfume
*EDTA: ethylenediaminetetraacetic acid

EXAMPLE 3. The results of biological tests

3.1. The study of the action of lipase P. acnes on the compounds according to the invention

First, using Western blotting, it was shown that lipase P. acnes strongly induced in inflammation in subjects with acne compared with samples of the healthy subjects (see Figure 1).

Secondly, the action of the recombinant lipase P. acnes on the compounds according to the invention was investigated as described below.

The enzymatic reaction was carried out, incubare the substrate in the desired concentration (500 μm) in Tris-buffer (left at room temperature for 1 h before testing), then initiated the reaction by addition of enzyme and incubation at 37°C. the Tests performed in glass vials amber color with a capacity of 2 ml of the Inspection is carried out without addition of enzyme to evaluate the possible spontaneous hydrolysis of the substrate in the buffer. In each moment of reaction selected sample (10 µl), which is then frozen to stop the reaction. Next get the derivative released linolenic acid with anthryldiazomethane (ADAM), which forms a fluorescent complex with a fatty acid. Formed product is subjected to separation using HPLC, and then quantify, using a standard set of concentrations derived commercially available linolenic acid, obtained in the same conditions.

As shown in figure 2, the compounds according to the invention are subjected to hydrolysis reaction in the presence of P. acnes, because there is a formation of α-linolenic acid.

Thus, as a result of hydrolysis of the compounds according to the invention under the action of P. acnes, visual is confirmed as diol, and PUFA. Therefore, the expression of lipase is a necessary condition for the observation of the splitting of the compounds according to the invention and, therefore, for a therapeutic effect. In addition, since the lipase P. acnes is present mainly in subjects with acne, as shown in figure 1, the compounds according to the invention will facilitate obtaining the adapted response for each subject.

3.2. Study of antibacterial activity of diols obtained after hydrolysis of the compounds according to the invention

These diols have the following General formula (II):

where n is an integer from 0 to 15, and m is 0, 1, 2, or 3.

For eight microbial strains was performed tests using the following method of cultivation.

The minimum inhibiting concentration (MIC) is determined using microspool in a liquid medium. Perform serial dilutions in two times of the products tested in culture medium (tripcase-soy agar) in a 96-well microplate in a final volume of 0.1 ml Wells inoculant 0.01 ml of bacterial suspension with a titer of approximately 1×107CFU/ml Microplates incubated under optimal growth and MIC determined visually.

The following Table 1 presents the results obtained when using different diols. The column is, marked "BS", are bacteriostatic activity, and the columns marked "SU", are bactericidal activity diols (1% corresponds to a concentration of 10 mg/ml).

td align="center"> of 0.625%
Table 1
Bacteria1,3-Butanediol1,2-Pentanediol1,2-Octandiol1,3-Nonanediol
BSSUBSSUBSSUBSSU
Staphylococcus aureus20%>20%20%20%0,312%0,312%0,312%0,312%
Staphylococcus epidermis10%20%10%10%0,312%0,312%0,312% 0,312%
P. acnes10%20%5%20%0,312%0,312%0,156%0,312%
Pseudomonas aeruginosa10%20%5%10%0,312%0,312%of 0.625%of 0.625%
Escherichia coli10%20%5%-10%20%0,156%0,156%0,156%of 0.625%
Candida albicans10%10%5%5%0,156%0,312%0,156%0,156%
Aspergillus niger10%>20%5%20%0,156%0,078%of 0.625%
M. furfur10%20%5%10%0,156%0,312%0,156%0,312%

The observed antibacterial effect is in accordance with literature data: namely, the activity depends on the length of the chain diol (Frankenfeld JW, Mohan RR, Squibb RL. J. Agric. Food Chem., 1975, 23: 418-425). So, 1,3-nonanediol and 1,2-octanediol are bacteriostatic and bactericidal (against gram-positive, gram-negative bacteria, fungi) in concentrations varying in the range of 6.25 mg/ml to 0.78 mg/ml Should be noted that the derived nonane apparently has the most significant activity for strains of P. acnes, in particular in respect of bacteriostatic and bactericidal effect was detected at concentrations of 1.56 mg/ml and 3.12 mg/ml, respectively.

3.3. Study of kinetics of antibacterial activity of 1,2-octandiol

The kinetics of antibacterial activity of 1,2-octandiol investigated by evaluating the ability to cause lethal for bacteria in time by counting residual colony forming units (CFU) after bringing in contact the CT under test solution with bacterial suspension.

Use the following bacterial strains: Staphylococcus aureus ADS and Propionibacterium acnes ATCC6919. As a culture medium for Staphylococcus aureus ATS use tripcase-soy agar, and as a culture medium for Propionibacterium acnes ATCC6919 use agar Sadler. Concentrated solutions containing 1% and 0.5% 1,2-octandiol, prepare extemporal in 1%Polysorbate 20 (WFI (water for injection) in sufficient quantity (qsp from ang. quantitiy sufficient per)) and then down to pH 7, using a 0.1 n NaOH solution.

Each of concentrated solutions with a volume of 5 ml inoculant 50 µl of bacterial suspension with a titer of approximately 1×108CFU/ml

For each contact time (tested contact time: 5 min, 15 min, 30 min and 60 min) calculate residual bacteria by taking an aliquot of 1 ml and 9 ml of neutralizing tripcase-soy broth and 10% of Polysorbate 80.

The calculation carried out by adding 1 ml of the neutralized mixture and four serial dilution 1/10 in appropriate cups with agar.

Cups with agar incubated at 36°C±1°C in aerobic conditions for S. aureus and anaerobic conditions for P. acnes (the package for incubation anaerobes (Generbag anaer), Biomerieux) for 72 hours and then count CFU.

The following Table 2 presents the results obtained.

Table 2
Staphylococcus aureus Loc RPropionibacterium acnes Log R
ConcentrationpH5 min15 min30 min60 min5 min15 min30 min60 min
1%7>5,3>5,3>5,3>5,3>5>5>5>5

0,5%70,40,10,20,50,20,71,83
Negative control: 1% excipient Polysorbate 206,50 000,1000,20,3

R means "decrease". R represents the ratio between the number of inoculated bacteria and the number of bacteria remaining after contacting the test solution with bacterial suspension.

Bactericidal action octandiol studied on two bacterial species (P. acnes, S. aureus) for the two following concentrations: 0.5% and 1%. At physiological pH values and at lower concentrations (0,5%) was observed, in particular, a reduction of more than 99.9% of the population of P. acnes after one hour of contact.

3.4. Study of anti-inflammatory activity of PUFA obtained after hydrolysis of the compounds according to the invention

Anti-inflammatory potential PUFA tested on human keratinocytes (Nast), stimulated PMA/A. The obtained results are shown in Figure 3, 4A, 4B and 4C.

The changes induced by these PUFA, judged by the production of eicosanoids and inflammatory cytokine, interleukin 8, during the inflammatory process triggered PMA/A.

Study the secretion of IL-8 (Fig 3)

Nasal cells incubated in 96-well tablets within 24 h in the presence of PUFA, washed, and then the incentive is irout PMA/A. After 6 h of stimulation produce a selection of supernatants and IL-8 were quantitatively determined using an ELISA kit (enzyme linked immunosorbent assay) OptEIA™ (BD Pharmingen).

The study of the metabolism of arachidonic acid (AA) (Figa, 4B, 4C)

Nasal-keratinocytes were incubated in 24-hole tablets in the presence of 1 MMKI [3H]AA for 18 hours in an atmosphere of 5% CO2. To test the ability of PUFA modulate the inflammatory response of keratinocytes [3N]-labeled Nasal cells pre-treated with PUFA within 24 hours, washed and then stimulated using 500 nm PMA and 1 μm A, for 5 hours. [3H]AA and metabolites released Nasal-cells into the culture medium, allocate column chromatography. The eluate evaporated in a stream of N2. The dry residue is transferred in methanol and applied on the wafer with silicon oxide for thin-layer chromatography, pre-activated for 1 hour at 100°C. Chromatographic solvent system represents the organic phase mixture ethyl acetate/water/isooctane/acetic acid (110:100:50:20, vol/vol.). [3H]AA and metabolites (6-keto-prostaglandin F, 6k-PGF; prostaglandin (PG) FαE2D2; thromboxane (TX) B2, leukotrienes (LT) B4C4D4) identify, using the scanner for TLC (thin layer chromatography) (Berthld).

Thus, figure 3 shows the activity of a specific PUFA in relation to the release of interleukin 8 (IL-8) Nasal-human keratinocytes stimulated by PMA/A. Inhibitory effect on the secretion of IL-8-stimulated keratinocytes visible to γ-linolenic acid and, in particular, for α-linolenic acid.

Similarly, pre-incubation of keratinocytes with PUFA, such as α-linolenic acid, stereonova acid or linoleic acid, leads to a significant inhibition of release of arachidonic acid and the release of metabolites of the inflammatory cascade catalyzed by cyclooxygenase and lipoxygenase (Figa, 4B and 4C).

Thus, all these results confirm the anti-inflammatory activity of ω-3 or ω-6 polyunsaturated fatty acids and, in particular, α-linolenic acid.

Therefore, the compounds according to the invention can be used to treat acne. Since the etiological picture of seborrheic dermatitis is similar to that for acne, the compounds according to the invention can potentially be used to treat seborrheic dermatitis. Indeed, the organism Malassezia at the initial stage of the inflammatory response in the context of this pathology, secretes lipase (DeAngelis YM et al. J. Invest. Dermatol., 2007. 127: 2138-46) in the hairy skin of the head, to which e can also be used to release the two active agents, alcantera with antifungal properties and PUFA, such as α-linolenic acid with anti-inflammatory properties. Moreover, some fatty acids, such as linoleic acid, are activators of nuclear PPARα receptors, which display a marked effect of regulating oil secretions (Downie MM et al., Br. J. Dermatol. 2004, 151: 766-75). Thus, the conjugates of diol and linoleic acid can be used, in particular, to limit the various symptoms of seborrhea, such as acne and seborrheic dermatitis.

1. The compound of the following General formula (I):

where
- n is an integer from 1 to 15,
- m is 0,1, 2 or 3, and
- R represents a hydrocarbon chain polyunsaturated fatty acid selected from omega-3 and omega-6 polyunsaturated fatty acids.

2. The compound according to claim 1, where n is an integer from 1 to 10.

3. The compound according to claim 1, where n is 1, 2, 3, 4 or 5.

4. The compound according to claim 1, where m is 0 or 1.

5. The compound according to claim 1, where a polyunsaturated fatty acid selected from α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosapentaenoic acid, linoleic acid, γ-linolenic acid, eicosadienoic acid, di-Homo-γ-l is Elenovo acid, arachidonic acid, docosatetraenoic acid, docosapentaenoic acid, atenolol acid and calendulas acid, and preferably represents an α-linolenic acid, stearidonic acid or linoleic acid.

6. The compound according to claim 1, selected from the following molecules:
1)
2)
3)
4)

7. The compound of formula (I) according to any one of claims 1 to 6 for use as a drug for the treatment of acne or seborrheic dermatitis.

8. Pharmaceutical composition for the treatment of acne or seborrheic dermatitis, containing an effective amount of at least one compound of formula (I) according to any one of claims 1 to 6 in combination with at least one pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, where the specified composition comprises from 0.01% to 10% by weight, preferably from 0.1% to 1% by weight, of the specified one or more than one compounds of formula (I) based on the total weight of the composition.

10. Cosmetic composition containing an effective amount of at least one compound of formula (I) according to any one of items 1 to 6 in combination with at least one cosmetically acceptable excipient.

11. The cosmetic composition of claim 10 where the specified compositions the Oia contains from 0.01% to 10% by weight, preferably from 0.1% to 1% by weight, of the specified one or more than one compounds of formula (I) based on the total weight of the composition.

12. The way to handle acne or seborrheic dermatitis for cosmetic purposes, comprising applying to the skin a cosmetic composition of claim 10 or 11.

13. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 6 by a combination of polyunsaturated fatty acid selected from omega-3 and omega-6 fatty acids, the functional group of carboxylic acid which is free or activated form, and a diol of the following formula (II):

where n is an integer from 1 to 15, preferably from 1 to 10, and m is 0, 1, 2 or 3, preferably 0 or 1.

14. The method according to item 13, where the reaction mix effected on the basis of polyunsaturated fatty acids, the functional group of carboxylic acid which is free form, in the presence of the agent combinations selected from the group consisting of diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, carbonyldiimidazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of hexaflurophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of tetrafluoroborate or O-(7-asobancaria-1-yl)-1,1,3,3-tetramethylurea of hexaflurophosphate, possibly in conjunction with the auxiliary and entom combination, selected from the group consisting of N-hydroxysuccinimide, N-hydroxybenzotriazole, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole, 1-hydroxy-7-isobenzofuranone, dimethylaminopyridine or N-hydroxysultaine.

15. The method according to 14, where agent combination is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and an auxiliary agent combination is dimethylaminopyridine.

16. The method according to item 13, where the reaction mix effected on the basis of polyunsaturated fatty acids, the functional group of carboxylic acid which is activated in the form of a carboxylic acid, in particular, in the presence of pyridine and dimethylaminopyridine.



 

Same patents:

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32 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

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60 cl, 3 tbl, 65 ex

FIELD: medicine, pharmaceutics.

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45 cl, 1 tbl, 1 dwg, 31 ex

FIELD: medicine.

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61 cl, 4 tbl, 16 dwg, 5 ex

FIELD: medicine, pharmaceutics.

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3 cl, 4 tbl, 6 ex

FIELD: organic chemistry, labeled compounds.

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1 ex

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FIELD: chemistry.

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15 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing pure methacrylic acid, which involves: a) gas-phase oxidation of a C4 compound to obtain a methacrylic acid-containing gas phase, b) condensing the methacrylic acid-containing gas phase to obtain an aqueous methacrylic acid solution, c) separating at least a portion of the methacrylic acid from the aqueous methacrylic acid solution to obtain at least one methacrylic acid-containing raw product, d) separating at least a portion of methacrylic acid from the at least one methacrylic acid-containing raw product by thermal separation to obtain pure methacrylic acid, wherein at step (d), methacrylic acid is separated from at least a portion of at least one methacrylic acid-containing raw product by fractionation, and wherein the pure methacrylic acid is collected through a side outlet used for the fractionation column, and the amount of pure methacrylic acid collected over a certain time interval ranges from 40% to 80% of the amount of the methacrylic acid-containing raw product fed into the fractionation column over the same time interval. The invention also relates to an apparatus for producing methacrylic acid using said method, the apparatus comprising: a1) a gas-phase oxidation unit, b1) an absorption unit, c1) a separation unit, and d1) a purification unit, wherein the purification unit has at least one distillation column, wherein the at least one distillation column has at least one side outlet for pure methacrylic acid. The invention also relates to a method of producing methacrylic esters, polymethacrylate, polymethacrylic esters, which includes a step for said production of pure methacrylic acid.

EFFECT: obtaining an end product with fewer by-products while simplifying the process.

32 cl, 3 tbl, 4 dwg, 6 ex

FIELD: machine building.

SUBSTANCE: invention refers to a method for obtaining an ether additive, which involves mixing of dicarboxylic acid with ether so that water, ether and excess alcohol is obtained with further separation of water and alcohol from ether by rectification; at that, as an acid there used is oxalic acid, and as alcohol - n-butanol or 2-ethylhexanol. Cyclohexane used as a solvent is supplied for mixing of oxalic acid with alcohol, and rectification is performed in two columns so that cyclohexane (solvent) is obtained in the first column, which is returned to the stage of mixing with oxalic acid and alcohol and supply of residue of the first column to the second one so that alcohol and target product (ether additive) are obtained in it.

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2 cl, 2 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to chemical engineering and specifically to processing fusel oil, which is a large-tonnage waste in the alcohol industry. Fusel oil from production of ethyl alcohol is processed by esterification with glacial acetic acid in the presence of a sulphuric acid catalyst, and neutralisation, wherein esterification is carried out while boiling the reaction mixture and continuously separating water using a separating flask. The obtained product is separated from the catalyst under a vacuum at temperature not higher than 110°C. The obtained product and the catalyst are separately neutralised and the obtained product is additionally dried.

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4 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel dimethacrylic esters of dimerised fatty acid used as binding materials when producing various composite materials, in filling compounds and anaerobic sealants. Dimethacrylic esters of dimerised fatty acid have the structural formula: in which R=CH2CH2OCH2CH2; СН2СН2ОСН2СН2ОСН2СН2; (СН2)4; СН2СН2;

EFFECT: improved method.

2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing alkoxy-polyoxyalkylene(meth)acrylates. Described is a method of producing alkoxy-polyoxyalkylene(meth)acrylate, in which: a) at least one metal compound of formula MetOR10 is taken, where Met denotes lithium, sodium, potassium, rubidium or caesium, and where R10 denotes hydrogen or a straight or branched alkyl residue, b) at least one alcohol R12OH is added, where R12 denotes a straight alkyl residue, with 1-18 carbon atoms or 2-(2-(2-methoxyethoxy)ethoxy)ethyl, where the molar mass of R12 is less than that of alkoxy-polyoxyalkylenes, c) at least one alkylene oxide of formula (VI) is added and reacts with the metal compound of formula MetOR10, where residues R11 denote, in each case independently from each other, hydrogen or a straight alkyl residue, and d) (meth)acrylic acid anhydride is directly added and reacts with the product from step c) in the presence of a stabiliser or a mixture of stabilisers.

EFFECT: simple and improved method of producing alkoxy-polyoxyalkylene(meth)acrylates.

9 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (meth)acrylic esters (F) based on alcohols having at least one carbon-carbon triple bond, characterised by that at least one alcohol having at least one carbon-carbon triple bond of formula (1) where R1 denotes hydrogen, alkyl having 1-18 carbon atoms; alkyl having 2-18 carbon atoms, aryl having 6-12 carbon atoms, cycloalkyl having 5-12 carbon atoms, interrupted, if necessary, by one or more oxygen and/or sulphur atoms and/or one or more substituted or unsubstituted amino groups, or a 5-6-member heterocycl having oxygen, nitrogen and/or sulphur atoms, wherein said residues can be substituted with aryl, alkyl, aryloxy, alkyloxy, heteroatoms/or heterocycles, respectively, and R2 denotes alkylene having 1-20 carbon atoms, cycloalkylene having 5-12 carbon atoms, arylene having 6-12 carbon atoms, or alkylene having 2-20 carbon atoms interrupted by one or more oxygen and/or sulphur atoms and/or one or more substituted or unsubstituted amino groups and/or one or more cycloalkyl groups, -(CO)-, -O(CO)O, -(NH)(CO)O-, -O(CO)(NH)-, -O(CO)- or -(CO)O, where the names of the residues can be replaced with aryl, alkyl, aryloxy, alkyloxy, heteroatoms and/or heterocycles respectively, n is a whole number from 0 to 3, preferably from 0 to 2 and more preferably from 1 to 2 and X; for each i=0 to n can be independently selected from a group comprising -CH2-CH2-O-, -CH2-CH(CH3)-O-, -CH(CH3)-CH2-O-, -CH2-C(CH3)2-O-, -C(CH3)2-CH2-O-, -CH2-CHVin-O-, -CHVin-CH2-O-, -CH2-CHPh-O- and -CHPh-CH2-O-, preferably from a group comprising -CH2-CH2-O-, -CH2-CH(CH3)-O- and -CH(CH3)-CH2-O-, and more preferably CH2-CH2-O-, where Ph denotes phenyl and Vin denotes vinyl, wherein the hydroxy groups of the alcohol are primary or secondary, esterified in the presence of at least one enzyme (E) with (meth)acrylic acid or re-esterified with at least one (meth)acrylic ester (D).

EFFECT: use of the present method enables to obtain esters of an acid based on alcohols which have carbon-carbon triple bonds with good output and low colour indices.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 11(E)-tetradecen-1-ylacetate, which is sex pheromone of sod webworms, the basic component of pheromones of omnivorous leaf-roller moths, stem moths, fir leaf-roller moths and certain other types of dangerous pests, involving a Grignard reaction of acrolein with ethylmagnesium bromide to obtain 1-penten-3-ol, ortho-ether Claisen rearrangement with participation of 1-penten-3-ol and triethyl ortho-acetate to obtain ethyl ether of 4(E)-heptenoic acid, reduction of the ethyl ether of 4(E)-heptenoic acid to obtain 4(E)-hepten-1-ol, substitution of the hydroxyl group of 4(E)-hepten-1-ol with Br to obtain 1-bromo-4(E)-heptene, cross-coupling reaction of 1-bromo-4(E)-heptene with 7-[(tetrahydro-2H-pyran-2-yl)oxy]heptylmagnesium bromide in the presence of a catalyst to obtain 11(E)-tetradecen-1-ol, acetylation of 11(E)-tetradecen-1-ol to obtain 11(E)-tetradecen-1-ylacetate, in which cross-coupling of 1-bromo-4(E)-heptene with 7-[(tetrahydro-2H-pyran-2-yl)oxy]heptylmagnesium bromide to obtain 11(E)-tetradecen-1-ol is carried out in the presence of a Li2CuCl4 in the medium of tetrahydrofuran in the following molar ratio [1-bromo-4(E)-heptene]: [7-[(tetrahydro-2H-pyran-2-yl)oxy]heptylmagnesium bromide]:[ Li2CuCl4]:[tetrahydrofuran]=1:1.2:0.03:20 for 1 hour at temperature of minus 75°C, then for 1 hour at temperature ranging from minus 75°C to 20°C and for 10 hours at 20°C. Since the 1-2% content of the (Z)-isomer already inhibits attractive properties of 11(E)-tetradecen-1-ylacetate, existing methods are not suitable for practical application.

EFFECT: method is distinguished by stereoselectivity.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where each R1, R2 and R3 is independently selected from a group comprising H, OH, F, Cl, Br, a methoxy group and an ethoxy group; or R1 and R2 together form -OCH2O-, and R3 is selected from a group comprising H, OH, methoxy group, ethoxy group and halogens; R4 denotes OH or o-acetoxybenzoyloxy nicotinoyloxy or iso-nicotinoyloxy; R5 denotes or , and at least one of R1, R2 and R3 is not hydrogen.

EFFECT: method for synthesis of a compound of formula (I) and use of the compound of formula (I) in preparing medicinal agents for preventing or treating cerebrovascular diseases.

17 cl, 14 tbl, 5 dwg, 12 ex

FIELD: chemistry.

SUBSTANCE: method involves reaction of a polyatomic alcohol - neopentyl glycol, trimethylol propane, pentaerythritol with trialkylacetic acid in molar ratio 1:1 in the presence of an acid catalyst which is a sulphonic acid derivative having pKa between -2 and +2, carried out at temperature 180°C or lower.

EFFECT: invention enables to obtain hydrolysis-resistant esters.

8 cl, 3 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I)

where Y represents a group of formula -(CR9R10)n-; X represents -C(=O)-; Z represents a group of formula -(CR13R14)q-; R1 is selected from a group, consisting of (a) C2-C12alkenyl, substituted with 4-chlorophenyl; or (b) C6-C10aryl, optionally substituted with one or two halogen atoms; R2 and R3 represent H; R4 is selected from a group, consisting of H, C1-C12alkyl, optionally substituted with hydroxyl, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted with an amino group or pyperidine, C-bound C1-C18heteroaryl, selected from pyridine and imidazole, C(=O)R15, C(=O)NR16R17 and ONR16C(=NR17)NR18R19; each R5a and R5b represents H, each R6, R7 and R8 is independently selected from a group, consisting of H, C1-C12alkyl and C6-C18aryl, each R9 and R10 represents H; each R13 and R14 represents H; R15 represents H, each R16, R17, R18, R19 and R20 is independently selected from a group, consisting of H, C1-C12alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or any two of R16, R17, taken together with atoms, to which they are bound, form a cyclic group, containing 5 carbon atoms, or n equals to 1; q represents an integer number, selected from a group, consisting of 1, 2, 3, 4 and 5; r equals to 1; or its pharmaceutically acceptable salt.

EFFECT: invention relates to a pharmaceutical composition for treatment of MC5R-associated conditions, which contains a formula (I) compound and a pharmaceutically acceptable carrier, a diluent or a filling agent.

23 cl, 6 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to a composition, possessing immunomodulating and anti-inflammatory properties. The dermatological composition, possessing immunomodulating and anti-inflammatory properties, as an active ingredient, contains an extract of the aboveground part/parts of oat, collected before ear formation. The cosmetic composition, possessing immunomodulating and anti-inflammatory properties. Application of the extract of the aboveground part/parts of oat, collected before ear formation, possessing immunomodulating and anti-inflammatory properties, as a medication.

EFFECT: composition and extract possess expressed immunomodulating and anti-inflammatory properties.

15 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic industry and represents a non-foaming cosmetic composition of an oil-in-water emulsion containing (i) retinol, (ii) at least one polar emollient specified in a group consisting of propylene glycol stearyl ester, propylene glycol isostearate and mixtures thereof (iii) at least one non-polar emollient specified in a group consisting of aromatic or linear esters, Gerbe ester, mineral oils, squalane, isohexadecane, squalene, liquid paraffin and mixtures thereof with the weight ratio of the above polar emollient and the above non-polar emollient is found within the range of approximately 95 to 5 to approximately 40 to 60.

EFFECT: provided considerable reduction of retinoid-caused skin irritation and higher efficacy or retinoid.

11 cl, 3 ex, 7 tbl, 3 dwg

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