Compound for treating lipase-mediated diseases


FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.

EFFECT: low activity of pancreatic lipase based on compounds of the said formula.

6 cl, 3 tbl, 23 ex

 

The technical field to which the invention relates

The invention relates to new heterocyclic compounds of benzoquinoines that affect enzyme activity of the lipase gene family. The present invention relates to pharmaceutical compositions that contain compounds derived from benzoquinoines, method for producing them and their pharmaceutically acceptable salts, derivatives, isomers, polymorphs, their solvate with selective activity against diseases and conditions mediated by the genes of the family of lipases.

Prior art

In many developed and developing countries continues to grow, the trend towards the adoption of a diet containing large amounts of fat and low concentrations of fibers, in combination with low intensity work and sedentary lifestyle. This excessive consumption of fat, accompanied by reduced conversion of fat into energy due to a sedentary lifestyle can lead to accumulation of fat in the body at different levels, including biological fluids, cells and tissues. Therefore, there is a constant population growth with increased risk of metabolic disorders such as overweight or obesity, which progresses in associated disorders like diabetes, cardio-with adistem disorders, metabolic syndrome and hypertension.

In General, the first-line treatment for individuals suffering from such metabolic disorders, in particular overweight or obese, includes the adoption of a diet with low fat and regular physical activity. However, adherence to such a regime may be insufficient, and as the disease progresses it becomes necessary treatment drugs.

Accordingly, studies have been conducted towards the development of drugs that are safe and effective for the prevention and treatment of clinical manifestations, which occur due to the accumulation of fat in biological fluids, cells and tissues. Thus, there continues to be a need to reduce in any way the absorption and accumulation of fat in the body.

One approach to reducing the accumulation of fat is the reduction or inhibition of agents that contribute to the digestion and absorption of fat at different levels in the body. Enzymes belonging to the family of lipase genes play a Central role in the metabolism, absorption and transport of lipids.

Hepatic lipase and lipoproteinlipase are proteins that mediate the binding, capture, catabolism and rebuilding of lipoproteins and postlip the Dov. Lipoproteinlipase and hepatic lipase function being associated with the surface of the lumen is covered with endothelial cells, respectively, in peripheral tissues and liver. Both enzymes are involved in the reverse transport of cholesterol, which is the movement of cholesterol from peripheral tissues to the liver or for excretion from the body, or to complete the metabolic cycle. It is known that genetic defects in the hepatic lipase, and lipoproteinlipase cause family disorders of lipoprotein metabolism. Defects in the metabolism of lipoproteins lead to severe metabolic disorders, including hypercholesterolemia, hyperlipidemia and atherosclerosis.

The enzymes lipase gene family are involved in a wide range of metabolic pathways in the range from digestion, absorption of lipids, capture of fatty acids, transport of lipoproteins, and inflammation (Howard Wong et al., 2002, The lipase gene family, " Journal of Lipid Research, Vol. 43: 993-999).

Pancreatic lipase is a key enzyme in lipid metabolism. It is synthesized in pancreatic acinar cells, where it is secreted into the lumen of the intestines, and promotes absorption in the intestine long-chain triglyceride fatty acids (Verger, R. 1984, Pancreatic Lipases Lipases In. B. Borgstrum and H.L. Brockman, editors. Elsevier, New York. 83-150; Lowe, ME. 1997, Molecular mechanisms of rat and human pancreatic triglyceride lipases. J. Nutr. 127: 549-557). Consider that the effect of triacylglycerides is antiatherogenic, because these enzymes reduce the levels of triacylglyceride and contribute to the formation of HDL (high density lipoprotein) (Olivecrona, G., and Olivecrona, T. (1995) Curr. Opin. Lipid. 6:291-305). Lipoproteinlipase is the main enzyme responsible for the distribution and utilization of triglycerides in the body. Lipoproteinlipase hydrolyzes triglyceride in IDL (lipoproteins, intermediate density) and HDL (high density lipoprotein) and is responsible for the restructuring of lipoproteins. Hepatic lipase also functions as phospholipase and hydrolyzes phospholipids in HDL.

Members of the family of lipases function in the metabolism of circulating lipoproteins. Hepatic lipase plays a role in the capture of HDL (Olivecrona, T. et al., 1993, Lipoprotein lipase and heratic lipase. Curr. Opin. Lipidol. 4: 187-196). It is synthesized exclusively in the liver, where it is predominantly found (Hixenbaugh, E.A., et al., 1989, Hepatic lipase in the rat ovary. J. Biol. Chem. 264:4222-4230).

The third member of the lipase gene family, lipoproteinlipase (LPL), distributed in various tissues with the highest concentrations occurring in adipose tissue and muscles. Lipase is associated with capillary endothelium, where it functions to supply the underlying tissue fatty acids, produced by the walking of the rich triglyceride core of circulating chylomicrons and VLDL (very low density lipoprotein) (Olivecrona, T. and G. Bengtsson-Olivecrona. 1993. Lipoprotein lipase and hepatic lipase. Curr. Opin. Lipidol. 4: 187-196). In this process LPL transforms these lipoproteins in the balance and HDL particles. More and more data indicate that LPL produced by macrophages in the vascular wall, can stimulate the development of atherosclerosis by promoting the accumulation of lipids inside the lesion. It was shown that LPL is involved in the pathogenesis of atherosclerosis (Mead JR, et al. 1999, “Lipoprotein Lipase, a key role in atherosclerosis?” FEBS Lett., Nov 26, 462(1-2):1-6). Several groups also suggested that LPL and hepatic lipase, it appears that serve as ligands in the metabolism of plasma lipoproteins (Nykjaer, A., et al., 1993, The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase. J. Biol. Chem. 268: 15048-15055; Krapp, A., S. et al., 1996. Hepatic lipase mediates the uptake of chylomicrons and VLDL into cells via the LDL receptor-related protein (LRP). J. Lipid Res. 37: 926-936). Transgenic animals expressing human lipoproteinlipase or hepatic lipase, there are reduced levels of plasma triglycerides and increased levels of high-density lipoprotein (HDL) (Shimada, M., et al (1993) J. Biol. Chem. 268:17924-17929; Liu, M.-S., et al. (1994) J. Biol. Chem. 269:11417-11424).

Later identified member of the lipase gene family is endothelial lipase. Although the function of this lipase is not currently defined, believe it plays a role in the metabolism of HDL (Jaye, M., et al., 1999, A novel endothelial-deried lipase that modulates HDL metabolism. Nat. Genet 21:424 to 428).

When increasingly recognized the possible role of lipases in the way of fat metabolism drugs that inhibit or reduce the activity of lipase at different levels in the body, form the front line treatment of diseases mediated by the accumulation of fat at higher levels.

A lipase inhibitor, which is sold as a drug against obesity include Orlistat (XENICAL®) and is described in U.S. patent No. 4598089. The application for the European patent EP No. 129748 refers to Orlistat and related compounds and their use in the inhibition of pancreatic lipase and treatment of hyperlipidemia and obesity. Orlistat inhibits only the intestinal lipase, such as gastric, pancreatic and carboxylation lipase, in particular pancreatic lipase, in the lumen of the intestine and blocks the digestion of dietary fat by preventing the interaction of the lipase with its lipid target. However, it appears that it has no effect on lipase, non-intestinal lipases, such as hepatic lipase or endothelial lipase, which are also recognized as playing a role in the catalysis of the hydrolysis of lipids (Drent ML, van der Veen EA. Lipase inhibition: A novel concept in the treatment of obesity. Int J Obes. Relat. Metab. Disord. 1993; 17:241-244). Orlistat also tends to cause a high incidence of unpleasant (relatively harmless) side effects such as diarrhea.

Connect the tion, which inhibit the activity of hepatic lipase and/or endothelial lipase were disclosed in PCT application WO No. 2004094393 for the treatment of diseases mediated hepatic and/or endothelial lipase. These compounds are primarily aimed at increasing the levels of HDL by inhibition of the activity of liver and/or endothelial lipase and are not intended for targeting intestinal or other lipases.

Therefore, desirable to develop new compounds that can be used with a decrease or inhibition of metabolism, absorption and accumulation of fat at various levels, including fluids, cells and tissues in the body, by inhibiting or reducing the activity of all members representing the interest of the lipase gene family, and not just a specific type lipase.

It was also reported that plant benzoquinone embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), obtained from the dried fruit Embrlia ribes, known as anti-fertility, increases the activity lipogenic enzymes, malate dehydrogenase, glucose-6-phosphate dehydrogenase and hydroxymethylglutaryl-COA reductase, although essentially no influence on the activity of lipolytic enzymes (Gupta, S. et al., Fitoterapia 60(4):331-338 (1989)). Embelin is also used as a remedy against tapeworms as having antitumor, prothiofos liteline and analgesic properties (Chitra et al. Chemotherapy 40:109 (1994)), and as penetrating into cells not peptide inhibitor of X-linked inhibitor of apoptosis (XIAP) (Nikolovska-Coleska et al. J. Med. Chem. 47:2430 (2004)).

A brief description of the invention

The present invention provides compounds of formula (I):

where each R1and R2independently selected from the group consisting of hydrogen, C3-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C5alkylcyclohexane,1-C5alkylcyclohexane,1-C13the alkylamine,1-C13arylamino, C(Oh)1-C6of alkyl, O-C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl, C(O)aryl and-C(O) aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1-C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups. However, in accordance with the present invention R1and R2does not represent a methyl, methoxy, ethyl, ethoxy, phenyl and hydroxy.

The present invention also relates to compounds of formula (I) and their derivatives, including b is C limit their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable complex and ethers, carbamates such compounds, their solvate and hydrate all their salt.

In another aspect the present invention provides the use of compounds of formula (I) with a decrease or inhibition of metabolism, absorption and accumulation of fat at various levels, including liquid, cellular and tissue levels in the body by inhibiting the activity of enzymes belonging to the family of lipase genes.

In another embodiment, the invention provides compounds of formula (II):

where each R1and R2independently selected from the group consisting of C3-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C5alkylcyclohexane,1-C5alkylcyclohexane,1-C13the alkylamine,1-C13arylamino, C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl and C(O)aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1 -C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups. However, in accordance with the present invention R1and R2does not represent a methyl, methoxy, ethyl and phenyl.

The present invention also relates to compounds of the formula (II) and their derivatives, including, without limitation, their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable esters, ethers, carbamates such compounds, their solvate and hydrate all their salt.

In another aspect the present invention provides compounds of formula (II) with a decrease or inhibition of metabolism, absorption and accumulation of fat at various levels, including liquid, cellular and tissue levels in the body by inhibiting the activity of enzymes belonging to the family of lipase genes.

In another embodiment, the invention provides compounds of formula (III):

where each R1and R2independently selected from the group consisting of hydrogen, C1-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C13the alkylamine,1-C13arylamino,1-the 5alkylcyclohexane,1-C5alkylcyclohexane, C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl and C(O)aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1-C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups.

The present invention also relates to compounds of the formula (III) and their derivatives, including, without limitation, their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable esters, ethers, carbamates such compounds, their solvate and hydrate all their salt.

In another aspect the present invention provides the use of compounds of the formula (III) with a decrease or inhibition of metabolism, absorption and accumulation of fat at various levels, including liquid, cellular and tissue levels in the body by inhibiting the activity of enzymes belonging to the family of lipase genes.

The present invention also provides a method of obtaining compounds of formula (I), (II) and (III) and their derivatives.

The present invention provides a pharmaceutical composition containing any of the compounds of the present invention, including their polymorphs, prodrugs, and the Windows or their pharmaceutically acceptable esters, ethers and oxime, which can be applied in reduction or inhibition of the enzyme activity of the lipase gene family, involved in the metabolism, absorption and accumulation of lipids in the body at different levels, including the level of biological fluids, cell and tissue levels, for the treatment, mitigation or prevention of diseases mediated by the enzyme lipase gene family, including, without limitation, overweight and obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndromes, other cardiovascular diseases and other metabolic disorders.

The present invention in another aspect also provides the use of compounds of formula (I), (II) and (III) and their derivatives to obtain funds for the care of skin, hair or for cosmetic purposes.

The present invention in another aspect also provides the use of compounds of formula (I), (II) and (III) and their derivatives for the prevention or treatment of cellular and tissue damage caused by microbial pathogens, which secretes lipase.

The present invention also relates to pharmaceutical preparative forms containing any of the compounds of formula (I), (II) and (III) and their derivatives or in combination with a suitable headlight is asepticheski acceptable excipients. Such formulation can be applied with a decrease or inhibition of the enzyme activity of the lipase gene family, involved in the metabolism, absorption and accumulation of lipids in the body at different levels, including the level of biological fluids, cell and tissue levels, for the treatment, mitigation or prevention of diseases mediated by the enzyme lipase gene family, such as overweight and obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, diabetes mellitus, atherosclerosis, other cardiovascular diseases, metabolic syndromes and metabolic disorders.

The present invention also provides a method of obtaining pharmaceutical preparations containing compounds of formula (I), (II) and (III) and derivatives thereof in a therapeutically effective amount or separately, or in combination with a pharmaceutically acceptable adjuvant. Compounds of formula (I), (II) and (III) and their derivatives can also be combined with other active ingredients.

The present invention also relates to a method for treating diseases mediated by the enzyme lipase gene family, the introduction of a therapeutically effective amount of any of compounds of formulas (I), (II) and (III) and their derivatives a person or an animal.

The present invention and the other goals, the characteristics and advantages of the present invention will become more apparent in the following detailed description of the invention and the accompanying embodiments.

Detailed description of the invention

The present invention provides new methods and compositions for use in the reduction or inhibition of the enzyme activity of the lipase gene family for treatment, mitigation or prevention of diseases and conditions mediated by the enzyme lipase gene family, the individual.

Definitions

No other clarification, the following definitions are set forth to illustrate and define the meaning and scope of various terms used for the present description of the invention.

The term "enzyme lipase gene family"used in this description, includes without limitation the hepatic lipase, intestinal lipases, including gastric lipase, pancreatic lipase and carboxylating the lipase, endothelial lipase, phospholipase and other related lipases.

Used in the present description, the term "pharmaceutically acceptable" refers to a substance, including a carrier, a diluent, a carrier-excipient or composition which is chemically and/or toxicologically compatible with the other ingredients that make up the preparative form that is not harmful to their Retz is pienta.

The term "alkyl", used to refer to him as such or as part of another substituent, unless there is no other definition, means a straight - or razvetvlenno-chain monovalent hydrocarbon radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl and n-hexyl.

The term "alkenyl", used alone or in combination with other terms, means a straight - or razvetvlenno-chain monovalent hydrocarbon group having the specified range of the number of carbon atoms, and groups such as vinyl, propenyl, crotonyl, isopentenyl and various isomers butenyl.

The term "quinil", used alone or in combination with other terms, means a straight or branched acyclic carbon chain which contains hydrocarbon group with mezhplanetnoi by a triple bond, having ranges specified number of carbon atoms and groups.

The term "cycloalkyl" means a cyclic, or a monocyclic or polycyclic alkyl radical having at least 3 carbon atoms, and usually from 3 to 7 carbon atoms. Examples are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "alkoxy" alone or in combination refers to a group of the formula alkyl-O-, in which the term "alkyl" has the R is it the specified value, such as methoxy, ethoxy, n-propoxy, isopropoxy, 2° butoxy and 3° butoxy or 2-methoxyethoxy.

The term "C1-C5alkylsilanes" means any of the1-C5alkyl group substituted cycloalkyl group and is composed of the group attached to the nucleus by alkyl late.

The term "C1-C6heteroseksualci" means geterotsyklicescoe group having 2-6 carbon atoms, preferably 3-5 carbon atoms, and containing at least one heteroatom selected from N, O and/or S, which may be attached via a heteroatom or a carbon atom.

The term "aryl" means an aromatic hydrocarbon group having a single (e.g., phenyl) or a condensed ring system such as naphthalene, anthracene, phenanthrene, etc.). Typical aryl group is an aromatic carbocyclic ring having 6, 7, 8, 9 or 10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indel, which may be optionally substituted by one or more substituents selected from hydroxy, amino, halogen, nitro, cyano, C1-C4of alkyl, C2-C4alkenyl,2-C4the quinil,1-C4alkoxy, C1-C4alkoxy, C1-C4dialkylamino, and alkyl parts have the same meaning as the definition is about before. The preferred aromatic hydrocarbon group is phenyl.

The term "C3-C9heteroaryl" means substituted or unsubstituted aromatic group having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, at least including one heteroatom selected from N, O and/or S, such imidazolyl, thiadiazolyl, pyridyl, (benzo)tieniu, (benzo)furillo, Honolulu, tetrahydroquinoline, finokalia or indolyl. The substituents on the heteroaryl group may be selected from the group of substituents listed above for aryl groups. Heteroaryl group may be attached through a carbon atom or, if possible, heteroatom.

The term "C6-C10aryloxy" means an aryl group containing 6, 7, 8, 9 or 10 carbon atoms, as defined above, attached to the oxygen atom. With3-C9heteroaromatic groups represent analogues With6-C10aryloxy group at least containing one heteroatom selected from N, O, or S.

The term "halogen" means fluorine-, chlorine-, bromine - or iodine.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group connected through the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl Deputy, and tertiary amino group bearing 2 identical or different alkyl or cyclo is skilnik Deputy, or 2 substituent of the nitrogen together form a ring, such as, for example, -NH2methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino, diethylamino, particularly preferably primary amino.

The term "cyano", separately or in combination, refers to-CN group.

The term "nitro", separately or in combination, refers to-NO2group.

The term "heterocyclic group" refers to radicals or groups derived from monocyclic or polycyclic saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms and containing 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur.

The term "Deputy" is a "not disturbing" deputies. The term "not disturbing" means that the group is appropriate and chemically stable enough for classes intended position and perform the intended or expected role. Thus, inappropriate groups are excluded from the definition of "not disturbing".

In addition, the compounds of formula (I) and their derivatives may be labeled with an isotope (for example,3H,14C,35S125I and so on).

"Prodrug" regarding the Xia to the compounds capable of being converted into compounds of the present invention interactions of the enzyme, gastric juice or the like under physiological conditionsin vivoin particular, compounds capable of being converted into compounds of the present invention after enzymatic oxidation, recovery, hydrolysis or the like, or compounds capable of being converted into compounds of the present invention, after hydrolysis or similar gastric juice or similar.

"Polymorph" refers to a compound that occurs in two or more forms.

The phrase "therapeutically effective amount" means an amount of compound of the present invention, which treats or prevents the particular disease, condition, or reduces, simplifies or eliminates one or more symptoms of the particular disease, condition or disorder; or prevents or delays the onset of one or more of the symptoms described in the present description of the disease, condition or disorder.

The use of terms C1-Cnis used to denote each of the C1C2C3... Cn. Thus, C1-C20includes C1C2C3C4C5C6C7C8C9C10C11C12C13C14C15 C16C17C18C19and C20. C1-C13includes each of the C1C2C3C4C5C6C7C8C9C10C11C12C13. C2-C13includes each of the C2C3C4C5C6C7C8C9C10C11C12C13etc.

For specialists in this field will be obvious that modifications and materials, and methods may be made without departing from the purpose and objectives of the present invention. The following General terms used in the examples are explained below:

(a) all operations carried out at room or ambient temperature were in the range of from 18 to 25°C;

b) the course of the reaction was monitored by thin-layer chromatography (TLC) and amount of interaction time is given for illustration only;

(C) the melting point is not corrected, the melting point of the presented materials received, as described, the polymorphism may lead to the selection of materials with other melting points from the same preparations;

d) the structure and purity of all final products were confirmed by at least one of the following techniques: TLC, NMR (NMR, nuclear magnetic resonance)spectroscopy, mass-spectrometry or microanalytical data;

(e) the outputs of the pre is presented for illustration only;

f) NMR data, if they are presented in the form of Delta values (δ) for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent;

g) chemical symbols have their usual meanings: also used the following abbreviations: about. (volume), mass. (mass), because (boiling point), so (melting point), l (liter), ml (milliliters), g (grams)mg (milligrams), mol (moles), mmol (mmol), EQ. (equivalents), °C (degrees Celsius), conc. (concentrated), SiO2(silicon dioxide), Na2SO4(sodium sulfate);

h) intermediate compounds used in the following examples were obtained from Sigma.

Lipase

Were described by 3 members of the family of human triacylglycerides: pankraticheskoi lipase, lipoproteinlipase and hepatic lipase (Goldberg, I.J., Le, N.-A., Ginsberg, H.N., Krauss, R., and Lindgren, F.T. (1988) J. Clin. Invest. 81, 561-568; Goldberg, I.J., Le, N., J. R. Paterniti, Ginsberg, H.N., Lindgren, F.T., and Brown, W.V. (1982) J. Clin. Invest. 70, 1184-1192; Hide, W.A., Chan, L., and Li, W.-H. (1992) J. Lipid. Res. 33, 167-178). Pancreatic lipase is primarily responsible for the hydrolysis of dietary lipids. Were described variants of pancreatic lipase, but their physiological role has not been defined (Giller, T., Buchwald, P., Blum-Kaelin, D., and Hunziker, W. (1992) J Biol. Chem. 267,16509-16516).

The lipase polypeptides, encoded by the genes of this lipase, have a length of approximately 450 amino acids of the leader signal peptide to facilitate secretion. Proteins lipase consists of two major domains (Winkler, K., D'arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Aminobenzoic domain contains the catalytic site, whereas the carboxyl domain is responsible for binding of substrates, the Association of cofactors and interaction with cellular receptors (Wong, H., Davis, R, Nikazy, J., Seebart, K.E., and Schotz, M.C. (1991) Proc. Natl. Acad. Sci. USA 88, 11290-11294; van Tilbeurgh, H., Roussel, A., Lalouel, J.-M., and Cambillau, C. (1994) J. Biol. Chem. 269, 4626-4633; Wong, H., Davis, R, Thuren, T., Goers, J.W., Nikazy, J., Waite, M., and Schotz, M.C. (1994) J. Biol. Chem. 269, 10319-10323; Chappell, D.A., Inoue, L, Fiy, G.L., Pladet, M.W., Bowen, S.L., Iverius, P.-H., Lalouel, J.-M., and Strickland, D.K. (1994) J. Biol. Chem. 269, 18001-18006). The overall level of amino acid homology between the family members is 22-65%, with local areas of high homology correspond to the structural homology that are associated with enzymatic function.

Family members of triacylglycerides share a number of conserved structural features. One such characteristic is a motif GXSXG", in which the Central serine residue represents one of the three residues constituting the catalytic triad" (Winkler, K., D'arcy, A., and Hunziker, W. (1990) Nature 343, 771-774; Faustinella, F., Smith, LOC. CIT, and Chan, L. (1992) Biochemistry 31, 7219-7223). Saved TSA is RTTY and his-tag residues comprise the remainder of the catalytic triad. A short stretch of amino acids 19-23 ("roof area") forms an amphipatic helical structure and covers the catalytic pocket of the enzyme (Winkler, K., D'arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Comparison of hepatic and lipoproteinlipase demonstrated that differences in the activity of enzymes triacylglycerides and phospholipase partially mediated this roof area (Dugi, K.A., Dichek H.L., and Santamarina-Fojo, S. (1995) J. Biol. Chem. 270, 25396-25401). Triacylglycerides have varying degrees of activity of binding heparin. Lipoproteinlipase has the highest affinity for heparin, and this binding activity was mapped to slices sequencing of positively charged residues in aminoclonazepam domain (Ma, Y., Henderson, H.E., Liu, M.-S., Zhang, H., Forsythe, I.J., Clarke-Lewis, L, Hayden, M.R., and Brunzell, J. D. J. Lipid Res. 35, 2049-2059).

Reported genetic sequences encoding human pancreatic lipase, hepatic lipase and lipoproteinlipase (access numbers in the genetic Bank respectively #M93285, #J03540 and #M15856). Messenger RNA of human hepatic lipase and pancreatic lipase have a length of approximately 1.7 and 1.8 thousand heterocyclic bases of nucleic acids, respectively. 2 of the mRNA transcript of 3.6 and 3.2 thousand base pairs are produced from the gene in the human lipoproteinlipase (Ranganathan, G., Ong, J.M., Yukht, A., Saghizadeh, M., Simsolo, R.., Pauer, A., and Kern, P.A. (1995) J. Biol. Chem. 270, 7149-7155).

Compounds that affect the activity of lipase

The present invention relates to compounds of formula (I)

and their derivatives, including, without limitation, their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable esters, ethers, carbamates such compounds, their solvate and hydrate and their salts, where each R1and R2independently selected from the group consisting of hydrogen, C3-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C5alkylcyclohexane,1-C5alkylcyclohexane,1-C13the alkylamine,1-C13arylamino, C(Oh)1-C6of alkyl, O-C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl, C(O)aryl and-C(O) aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1-C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups. However, in accordance with the present invention R1and R2not to depict ablaut a methyl, methoxy, ethyl, ethoxy, phenyl and hydroxy.

In another embodiment, the invention relates to compounds of the formula (II):

and their derivatives, including, without limitation, their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable esters, ethers, carbamates such compounds, their solvate and hydrate and their salts, where each R1and R2independently selected from the group consisting of C3-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C5alkylcyclohexane,1-C5alkylcyclohexane,1-C13the alkylamine,1-C13arylamino, C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl and C(O)aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1-C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups. However, in accordance with the present invention R1and R2does not represent a methyl, methoxy, ethyl and phenyl.

In another embodiment, izaberete the s refers to compounds of the formula (III):

and their derivatives, including, without limitation, their polymorphs, isomers and prodrugs, and their geometric or optical isomers and their pharmaceutically acceptable esters, ethers, carbamates such compounds, their solvate and hydrate and their salts, where each R1and R2independently selected from the group consisting of hydrogen, C1-C13of alkyl, C1-C20haloalkyl,2-C13alkenyl,2-C13the quinil,4-C6cycloalkyl,4-C6cycloalkenyl,1-C13alkoxyalkyl,1-C13the alkylamine,1-C13arylamino,1-C5alkylcyclohexane,1-C5alkylcyclohexane, C(Oh)1-C6of alkyl, geterotsiklicheskie, aryl, alkylaryl and C(O)aryl; where each of the above groups may optionally have 1 to 6 substituents independently selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thio, C1-C6of alkyl, cycloalkyl, aryl, alkoxy, aryloxy groups.

In one embodiment, the compounds of formula (III), we have R1and R2independently selected from C(O)aryl, C(O)alkylaryl, C(O)glodariu, C(O)nitroarene or(O)of alkoxyaryl.

Another variant of implementation relates to compounds of the formula (III), where R1and R2ezavisimo selected from methylphenylcarbinol, ethylvinylbenzene, propylenecarbonate, butylphenylmethyl, chlorophenylalanine, brompheniramine, jumpercable, florfenicol, nitrophenylarsonic, methoxyphenylalanine or ethoxyphenylurea.

Other embodiments of relate to compounds of the formula (III) where R1and R2independently selected from 2-methylphenylcarbinol, 3-methylphenylcarbinol, 4-methylphenylcarbinol, 4-tert-butylphenylmethyl, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-brompheniramine, 3-brompheniramine, 4-brompheniramine, 2-jumpercable, 3-jumpercable, 4-jumpercable, 2-florfenicol, 3-florfenicol, 4-florfenicol, 2-nitrophenylarsonic, 3-nitrophenylarsonic, 4-nitrophenylarsonic, 2-methoxyphenylacetyl, 3-methoxyphenylalanine and 4-methoxyphenylalanine.

Accordingly, the present invention also encompasses prodrugs of the compounds of the present invention. The term "prodrug" includes a compound that is transformed in vivo to yield compounds of formula (I), (II) or (III). Information on the use of prodrugs may be found in the publications "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, by T. Higuchi and W. Stella, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In the present invention are also included, where Jamie active metabolites of compounds within the scope of formula (I), (II) or (III).

Compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All suitable optical isomers and stereoisomeric forms of the compounds of the present invention, and their mixtures, including racemic mixtures, form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if the connection of the present invention includes a double bond or a condensed ring, CIS - and TRANS-forms, as well as mixtures are included in the scope of the invention. In respect of such compounds, the present invention includes, depending on the appropriate application form of racemate, a single enantiomeric form, single diastereomeric forms or their mixtures. In addition, such compounds may also exist as tautomers. Accordingly, the present invention relates to the use of such suitable tautomers and their mixtures. Diastereomer mixture can be divided into their separate diastereoisomeric on the basis of their physical chemical differences by methods well known to specialists in this field, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into diastereomers with the feature interaction with an appropriate optically active compound (for example, chiral auxiliary agent such as a chiral alcohol or acid chloride of Mosera), division of diastereoisomers and transformation (e.g., hydrolysis) of individual diastereoisomers in the corresponding pure enantiomers or separation of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. Some of the compounds of the present invention can be atropisomers (for example, substituted barely) and are considered part of the present invention. Enantiomers can also be separated using chiral HPLC column.

In addition, the compounds of the present invention can exhibit polymorphism. Scope of the present invention includes all polymorphic forms of the compounds according to the invention, which constitute another aspect of the invention. It should be understood that the present invention covers any and all racemic, optically active, polymorphic, and stereoisomeric forms or mixtures thereof, and the form or forms have properties that can be used in the treatment specified in the present description States.

In addition, the present invention also includes labeled with isotopes connection this is the invention, which are identical to those given here to the compounds, but in which one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as, respectively2H,3H,11C,13C,14C,13N15N15O,17O,18O, 31P, 32P,35S18F,123I125I and36Cl. Some labeled isotopes of the compounds of the present invention (e.g., compound labeled with3H and14C) can be used in the analysis of distribution in the tissues of the joints and/or substrates. Particularly preferred isotopes, tritium-labeled (i.e.3H) and carbon-14 (i.e.14C) in view of the ease of their production and the possibility of detection. In addition, the substitution of heavier isotopes such as deuterium (i.e.2H), may provide some therapeutic advantages resulting from greater metabolic stability (e.g., increased half-life or the needs of low dosages), and therefore, in some circumstances, it may be preferable. Positron emitting Soto is s, such as15O,13N11C and18F, can be used for studies of positron emission tomography (REET) to study the employment receptor substrates. Labeled with isotopes of the compounds of the present invention can generally be obtained by procedures similar to the procedures disclosed below in the "Examples", by substitution of isotope-labeled reagent on non-isotope-labeled reagent.

One aspect of the invention is the provision of a method of obtaining compounds of formula (I), (II) or (III). Specialists in this field will be clear from this description how to get the most preferred compounds of the present invention using any suitable known way. Compounds of formula (I), (II) or (III) and, unless otherwise indicated, R1, R2as described above, can appropriately be obtained in accordance with scheme 1.

In addition, in the present description, the examples also illustrate the formation of compounds of the present invention. In addition, professionals in this field will be clear from this description of how to modify the scheme 1 and the details are described below in the present description examples for obtaining the desire of any particular compound of formula (I), (II) or (III) of the present invention. It should be understood that the circuit predstavlena solely for the purpose of illustration and depicts a possible way of synthesis of compounds of formula (I), (II) or (III) and does not limit the invention. Specialists in this field will be clear that for the synthesis of compounds of the present invention can be used other ways of synthesis. Although in scheme 1, shown below, depicts the specific starting materials and reagents, a suitable replacement can be easily made to provide a variety of derivatives and interaction conditions. In addition, many of the compounds obtained as described below, can be further modified in light of the description using conventional chemistry known to specialists in this field.

Scheme I

In the diagram I shows a General Protocol for obtaining compounds of formula (I), (II) or (III) of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone or its oxime or substituted oxime, or a suitable salt or analogues. Source material - 2,5-dihydroxy-3-undecyl-1,4-benzoquinone - interacts with alkylchloride or acylchlorides, or arylhalides or aroylchlorides, or replaced by arylhalides or substituted by aroylchlorides in a suitable inert halogenosilanes solvent (such as dichloromethane) in the presence of a suitable aromatic base (e.g. pyridine) in controlled conditions, such as temperature from about 10°to about 40°C, during the PE the iodine from about 1 h to about 24 h to yield compound of formula (I), (II) or (III) in crude form. For isolation and purification of the compounds of the present invention can use conventional methods and/or methods of separation and purification, well known to the average person skilled in the art. Such techniques are well known to the average person skilled in the art and can include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography using conventional adsorbents such as silica gel, and thin-layer tomography), methods of recrystallization and differential (i.e. liquid-liquid) extraction.

Associated with lipase diseases and conditions

An aspect of the present invention is the provision of compounds of formula (I), (II) or (III) and their derivatives for use as therapeutically active substances.

The above-described compounds of the present invention can be used for reducing or inhibiting the activity of enzymes lipase gene family for treatment, mitigation or prevention of diseases mediated by the enzyme lipase gene family. These compounds can be used to decrease or inhibition of the metabolism, absorption and accumulation of fat at various levels, including the levels of biological fluids, cell and tissue levels in the body by ingibirovany who or reduce the activity of enzymes, belonging to the family of genes lipase. Thus, the compounds of the present invention and their derivatives, including their composition, can be applied with a decrease or inhibition of activity of enzymes belonging to the family of lipase genes involved in metabolism, absorption and accumulation of lipids in the body at different levels, including the level of biological fluids, cell and tissue levels, for the treatment, mitigation or prevention of diseases mediated by the enzyme lipase gene family, including, without limitation, overweight and obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndromes, other cardiovascular diseases and other metabolic disorder.

In another aspect, compounds of the present invention and their derivatives, including their composition, can be used in the prevention or treatment of cellular and tissue damage caused by microbial pathogens, which secretes lipase.

In another aspect, compounds of the present invention and their derivatives, including their composition, can also be used to care for skin and hair or for cosmetic purposes.

The embodiment of the present invention is the provision of a method of treatment status is of any, diseases and/or disorders mediated by enzymes belonging to the family of lipase genes, including, without limitation, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndromes, other cardiovascular diseases and other metabolic disorders, reduction or inhibition of the metabolism, absorption and accumulation of fat at various levels, including the level of biological fluids, cell and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the family of lipase genes, in a mammal, including humans, which includes the introduction of the specified mammal an effective treating amount of a compound of formulas (I), (II) or (III) or its derivatives.

In another embodiment, the present invention provides a method of treating or preventing cell and tissue damage caused by microbial pathogens, which secretes lipase inhibition or reduction in the activity of enzymes belonging to the family of lipase genes, in a mammal, including humans, which includes the introduction of the specified mammal an effective treating amount of a compound of formula (I), (II) or (III) or its derivatives.

According to one variant domestic the present invention is to provide pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I), (II) or (III) or its derivative and a pharmaceutically acceptable inert adjuvant, diluent or carrier. Alternatively, the pharmaceutical composition may include at least one additional pharmaceutically active agent. Additional pharmaceutically active agent may be selected from chemically synthesized compounds or compounds of natural origin having the desired pharmacological activity.

Preparative form

The compound of formula (I), (II) or (III) or its derivative, you can enter any normal by oral, buccal, intranasal, inhalation spray in a standard dosage form, parenteral (e.g. intravenous, intramuscular, subcutaneous, vnutrigrudne and infusion techniques), topically (e.g., powders, ointments or drops), transdermal, tanks, vagina, intraperitoneally, into the bladder or rectum. In another aspect of the invention, the compound of the present invention and at least one other pharmaceutically active agent can be entered either by itself, or in pharmaceutical compositions containing them both. In General, it is preferable that such introduction was oral. However, if you are receiving treatment the individual is not SP is capable to swallow or oral administration is difficult or otherwise undesirable, it may be appropriate parenteral or transdermal administration.

The compound of formula (I), (II) or (III) or its derivative can be introduced in the form of any preparative forms of modified release, controlled release or measured at the time of release (see, e.g., Langer, Science 249:1527-1533 (1990)). In one embodiment, it is possible to use the pump (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al, N. Engl. J. Med. 321:574 (1989)) In another embodiment, it is possible to use polymeric materials (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)).

The dose of a compound of formula (I), (II) or (III) or its derivative to be administered to a mammal, including a human or animal, for the above purpose, definitely not limited. Rather, it is quite variable and depends on pathologies, conditions, symptoms, or age of the subject, and the judgment of the attending physician or veterinarian. The General range of effective frequencies of administration of compounds of the present invention is from about 0.001 mg/kg body weight to about 100 mg/kg of body weight of the subject per day. The preferred range of effective frequencies in which edenia compounds of the present invention is from about 0.01 mg/kg body weight to about 50 mg/kg of body weight of the subject per day. The number is chosen based on various factors, including the environment into which the composition, the area of cells to be treated, the age, health status, gender, and body weight of the patient or animal to be treated, etc. Useful amounts include 1, 5, 15, 20, 25, 30, 40, 60, 150, 200 mg, 1 g, 2 g, 3 g and are in the range of from 10 mg to 100 mg, from 50 mg to 5 g, from 100 mg to 10 g, from 250 mg to 2.5 g, from 500 mg to 1.25 g, etc. on the dosage. Although it may be worthwhile introducing a daily dose of the compounds of the present invention with portions in different hours of the day in each given case, the amount of coupling of the present invention will depend on such factors as the solubility of the compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention, used in the preparative form and route of administration (e.g. oral, transdermal, parenteral or local).

The dosage of the compounds according to the present invention it is possible to introduce people any suitable means, and oral administration is preferred. A separate oral dosage form, for example tablets or capsules, should generally contain from about 0.1 mg to about 100 mg of the compounds of the present invention in a suitable pharmaceutically acceptable excipient, diluent or carrier. Depending on the need the ti dosage for intravenous administration are generally in the range from about 0.1 mg to about 10 mg per dose. For intranasal or inhalation dosage generally prepared in the form of a solution with a concentration of from about 0.1% to about 1% (wt./vol.). In practice, the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary, for example, depending on the age, weight and response of the individual patient. The above dosages are illustrative for the average case, but, of course, there may be individual cases where possible ranges higher or lower dosages. Such dosages of the compounds of the present invention are within the scope of the present invention.

Another preferred embodiment of the present invention is the provision of compounds of formula (I), (II) or (III) or a derivative thereof for the manufacture of pharmaceutical preparative forms for the prevention and treatment of conditions, diseases and/or disorders mediated by enzymes belonging to the family of lipase genes, including, without limitation, overweight and obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndromes, other cardiovascular diseases and other metabolic disorders. Pharmaceutical preparative fo the mu containing the compound of formula (I), (II) or (III) or its derivatives, can be a conventional manner, known to specialists in this field, using one or more pharmaceutically acceptable diluents, carriers or excipients.

For oral administration of the pharmaceutical formulation that can be applied in the present invention include tablets, chewable tablets, tablets, controlled release, capsules, lozenges, granules, powders, pills, micro-capsules, elixirs, syrups and suspensions.

In General, tablets can be obtained by methods known in the pharmaceutical science, direct compression, wet granulation or dry granulation. Their formulation usually include diluents, binding agents, lubricants and disintegrating agents, as well as the compounds of the present invention. The usual diluents include, for example, various types of starch, lactose, lures, kaolin, phosphate, or calcium sulfate, inorganic salts such as sodium chloride and powdered sugar. You can also use powdered cellulose derivatives. Conventional tablet binding agents include substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Also suitable natural and synthetic resins, on the tea acacia, alginates, methylcellulose, polyvinylpyrrolidone and the like. As binding agents can also serve as polyethylene glycol and waxes.

The lubricating substance is in General necessary in tablet formulations form to prevent adhesion of the tablet and punches to the head of the extruder. Lubricating substance selected from such moving solid substances as talc, magnesium stearate and calcium, stearic acid and hydrogenated vegetable oils. Tablet disintegrating agents include substances which swell when wetted for the destruction of the tablet and release of the compound, prodrug, isomer or pharmaceutically acceptable salt according to the present invention. They include starches, clays, cellulose, algini and resin. More specifically, it is possible to use, for example, corn and potato starches, methylcellulose, agar, bentonite, cellulose wood, powder, natural sponge, cation-exchange resins, alginic acid, diatomaceous earth, citrus pulp and carboxymethylcellulose, and sodium lauryl sulfate. Tablets are often coated with sugar as odorants and sealant or forming a film of protective agents to modify the dissolution properties of the tablets. Compounds according to the invention can also be in the form of chewing tablets through the use of large quantities of vases is in good taste, such as lures in preparative form, which is now quite customary in this field.

As discussed above, the effect of the compounds of the present invention can be controlled, that is, to hold, or to extend, or limit time corresponding preparative form. For example, you can get a slowly soluble pellet of the compound of the present invention and included in a tablet or capsule. The method can be improved by the production of granules with several different speeds of dissolution with subsequent filling of capsules with a mixture of these granules. Tablets or capsules may be coated with a membrane, which resists dissolution in the forecast period of time.

Capsules can be obtained by mixing the compounds according to the invention with a suitable diluent and filling capsules appropriate amount of the mixture. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, lures and sucrose, flour cereals and similar food powders.

Liquid preparations for oral administration can, for example, take the form of solutions, syrups or suspensions, or may be presented in the form of su is th product for dissolving water or other suitable vehicle before use. Such liquid preparations can be obtained by conventional means with pharmaceutically acceptable additives such as suspendida/increasing viscosity agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol, medium chain triglycerides) and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid).

For parenteral administration the compounds according to the invention can be in injectable form, including using conventional catheterization techniques or infusion. Formulation for injection may be presented in a standard dosage form, for example in ampoules or in mnogochasovykh containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain such components agents, as suspendida, stabilizing and/or dispersing agents. Injectable solutions or suspensions can be in accordance with known methods using suitable non-toxic acceptable for parenteral diluents or solvents, such as lures, 1,3-butanediol, water, a solution of the Ring is a or isotonic solution of sodium chloride, or suitable dispersing or wetting and suspendresume agents, such as sterile, soft, fixed oils, including synthetic mono - or diglycerides, and fatty acids, including oleic acid, and a surfactant, such as hydroxypropylcellulose, and if necessary, the pH of the solution to properly communicated and tabularised. In General, oil solutions are suitable for the purposes of intra-articular, intramuscular and subcutaneous injection. Such aqueous solutions are suitable for the purposes of intravenous injection. Alternatively, the active ingredient can be provided in powder form for dissolving a suitable carrier, such as sterile pyrogen-free water, before use. Parenteral drugs can also produce long acting dissolution or suspendirovanie compounds, prodrugs or pharmaceutically acceptable salts of the present invention, as it is possible, for example, in oily or emulsified media that allow him only slowly dispergirujutsja in serum.

For intranasal or administration by inhalation the compounds according to the present invention is acceptable delivered in the form of a solution or suspension of the supplied pump container with an aerosol which is extruded or you aceveda patient, or feed spray aerosol under pressure in the container or nebulizer with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the standard dosage may be determined by providing a valve for supplying a measured quantity. Under excessive pressure container or nebulizer may contain a solution or suspension of the active compound. With the introduction of intranasal spray or inhalation of these compositions have, in accordance with techniques well known in the field of pharmaceutical preparative forms, and they can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, stimulants suction to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in this field. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be compiled with the content of the powder mixture of compounds according to the invention and a suitable powder for inhalation bases such as lactose or starch.

Connections really invented the Y. you can also enter local, and this can be accomplished, for example, using creams, jelly, lubricants, lotions, gels, pastes, ointments and the like in accordance with standard pharmaceutical practice. Compounds of the present invention can also enter transdermal (e.g., by applying a transdermal system).

You can use any suitable preparative form for transdermal application, containing the compound of the present invention, and such formulation should in General also contain suitable transdermal carrier, such as absorbable pharmacologically acceptable solvent, to stimulate and facilitate the passage of compounds through the skin of the subject. For example, suitable transdermal devices may be in the form of a bandage having the element substrate and the reservoir containing the discussed connection. Such transdermal device type bandage may also include suitable carriers, regulating the rate of release of the barriers and means for attaching the transdermal device to the skin of the subject.

When desirable, the introduction of the compounds of the present invention in the form of a suppository, you can use any appropriate basis. Cocoa butter is a traditional basis suppositories, which can be modified by the addition of waxes to lift the melting points. Widely used mixed with water framework suppositories containing, in particular, polyethylene glycols of various molecular weights.

In other embodiments, implementation of connection in the present invention can be incorporated into food or drinks.

Compounds of the present invention can also enter the mammal, except man. The route of administration and dosage, subject to the introduction of this mammal will depend, for example, the species of animal and the disease or disorder to be treated. Compounds of the present invention it is possible to enter an animal in any suitable way, for example oral, parenteral or transdermal, in any suitable form, such as, for example, capsule, bolus, tablet, pill, for example, is obtained by mixing the compound, prodrug, isomer or pharmaceutically acceptable salt according to the present invention with a suitable diluent, such as carbopack or Carnauba wax, together with a lubricating substance, liquid wetting agent, or pasta, for example, obtained by dispersing the compounds of the present invention in a pharmaceutically acceptable oil such as peanut oil, sesame oil or corn oil. The compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention can also introduces the animals in the form of the implant. Such preparative forms receive the usual way in accordance with standard veterinary practice. Alternatively, the compounds of the present invention can be used to enter the water supply, for example, in the form of liquid or soluble concentrate. In addition, the compounds of the present invention, for example, within the pharmaceutical compositions of the present invention, it is possible to enter in food animals, for example, you can get a concentrated feed additive or premix for mixing with the normal animal feed usually along with an appropriate carrier. The media promotes the uniform distribution of the compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention, for example, in the stern ready that is mixed with the premix. Suitable carriers include, without limitation liquid such as water, oils, such as soybean, corn, cotton seeds, or volatile organic solvents and solids, for example a small portion of food or variety of suitable foods containing alfalfa, soybean oil, cotton seed oil, flax seed, core, corn cobs, corn, molasses, urea and bone meal and mineral mixture.

In another aspect of the present invention the biological analysis was carried out using the joining of formula (I), (II) and (III)demonstrate a strong inhibition of lipases.

The following examples illustrate embodiments of the present invention. However, it should be understood that embodiments of the invention are not limited to the specific details of these examples, because the average person skilled in the art will be known or apparent its different variations in the light of the present description.

EXAMPLES

Example 1

Extraction and isolation of the source material: 2,5-dihydroxy-3-undecyl-1,4-benzoquinone

Structure No. 1: 2,5-dihydroxy-3-undecyl-p-benzoquinone (embelin)

Powdered berries Embella ribes extracted successively simple petroleum ether, chloroform, ethyl acetate, methanol and water. The chloroform extract is subjected to re-crystallization using a simple petroleum ether as to make the agent. Stage crystallization is repeated to increase the output. The mother liquor fractionary chromatography on a column of silica gel (100-200 mesh) using a simple petroleum ether-chloroform as an eluting solvent (gradient elution) to further enhance the output. All factions control on the plate for TLC (Silica gel 60 F254, Merck) n-propanol:n-butanol:liquid ammonia (6:1:3) as with the system solvent TLC. On the basis of TLC similar factions unite together and concentrate under reduced pressure. Connection purified by re-crystallization in a simple petroleum ether to yield 140 g (3.5%) of the extract. About 50 g of the extract is boiled in a vessel under reflux in a simple petroleum ether (500 ml), until the extract is not soluble in the solvent. The solution is cooled to room temperature and filtered. The above procedure is repeated to obtain the compound of the desired purity. The compound obtained shows1H NMR (300 MHz, CDCl3) δ: 0.87 (m, 3H), 1.0 to about 1.75 (m, 18H), 2,43 (m, 2H), of 5.99 (s, 1H), 7,66 (USS, 2H). TOF MS ES: 295 (M+H). MP. 142-143°C.

Example 2

2,5-Di-O-(3-fortuneserver)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 2: 2,5-bis-(3-ftorhinolonami)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (10 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 3-perbenzoate (1.35 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in Huck is ane) to net weight (0.96 g, 52,7%).

1H NMR (300 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.9 Hz), 1,0-1,6 (m, 18H), 2,5 (t, 2H5J = 7,6 Hz), 6,8 (s, 1H), and 7.3 to 8.0 (m, 8H). TOF MS ES: 539 (M+H). MP. 73,2-75,6°C.

Example 3

2,5-di-O-(4-tert-butylphenylmethyl)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 3: 2,5-bis-(4-tert-butyltrichlorosilane)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). Added 4-tert-butylbenzoate (1,67 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1.47 g, 28.3 per cent).

1H NMR (300 MHz, CDCl3) δ: 0,86 (t, 3H, J = 7.0 Hz), 1,0-1,6 (m, 36H), 2,5 (t, 2H, J = 7.5 Hz), 6.75 in (s, 1H), and 7.4 to 8.2 (m, 8H). TOF MS ES: 615 (M+H). Viscous mass.

Example 4

2,5-Di-O-(2-fortuneserver)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 4: 2,5-bis-(2-ftorhinolonami)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). is it add 2-perbenzoate (1.35 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (0.96 g, 52.7 percent).

1H NMR (300 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.9 Hz), 1,1-1,7 (m, 18H), 2,5 (t, 2H, J = 8.0 Hz), 6,8 (s, 1H), 7,2-8,2 (m, 8H). TOF MS ES: 539 (M+H). MP. 66,2-68°C.

Example 5

2,5-Di-O-(2-brompheniramine)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 5: 2,5-bis-(2-brompheniramine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 2-bromobenzoate (1.9 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1.56 g, 69.6 per cent).

1H NMR (400 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.8 Hz), 1,0-1,8 (m, 18H), 2,5 (t, 2H, J = 6.8 Hz), 6,8 (s, 1H), and 7.4 to 8.2 (m, 8H). TOF MS ES: 680 (25, M++Na), 682 (100, M++2+Na), 684 (25 M ++4+Na). MP. 77,1 and 78.6°C.

Example 6

2,5-Di-O-(3-brompheniramine)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 6: 2,5-bis-(3-brompheniramine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 3-bromobenzoate (1.9 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1.4 g, 62%).

1H NMR (400 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 7.2 Hz), 1,0-1,8 (m, 18H), of 2.51 (t, 2H, J = 7,2 Hz), 6,8 (s, 1H), between 7.4 to 8.4 (m, 8H). TOF MS ES: 680 (5, M++Na), 682 (20, M++2+Na), 684 (5, M++4+Na). MP. of 98.2-99,6°C.

Example 7

2,5-Di-O-(3-khlorfenilalanin)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 7: 2,5-bis-(3-chlorophenylalanine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 3-chlorobenzylchloride (1.5 g, 8.50 mmol) at 15-20°C. and stirred, bring those is the temperature value to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1.25 g, 64.4 per cent).

1H NMR (300 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.9 Hz), 1,1-1,7 (m, 18H), 2,5 (t, 2H, J = 7,6 Hz), 6,8 (s, 1H), and 7.4 to 8.2 (m, 8H). TOF MS ES: 593 (9, M++Na), 595 (3, M++2+Na). MP. 102,8-104,6°C.

Example 8

2,5-Di-O-(2-khlorfenilalanin)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 8: 2,5-bis-(2-chlorophenylalanine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 2-chlorobenzylchloride (1.5 g, 8.50 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1,14 g, 58.7 percent).

1H NMR (300 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.9 Hz), 1,0-1,6 (m, 18H), 2,5 (t, 2H, J = 8.0 Hz), 6,8 (s, 1H), 7,2-8,2 (m, 8H). TOF MS ES: 593 (100, M++Na), 595 (35, M++2+Na). MP. 56,2-57,8°C.

Example 9

2,5-Di-O-(4-khlorfenilalanin)-3-undecyl-1,4-benzo the quinone

Synthesis, structure No. 9: 2,5-bis-(4-chlorophenylalanine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 4-chlorobenzylchloride (1.5 g, 8.50 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1,21 g, 62.4 per cent).

1H NMR (400 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 7.0 Hz), 1,1-1,7 (m, 18H), 2,5 (t, 2H, J = 7,6 Hz), 6,8 (s, 1H), and 7.3 to 8.1 (m, 8H). TOF MS ES: 593 (10, M++Na), 595 (3, M++2+Na). MP. 110,2-112°C.

Example 10

2,5-Di-O-(4-brompheniramine)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 10: 2,5-bis-(4-brompheniramine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 4-bromobenzoate (1.9 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, the industry is up (water, the brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1,49 g, 66.5 per cent).

1H NMR (400 MHz, CDCl3) δ: 0.8 in (t, 3H, J = 6.8 Hz), 1,0-1,8 (m, 18H), 2,5 (t, 2H, J = 7,6 Hz), 6,7 (s, 1H), 7,6 to 8.2 (m, 8H). TOF MS ES: 680 (5, M++Na), 682 (20, M++2+Na), 684 (5, M++4+Na). MP. to 124.4-a 126.7°C.

Example 11

2,5-Di-O-(3-nitrophenylarsonic)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 11: 2,5-bis-(3-nitrophenylarsonic)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 3-nitrobenzanthrone (1.6 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (0.95 g, 47%).

1H NMR (300 MHz, CDCl3) δ: 0,86 (t, 3H, J = 6.9 Hz), 1,1-1,6 (m, 18H), 2,5 (t, 2H, J = 8.0 Hz), 6,8 (s, 1H), 7,6 to 8.6 (m, 8H). TOF MS ES: 593 (M+H). MP. 112,6-to 114.4°C.

Example 12

2,5-Di-O-(4-methylphenylsulphonyl)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 12: 25-bis-(4-methylphenylcarbinol)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.15 g, 0.5 mmol) in dichloromethane (20 ml) is added pyridine (0,41 ml, 5.1 mmol). To it add 4-trouillard (0,23 g, 1.53 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (84 mg, 32%).

1H NMR (300 MHz, CDCl3) δ: 0,85 (m, 3H), of 1.0 to 1.8 (m, 18H), 2,44 (m, 8H), 6,74 (s, 1H), 7,25 is 8.25 (m, 8H). TOF MS ES: 553 (100, M++Na). MP. 94,8 of 96.2°C.

Example 13

2,5-Di-O-(3-methylphenylcarbinol)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 13: 2,5-bis-(3-methylphenylcarbinol)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.5 g, 1.7 mmol) in dichloromethane (20 ml) is added pyridine (0,55 ml, 6.8 mmol). To it add 3-trouillard (0,654 g of 4.25 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in GE is San) to net weight (0.64 g, 71%).

1H NMR (300 MHz, CDCl3) δ: of 0.85 (t, 3H, J = 7.5 Hz), 1.0 to 1.5 (m, 18H), of 2.3-2.5 (m, 8H), to 6.75 (s, 1H), 7,30-to 7.61 (m, 5H), 7,9-8,10 (m, 3H). TOF MS ES: 553 (100, M++Na). MP. 80,4-81,7°C.

Example 14

2,5-Di-O-(2-nitrophenylamino)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 14: 2,5-bis-(2-nitrophenylarsonic)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 2-nitrobenzoate (1.6 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (0.95 g, 47%).

1H NMR (400 MHz, CDCl3) δ: 0,86 (t, 3H, J = 6.5 Hz), 1,1-1,6 (m, 18H), and 2.6 (t, 2H, J = 8.0 Hz)and 6.9 (s, 1H), 7,7-to 8.1 (m, 8H). TOF MS ES: 615 (100, M++Na). MP. 72,2-73,8°C.

Example 15

2,5-Di-O-(phenylcarbamoyl)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 15: 2,5-bis-(phenylcarbamoyloxy)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.3 g, of 1.02 mmol) in dichloromethane (20 ml) is added pyridine (0.3 ml, 4,08 mmol). To him dobavlaut the benzoyl chloride (0.26 g, 2.55 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (0,285 g, 56,80%).

1H NMR (400 MHz, CDCl3) δ: 0,85 (m, 3H), 1,10-1,68 (m, 18H), of 2.50 (m, 2H), 6,77 (s, 1H), 7,42-to 7.64 (m, 6H), 8,11-by 8.22 (m, 4H). TOF MS ES: 525 (100, M++Na). MP. of 98.2-99,6°C.

Example 16

2,5-Di-O-(4-fortuneserver)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 16: 2,5-bis-(4-ftorhinolonami)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 4-perbenzoate (1.35 g, 8.5 mmol) at 15-20°C. and stirred, give the ability to reach temperatures of 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to a net weight of 0.85 g, 46.4 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,86 (t, 3H, J = 6,7 Hz), and 1.0 to 1.7 (m, 18H), 2,5 (t, 2H, J = 7,3 Hz), 6,7 (s, 1H), 7,1-7,2 (m, 4H), of 8.1 to 8.2 (m, 4H). MP. 958-97,7°C.

Example 17

2,5-Di-O-(3-methoxyphenethyl)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 17: 2,5-bis-(3-methoxyphenylalanine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 3-methoxybenzoate (1.45 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1,32 g, 69%).

1H NMR (400 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 7.0 Hz), 1,1-1,7 (m, 18H), 2,5 (t, 2H, J = 7.9 Hz), a 3.9 (s, 6H), 6,8 (s, 1H), of 7.2 to 7.7 (M, 8H). TOF MS ES: 585 (100, M++Na). MP. 77,1 and 78.6°C.

Example 18

2,5-Di-O-(4-methoxyphenethyl)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 18: 2,5-bis-(4-methoxyphenylalanine)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 4-methoxybenzophenone (1.45 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and peremeci is the W continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (1,37 g, 71,7%).

1H NMR (400 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6,7 Hz), 1,1-1,7 (m, 18H), 2,5 (t, 2H, J = 7,6 Hz)of 3.9 (s, 6H), 6,9 (s, 1H), 7,0-7,2 (m, 4H), 8,10-8,13 (m, 4H). TOF MS ES: 585 (100, M++Na). MP. 99,2-100,5°C.

Example 19

2,5-Di-O-(2-jumpercables)-3-undecyl-1,4-benzoquinone

Synthesis, structure No. 19: 2,5-bis-(2-jumpercables)-3-undecyl-1,4-benzoquinone

To a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is added pyridine (1.1 ml, to 13.6 mmol). To it add 2-identilied (of 2.26 g, 8.5 mmol) at 15-20°C. and stirred, bring the temperature up to 30°C and stirring is continued for 3 h (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to the crude product, which was purified by chromatography on a column of SiO2(10-20% EtOAc in hexane) to net weight (0,89 g, 35%).

1H NMR (300 MHz, CDCl3) δ: of 0.87 (t, 3H, J = 6.9 Hz), 1,2-1,7 (m, 18H), 2,5 (t, 2H, J = 7,6 Hz), 6,8 (s, 1H), 7,2-8,2 (m, 8H). TOF MS ES: 777 (100, M++Na). MP. 64,2-of 67.6°C.

Example 20

Analysis of the lipase inhibitory activity

Getting ispy is been created designs: patterns No. 1-19 was dissolved in 1 ml DMSO (dimethyl sulfoxide) to obtain a 10 mm stock solution, mixed vortex mixer to dissolve and kept at 4°C. Different concentrations of the working samples were prepared in 0.2 M phosphate buffer at pH 8.0. This sample was used as the test sample for all further analyses.

Analysis of lipase: an analysis of the lipase was performed by the method described by Winkler and Stuckmann, 1979, with a modification (Winkler, U.K. & Stuckmann, M. Glycogen, hyaluronate, and some other polysaccharides greatly enhance the formation of exolipase by Serratia marcescens. J. Bacteriol. 138: 663-670 (1979)). The analysis was structured using a 96-well format. The substrate used in this analysis consisted of a p-nitrophenolate (Sigma, catalog No. N-2752). 4.5 mg p-nitrophenolate was dissolved in 200 μl of N,N-dimethylformamide (Sigma, catalogue number D-4551) and the volume was brought to 10 ml of 0.1 M phosphate buffer at pH 8.0. A sample of pancreatic lipase (Sigma, catalogue number L-3126) was prepared by dissolving the enzyme in 0,1M phosphate buffer at a concentration of 5 mg/ml Reaction mixture consisted of 150 µl of substrate solution; 40 μl of phosphate buffer (pH 8.0, 0.2 M) and 10 μl of a solution of lipase. The reaction mixture was incubated at 37°C and the optical density was measured at 405 nm after incubation. The enzyme activity was represented in the form of international units (IU).

The lipase activity: one enzyme unit of lipase is defined as the amount that releases 1 nm of free phenol of the substrate (p-nitrophe aparimita) in 1 min at 1 ml under standard conditions analysis (Winkler and Stuckmann, 1979; Yadav RP, Saxena RK, Gupta R, Davidson WS. Purification and characterization of a region-specific lipase from Aspergillus terreus. Biotechnol. Appl. Biochem. (1998) 28, (243-249)). It is derived from the standard graphs of p-NITROPHENOL (Sigma, 104-8).

Analysis of the inhibition of lipase: analysis of the inhibition of the enzyme was performed dependent on dose. The concentrations tested synthetic analogues were 100 μm and 200 μm. The analysis was similar analysis, openomy above, except that used 40 μl of the test sample instead of the phosphate buffer in the control. The optical density was measured after 0 h and after incubation at 37°C.

Enzyme inhibition: inhibition of the enzyme was represented as the relative activity and the percentage of inhibition on the basis of changes in international units (IU).

61,31
Table 1
The effect of the compounds of structures No. 1-19 on the inhibition of pancreatic lipase
Sample% inhibition (200 µm)% inhibition (100 μm)
Control (without inhibitor)0,000,00
Structure No. 169,4667,87
to 97.91a 99.16
Structure No. 3a 99.1699,54
Structure No. 4of 99.9699,62
Structure No. 5100,00100,00
Structure No. 6100,00100,00
Structure No. 7100,00100,00
Structure No. 8100,00100,00
Structure No. 9100,0098,40
Structure No. 1097,0287,49
Structure No. 1197,9597,38
Structure No. 1299,1288,49
Structure No. 13100,00100,00
Structure No. 1465,88
Structure No. 15100,00100,00
Structure No. 16100,0089,55
Structure No. 1796,4678,31
Structure No. 1894,08of 55.64
Structure No. 19100,0029,18

Example 21

The definition of IC50

Preparation of test samples: synthetic analogues were dissolved in 1 ml of DMSO to obtain a 10 mm stock solution. The samples were vortex mixed by a stirrer to dissolve and kept at 4°C. Different concentrations of the working samples were obtained in 0.2 M phosphate buffer, pH 8.0. This sample was used as the test sample for all further analyses.

Analysis of the inhibition of lipase: analysis of the inhibition of the enzyme was performed dependent on dose. The concentrations tested synthetic analogues were from 6.25 μm to 200 μm. The analysis was similar analysis, openomy above, except that used 40 μl of the test sample, instead of the phosphate buffer is control. The optical density was measured after 0 h and after incubation at 37°C. the enzyme Activity was measured in international units (IU).

The lipase activity: one enzyme unit of lipase is defined as the amount that releases 1 nm of free phenol of the substrate (p-nitrophenolate) in 1 min at 1 ml under standard conditions analysis. It is derived from the standard graphs of p-NITROPHENOL (Sigma, 104-8).

The inhibition percentage: enzyme inhibition was represented as the percentage of inhibition on the basis of changes in international units (IU).

The calculation of the IC50: IC50each analog was calculated manually on the graph, depending on the dose (from 6.25 μm to 200 μm) of each analog at a concentration at which the % inhibition of lipase was measured as 50% in two direct relatives (inhibition more and less than 50%). The value of the IC50was obtained by linear regression. The obtained value is based on interpolated data.

Table 2
IC50compounds of structures No. 1-19 for inhibition of pancreatic lipase
IC50(µm)
Structure No. 121,94
Structure No. 2 <6,25
Structure No. 3<6,25
Structure No. 47,78
Structure No. 510,98
Structure No. 613,51
Structure No. 716,72
Structure No. 820,61
Structure No. 922,80
Structure No. 1023,69
Structure No. 1126,97
Structure No. 1241,34
Structure No. 1344,68
Structure No. 1445,32
Structure No. 1555,57
Structure No. 1672,81
Structure No. 1781,91
Structure No. 1894,22
Structure No. 19 129,39

Example 22

Inhibition suction lipase

Starving during the night 4-week-old male Wistar rats (range of weight: 150-200 g) were used for studying the absorption of lipids. Rats were divided into 2 groups of 6 rats each, and 100 µl of blood was taken from the orbital sinus for estimation of lipid profile plasma in 0 hours 1 ml of the fat-rich fluid was injected RO (oral) via a stomach tube. In addition, the experimental group oral was administered 100 μl of the test compounds (structure No. 1-19 derivatives of 2,5-di-O-aroyl-3-undecyl-1,4-benzoquinone), dissolved in 500 μl of medium; the control group received the same volume of media.

100 μl of blood was taken 1 h after feeding to assess the overall content of triglycerides. The results are shown in the following table. The experimental group was significantly lower levels of triglycerides.

/tr>
Table 3
The levels of triglycerides
GroupTriglycerides (mg/DL)
h <0>h <1>
Group - 1 (control)
17779,5127135,1
272160
354171
46663
57990
6129200
Group 2 (experimental: structure No. 2-19)
76470,67466,5
84248
96691
1010667
117650
127069

Example 23

Inhibition of cell capture lipids

The cell line of murine macrophages (J774A.1) were sown in 6-hole culture plates (1×105cells per well) in the modified Dulbecco Wednesday Needle (DMEM)containing 10% fetal calf serum. To each well was added 100 mg of oxidized low-density lipoprotein (LDL). Each tablet in the hole in three repetitions were added one of the compounds (structure No. 1-19) (10 μm), while the 3 holes were kept as control. The experiment was finished after 48 hours Cells were stained with neutral red oil stained in counterflow with hematoxylin and examined under a microscope. Compared to control, treatment with compounds of structures No. 2-19 significantly inhibited the capture of LDL by macrophages.

All publications and patent applications cited in the present description, is included as a reference, as if each publication and a patent application was specifically and individually indicated as included in the reference.

Although the foregoing invention has been described in some is atalah by way of illustration and example in the interests of clarity and understanding, for medium to specialists in this field in light of the provisions of the present invention will be obvious that it is possible to make certain changes and modifications without departing from the spirits or scope of the attached claims.

1. The compound of formula (I):

where each R1and R2represents O-C(O)phenyl, where phenyl is substituted by 1 Deputy selected from halogen, nitro, C1-C6the alkyl or C1-C6alkoxy;
and its pharmaceutically acceptable salts.

2. The compound of formula (II):

where each R1and R2represents C(O)phenyl, where phenyl is substituted by 1 Deputy, independently selected from halogen, nitro, C1-C6the alkyl or C1-C6alkoxy;
and its pharmaceutically acceptable salts.

3. The compound according to claim 1, having the formula (III):

where each R1and R2represent phenyl, where phenyl is substituted by 1 Deputy selected from halogen, nitro, C1-C6the alkyl and C1-C6alkoxy;
and its pharmaceutically acceptable salts.

4. The compound of formula (II) according to claim 2, where R1and R2independently from each other selected from the group consisting of C(O)phenyl, substituted C1-C6the alkyl, C(O)phenyl, substituted by halogen; C(O)phenyl which, substituted nitro group; C(O)phenyl, substituted C1-C6alkyloxy; and its pharmaceutically acceptable salts.

5. A compound selected from the group consisting of:
i) 2,5-bis-(3-ftorhinolonami)-3-undecyl-1,4-benzoquinone;
ii) 2,5-bis-(4-tert-butyltrichlorosilane)-3-undecyl-1,4-benzoquinone;
iii) 2,5-bis-(2-ftorhinolonami)-3-undecyl-1,4-benzoquinone;
iv) 2,5-bis-(2-brompheniramine)-3-undecyl-1,4-benzoquinone;
v) 2,5-bis-(3-brompheniramine)-3-undecyl-1,4-benzoquinone;
vi) of 2,5-bis-(3-chlorophenylalanine)-3-undecyl-1,4-benzoquinone;
vii) of 2,5-bis-(2-chlorophenylalanine)-3-undecyl-1,4-benzoquinone;
viii) of 2,5-bis-(4-chlorophenylalanine)-3-undecyl-1,4-benzoquinone;
ix) of 2,5-bis-(4-brompheniramine)-3-undecyl-1,4-benzoquinone;
x) of 2,5-bis-(3-nitrophenylarsonic)-3-undecyl-1,4-benzoquinone;
xi) of 2,5-bis-(4-methylphenylcarbinol)-3-undecyl-1,4-benzoquinone;
xii) of 2,5-bis-(3-methylphenylcarbinol)-3-undecyl-1,4-benzoquinone;
xiii) of 2,5-bis-(2-nitrophenylarsonic)-3-undecyl-1,4-benzoquinone;
xv) of 2,5-bis-(4-ftorhinolonami)-3-undecyl-1,4-benzoquinone;
xvi) of 2,5-bis-(3-methoxyphenylalanine)-3-undecyl-1,4-benzoquinone;
xvii) of 2,5-bis-(4-methoxyphenylalanine)-3-undecyl-1,4-benzoquinone;
xviii) of 2,5-bis-(2-jumpercables)-3-undecyl-1,4-benzoquinone;
and its pharmaceutically acceptable salts.

6. Pharmaceutical whom azizia, inhibiting or reducing the activity of pancreatic lipase containing a therapeutically effective amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt, pharmaceutically acceptable inert adjuvant, diluent or carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dialkyl ether of naphthalene dicarboxylic acid used in production of different polymer materials such as polyesters or polyamides from a liquid-phase reaction mixture containing low-molecular alcohol, naphthalene dicarboxylic acid, and material which contains polyethylene naphthalate, in mass ratio of alcohol to acid between 1:1 and 10:1, at temperature between 260°C and 370°C and pressure between 5 and 250 absolute atmospheres.

EFFECT: method enables production of highly pure NDC.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing dimethyl-1,5-naphthalene dicarboxylate that is used in preparing polymers based on thereof and articles made of these polymers. The economic and effective method involves the following stages: (1) dehydrogenation of 1,5-dimethyltetraline to yield 1,5-dimethylnaphthalene; (2) oxidation of 1,5-dimethylnaphthalene prepared at dehydrogenation stage to yield 1,5-naphthalene dicarboxylic acid being without accompanying isomerization stage, and (3) esterification of 1,5-naphthalene dicarboxylic acid prepared at oxidation stage in the presence of methanol to yield the final dimethyl-1,5-naphthalene dicarboxylate.

EFFECT: improved preparing method.

9 cl, 3 dwg, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing acylated 1,3-dicarbonylic compounds used as agrochemicals or intermediate products in manufacturing agrochemicals. Also, invention describes a method for preparing tautomeric forms of acylated 1,3-dicarbonylic compounds. Method involves the arrangement reaction of the corresponding enol ester and this rearrangement reaction is carried out in the presence of alkaline metal azide. Method provides eliminating the requirement in expensive isolating process of catalyst/reagent in systems for waste treatment.

EFFECT: improved preparing method.

7 cl, 3 ex

The invention relates to the field of organic chemistry

FIELD: chemistry.

SUBSTANCE: invention relates to a mixture of isoalkanes as oil bodies for cosmetic or pharmaceutical agencies, whose 1H-NMR-spectrum in the region of a chemical shift δ of from 0.6 to 1.0 ppm relative tetramethylsilane, has a surface integral of from 25 to 70% of the total integral surface. The mixture, which has density from 0.7 to 0.82 g/cm3, contains not less than 70 wt % alkanes with 8-20 carbon atoms, and the fraction of side chains with alkyl groups which have 2 or more carbon atoms is less than 20% of the total number of branching sites and is free from squalane. The invention also relates to a method of preparing said mixture, as well as a cosmetic or pharmaceutical agent based on said mixture and a hair cosmetic agent also based on said mixture.

EFFECT: improved method.

24 cl, 2 tbl, 809 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a mixture of isoalkanes as oil bodies for cosmetic or pharmaceutical agencies, whose 1H-NMR-spectrum in the region of a chemical shift δ of from 0.6 to 1.0 ppm relative tetramethylsilane, has a surface integral of from 25 to 70% of the total integral surface. The mixture, which has density from 0.7 to 0.82 g/cm3, contains not less than 70 wt % alkanes with 8-20 carbon atoms, and the fraction of side chains with alkyl groups which have 2 or more carbon atoms is less than 20% of the total number of branching sites and is free from squalane. The invention also relates to a method of preparing said mixture, as well as a cosmetic or pharmaceutical agent based on said mixture and a hair cosmetic agent also based on said mixture.

EFFECT: improved method.

24 cl, 2 tbl, 809 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a mixture of isoalkanes as oil bodies for cosmetic or pharmaceutical agencies, whose 1H-NMR-spectrum in the region of a chemical shift δ of from 0.6 to 1.0 ppm relative tetramethylsilane, has a surface integral of from 25 to 70% of the total integral surface. The mixture, which has density from 0.7 to 0.82 g/cm3, contains not less than 70 wt % alkanes with 8-20 carbon atoms, and the fraction of side chains with alkyl groups which have 2 or more carbon atoms is less than 20% of the total number of branching sites and is free from squalane. The invention also relates to a method of preparing said mixture, as well as a cosmetic or pharmaceutical agent based on said mixture and a hair cosmetic agent also based on said mixture.

EFFECT: improved method.

24 cl, 2 tbl, 809 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a mixture of isoalkanes as oil bodies for cosmetic or pharmaceutical agencies, whose 1H-NMR-spectrum in the region of a chemical shift δ of from 0.6 to 1.0 ppm relative tetramethylsilane, has a surface integral of from 25 to 70% of the total integral surface. The mixture, which has density from 0.7 to 0.82 g/cm3, contains not less than 70 wt % alkanes with 8-20 carbon atoms, and the fraction of side chains with alkyl groups which have 2 or more carbon atoms is less than 20% of the total number of branching sites and is free from squalane. The invention also relates to a method of preparing said mixture, as well as a cosmetic or pharmaceutical agent based on said mixture and a hair cosmetic agent also based on said mixture.

EFFECT: improved method.

24 cl, 2 tbl, 809 ex

Styling powder // 2420334

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, and represents an application of a styling powder containing 50 to 95 wt % of an aqueous solvent selected from the group containing water or water mixed with an alcohol containing 1 to 4 carbon atoms, 0.5 to 15 wt % of a water-repellent silicon dioxide powder and 1 to 15 wt % of at least one filming and strengthening polymer for temporary moulding of keratin fibres.

EFFECT: invention provides a permanent hair styling and excessive mat effect.

6 cl, 3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to cosmetic industry, in particular to protective and regenerating composition. Composition for cosmetic care, containing the first cosmetically active ingredient, which contains dried extract of grape shoots, and the second active ingredient, which contains component of ectoine type, taken in specified quantity. Cosmetic composition for local application on skin. Method of cosmetic care.

EFFECT: composition is efficient for skin regeneration and against aging.

18 cl, 3 dwg, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to cosmetic industry, in particular to protective and regenerating composition. Composition for cosmetic care, containing the first cosmetically active ingredient, which contains dried extract of grape shoots, and the second active ingredient, which contains component of ectoine type, taken in specified quantity. Cosmetic composition for local application on skin. Method of cosmetic care.

EFFECT: composition is efficient for skin regeneration and against aging.

18 cl, 3 dwg, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to creation of preparations for local application on skin with wound-healing effect. In order to increase ability of live body to tissue regeneration, such as ability of fibroblast to collagen production in derma in injured skin region, for instance, such as large wrinkle or wound, as active component of preparation for local application on skin, flavanon derivative, such as farrerol, can be applied. Additionally, for efficient detection of substance, which has excellent effect on wound healing acceleration, reconstructive action of collagen fibre bundles was tested with application of skin wound model.

EFFECT: creation of preparation with wound-healing effect.

8 cl, 11 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to aromatising agents, including mint, fruit or spicy aromatising agents, which are specifically made for virtually complete removal low-molecular sulphur compounds, particularly dimethylsulphoxide (DMSO) which is defined as the main precursor of compounds with a foul smell, such as dimethyl sulphide or methyl mercaptan. The synthesis method involves washing with water, as well as non-selective removal of undesirable components and exposing the aromatising agents to extreme conditions which can decompose other components and lead to undesirable change in taste or flavour. Other processing methods with the aim of selective removal of undesirable components involve distillation in order to remove polar low-boiling components, filtration through adsorbents which are selective towards sulphur components, countercurrent extraction and column chromatography.

EFFECT: produced aromatising agents are especially useful in oral care compositions which contain components with chemical reducing capability, such as tin ions, which react with sulphur-containing compounds to form foul smelling products.

12 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to cosmetology and represents composition for personal care, which includes water, at least one oil or one softening preparation, at least one crystalline polymer with side chain, which contains, at least one functional group, consisting of dimeticon and hydroxyl group, and at least one emulsifier.

EFFECT: invention ensures improvement of resistance to water and removal, release of active ingredient by more regulated way, enhancement of SPF sun-protecting compositions, holding aroma and holding volatile ingredients.

23 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a mixture of isoalkanes as oil bodies for cosmetic or pharmaceutical agencies, whose 1H-NMR-spectrum in the region of a chemical shift δ of from 0.6 to 1.0 ppm relative tetramethylsilane, has a surface integral of from 25 to 70% of the total integral surface. The mixture, which has density from 0.7 to 0.82 g/cm3, contains not less than 70 wt % alkanes with 8-20 carbon atoms, and the fraction of side chains with alkyl groups which have 2 or more carbon atoms is less than 20% of the total number of branching sites and is free from squalane. The invention also relates to a method of preparing said mixture, as well as a cosmetic or pharmaceutical agent based on said mixture and a hair cosmetic agent also based on said mixture.

EFFECT: improved method.

24 cl, 2 tbl, 809 ex

Up!