KR20080030044A - Compositions for treatment of lipase-mediated diseases - Google Patents

Abstract

Novel benzoquinone-derived compounds and polymorphs and prodrugs thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers, carbamates, oximes of such compounds, polymorphs, prodrugs and isomers are provided. Process for preparation of compounds of the invention and pharmaceutical compositions containing such compounds and active polymorphs, prodrugs, isomers or pharmaceutically acceptable salts, esters thereof and their use for reducing or inhibiting activity of lipase gene family for treatment, amelioration or prevention of lipase gene family mediated diseases and conditions including overweight, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, diabetes, atherosclerosis, other cardiovascular diseases, metabolic syndromes, metabolic disorders, skin, hair, and cosmetic are provided.

Description

COMPOSITIONS FOR TREATMENT OF LIPASE-MEDIATED DISEASES}

The present invention relates to novel heterocyclic compounds of benzoquinone which affect the enzymatic activity of the lipase gene family. The present invention provides pharmaceutical compositions containing benzoquinone derived compounds, methods for their preparation and pharmaceutically acceptable salts, derivatives, isomers of compounds having selective activity against diseases and disorders mediated by lipase family genes, It relates to a polymorph and a solvent compound.

In many developed and developing countries, the tendency to adopt diets containing high fat content and low fiber concentrations is steadily rising, which is accompanied by a non-labor-intensive sedentary lifestyle. Such excessive fat intake, accompanied by a reduction in the conversion of fat to energy due to a sedentary lifestyle, can lead to the accumulation of fat in the body at various levels, including body fluids, cells and tissues. As a result, the risk of metabolic disorders such as overweight or obesity is steadily increasing in the population, and such risks progress to related diseases such as diabetes, cardiovascular disease, metabolic syndrome, and hypertension.

In general, the first line of concern for individuals suffering from such metabolic diseases, particularly body weight or obesity, includes the adoption of low fat diets and regular exercise. However, following such prescriptions can be difficult, and as the disease progresses, treatment with therapeutic drugs is needed.

Therefore, research has been conducted to develop effective and safe drugs for the prevention and treatment of clinical symptoms caused by the accumulation of fat in body fluids, cells and tissues. Therefore, there is a continuing need to reduce the absorption and accumulation of fat in the body in any way.

One approach to preventing or reducing fat accumulation is by reduction or inhibitors that assist in the intake and absorption of fat at varying levels in the body. Enzymes belonging to the lipase gene family are most important for lipid metabolism, absorption and transport.

Hepatic Lipases and Lipoproteins Lipases are multifunctional proteins that mediate the binding, absorption, catabolism, and remodeling of lipoproteins and phospholipids. Lipoprotein lipase and hepatic lipase function by binding to the luminal surface of peripheral tissues and endothelial cells of the liver, respectively. Both enzymes are involved in reverse cholesterol transport, which transports cholesterol from peripheral tissues to the liver either for secretion from the body or for recycling. Genetic defects of both liver lipases and lipoprotein lipases are known to be due to family diseases of lipoprotein metabolism. Defects in the metabolism of lipoproteins lead to serious metabolic diseases such as hypercholesterolemia, hyperlipidemia, and atherosclerosis.

Enzymes of the lipase gene family are involved in a wide array of metabolic pathways: lipid digestion, absorption, fatty acid uptake, lipoprotein transport and also inflammation (Wong Howard et al., 2002, The lipase gene family, Journal of Lipid Research, Vol. 43: 993-999).

Pancreatic lipase is one of the key enzymes in lipid metabolism. It is synthesized by the acinar cells of the pancreas, where lipase is secreted into the lumen of the small intestine and assists the small intestine absorption of long-chain triglyceride fatty acids (Verger, R. 1984, Pancreatic Lipases In Lipases.B. Borgstrom and HL). .... Brockman, editors Elsevier , New York 83-150; Lowe, ME 1997, Molecular mechanisms of rat and human pancreatic triglyceride lipases J. Nutr 127: 549-557).

The action of triacylglycerol lipase is believed to be atherosclerosis preventive because these enzymes lower serum triacylglycerol levels and promote HDL formation (Olivecrona, G., and Olivecrona, T. (1995) Curr. Opin. Lipid. 6: 291-305). Lipoprotein lipase is a major enzyme that contributes to the distribution and utilization of triglycerides in the body. Lipoprotein lipase hydrolyzes triglycerides into chylomicrons and VLDL. Hepatic lipase hydrolyzes triglycerides into IDL and HDL and contributes to lipoprotein reconstitution. Liver lipases also function as phospholipases and hydrolyze phospholipids into HDL.

Lipase members function in the metabolic process of circulating lipoproteins. Liver lipases play a role in the uptake of HDL cholesterol (Olivecrona, T., et al. 1993, Lipoprotein lipase and hepatic lipase. Curr . Opin . Lipidol . 4: 187-196). It is almost synthesized in the liver and found preferentially there (Hixenbaugh, E. A, et al., 1989, Hepatic lipase in the rat ovary. J. Biol . Chem . 264: 4222-4230).

Lipoprotein lipase (LPL), the third member of the lipase gene family, is distributed in various tissues, with the highest concentrations occurring in adipocyte tissues and muscles. The lipase is bound to the capillary endothelium and serves to supply the underlying tissue with fatty acids derived from circulating kilomicrons and the triglyceride-rich nuclei of LDL (Olivecrona, T., and G. Bengtsson-Olivecrona). . 1993. Lipoprotein lipase and hepatic lipase Curr Opin Lipidol 4:.... 187-196). In the process, LPL converts these lipoproteins into residual and HDL particles. Evidence of accumulation suggests that LPL produced by macrophages in the vascular wall may facilitate the development of atherosclerosis by promoting lipid accumulation in the lesion. LPL has been shown to be involved in the development of atherosclerosis (Mead JR, et al. 1999, "Lipoprotein Lipase, a key role in atherosclerosis?" FEBS Lett., Nov 26, 462 (1-2): 1-6 ). Several research groups have also suggested that both LPL and hepatic lipase, in addition to their traditional role as lipolytic enzymes, also appear to act as ligands in the metabolism of plasma lipoproteins (Nykjaer, A., et al., 1993, alpha 2-macroglobulin receptor / low density lipoprotein receptor-related protein binds to lipoprotein lipase and binds to lipase-associated, very low density lipoprotein J. Biol. Chem. 268: 15048-15055; Krapp , A., S. et al., 1996. Liver lipase mediates the uptake of kilomicrons and VLDL into cells via LDL receptor-associated protein (LRP) J. Lipid Res. 37: 926-936). Transgenic animals expressing human lipoprotein lipase or liver lipase have 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).

A member of the more recently discovered lipase gene family is endothelial lipase. Although the function of this lipase is uncertain at present, it is believed to play a role in HDL metabolism (Jaye, M., et al., 1999, a novel endothelial-induced lipase that mediates HDL metabolism. Nat. Genet 21: 424 -428).

Using the potential of lipases to be increasingly recognized in the fat metabolism pathway, drugs that inhibit or reduce the activity of various levels of lipases in the body are at the forefront of therapeutics for the treatment of diseases mediated by elevated levels of fat accumulation. Form.

Lipase inhibitors marketed as anti-obesity drugs include Orlistat (XENICAL ^® ) described in US Pat. No. 4,598,089. European patent application EP129748 relates to Orlistat and related compounds and their use for inhibiting pancreatic lipase and for treating hyperlipidemia and obesity. Orlistat blocks the digestion of food fat by only inhibiting intestinal lipases such as gastric, pancreatic and carboxyester lipases, especially pancreatic lipases in the digestive tract and preventing lipase from interacting with its lipid targets. However, it does not appear to affect lipases other than hepatic lipases or endothelial lipases that are recognized to play a role in catalyzing the hydrolysis of intestinal lipases, such as 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 tends to cause high frequency of unpleasant (relatively harmless) side effects such as diarrhea.

Compounds that inhibit hepatic lipase and / or endothelial lipase activity are disclosed in PCT Application No. WO2004094393 for the treatment of liver and / or endothelial lipase mediated diseases. Compounds are indicated primarily for increasing HDL levels by inhibiting the activity of liver and / or endothelial lipases and are not intended to target intestinal or other lipases.

It is therefore useful for reducing or inhibiting the metabolism, absorption, and accumulation of fat at various levels, including fluids, cells, and tissues of the body by inhibiting or reducing the activity of the lipase gene family of interest and not just that particular type of lipase. It is desirable to develop new compounds.

The vegetable benzoquinone embellin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), which is obtained from the dry fruits of Emelia ribes and is known as a contraceptive, is also an adipogenic enzyme. It has been reported to increase the activity of maleate dehydrogenase, glucose-6-phosphate dehydrogenase and hydroxymethylglutaryl-CoA reductase, while essentially not affecting lipolytic enzyme activity ( Gupta S. et al, Fitoterapia 60 (4): 331-338 (1989) .Embelin is also a tapeworm repellent, as an agent with antitumor, anti-inflammatory and analgesic properties (Chitra et al. Chemotherapy 40: 109 (1994). ) And as a cell-permeable, non-peptide inhibitor of X-linked inhibitors of apoptosis (XIAP) (Nikolovska-Coleska et al. J. Med. Chem. 47: 2430 (2004).

Summary of the Invention

The present invention provides a compound of formula (I):

Where

R ₁ and R ₂ are each hydrogen, C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, Independently selected from the group consisting of C (O) C ₁ -C ₆ alkyl, OC (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl and OC (O) aryl Wherein each group described above is 1 to 6 independently selected from hydrogen, halo, nitro, amino, cyano, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups Substituents may optionally be included. But according to the invention R ₁ and R ₂ are not methyl, methoxy, ethyl, ethoxy, phenyl, and hydroxy.

The invention also relates to compounds of formula (I) and derivatives thereof, such as, but not limited to, polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers of such compounds , Carbamate, all their solvent compounds and hydrates and salts.

In another aspect, the present invention provides a formula for reducing or inhibiting the metabolism, absorption, and accumulation of fat at various levels, including fluid, cell, and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. The use of the compound of (I) is provided.

In another embodiment, the present invention provides a compound of formula (II)

Where

R ₁ and R ₂ are each C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ( O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cyano, It may optionally contain 1 to 6 substituents independently selected from isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups. But according to the invention R ₁ and R ₂ are not methyl, ethyl, and phenyl.

The invention also relates to compounds of formula (II) and derivatives thereof, such as, but not limited to, polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers of such compounds , Carbamate, all their solvent compounds and hydrates and salts.

In another aspect, the present invention provides a formula for reducing or inhibiting the metabolism, absorption, and accumulation of fat at various levels, including fluid, cell, and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. The use of the compound of (II) is provided.

In another embodiment, the present invention provides a compound of formula (III):

Where

R ₁ and R ₂ are each hydrogen, C ₁ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, Independently selected from the group consisting of C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cya It may optionally contain 1 to 6 substituents independently selected from no, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups.

The invention also relates to compounds of formula (III) and derivatives thereof, such as, but not limited to, polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers of such compounds , Carbamate, all their solvent compounds and hydrates and salts.

In another aspect, the present invention provides a formula for reducing or inhibiting the metabolism, absorption, and accumulation of fat at various levels, including fluid, cell, and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. Provided is the use of the compound of (III).

The invention also provides a process for the preparation of the compounds of formulas (I), (II) and (III) and derivatives thereof.

The invention includes, but is not limited to, lipase gene family enzymes including overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases, and other metabolic diseases Patterns useful for reducing or inhibiting the activity of lipase gene family enzymes involved in the metabolism, uptake, and accumulation of lipids at various levels, including fluid, cellular and tissue levels, for the treatment, amelioration or prevention of diseases mediated by A pharmaceutical composition comprising any one of the compounds of the invention, and polymorphs thereof, prodrugs, isomers or pharmaceutically acceptable esters, ethers, carbamates, and oximes.

In a further aspect the invention also provides the use of the compounds of formulas (I), (II) and (III) and their derivatives for use in skin, hair care or cosmetic preparations.

The invention also provides a further aspect of a compound of formulas (I), (II) and (III) and derivatives thereof used to prevent or treat cellular and tissue damage caused by microbial pathogens that secrete lipases. Serves the purpose.

The invention also relates to pharmaceutical compositions comprising any of the compounds of formulas (I), (II) and (III) and derivatives thereof, by themselves or in combination with suitable pharmaceutically acceptable excipients. Such formulations may be useful for the treatment of diseases mediated by lipase gene family enzymes, including overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, other cardiovascular diseases, metabolic syndrome, and metabolic diseases It is useful for reducing or inhibiting the activity of lipase gene family enzymes involved in the metabolism, uptake, and accumulation of lipids at various levels, including body fluid, cell and tissue levels, for treatment, improvement or prevention.

The invention also provides a process for the manufacture of a medicament comprising the compounds of formulas (I), (II) and (III) and derivatives thereof alone or in therapeutically effective amounts or in combination with pharmaceutically acceptable adjuvants. . The compounds of formulas (I), (II) and (III) and their derivatives can further be combined with other active ingredients.

The invention also provides a method of treating a disease mediated by lipase gene family enzymes by administering to a human or animal patient a therapeutically effective amount of any compound of formulas (I), (II) and (III) and derivatives thereof It is about.

Other objects, features, and advantages of the present invention and the present invention will become apparent from the following detailed description of the invention and the appended embodiments.

The present invention provides novel methods and compositions for use in reducing or inhibiting the activity of lipase gene family enzymes for the treatment, amelioration or prevention of lipase gene family enzyme mediated diseases and disorders in a subject.

Justice

Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of various terms used to describe the invention.

As used herein, the term "lipase gene family enzyme" includes, but is not limited to, liver lipase; Intestinal lipases including gastric lipase, pancreatic lipase, and carboxyester lipase; Endothelial lipase; Phospholipase and other related lipases.

As used herein, the term “pharmaceutically acceptable” refers to materials including carriers, diluents, vehicle excipients, or chemically and / or toxicologically compatible compositions, and other ingredients including formulations that are not detrimental to their receptors. Say

The term "alkyl" by itself or as part of another substituent, unless otherwise specified, is a monovalent hydrocarbon radical of a straight or branched chain, such as 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, refers to a straight or branched monovalent hydrocarbon group having the indicated range of carbon atoms, such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl Isomeric means.

The term “alkynyl”, used alone or in combination with other terms, refers to a straight or branched acyclic carbon chain having the indicated number of carbon atoms, and groups, and containing carbon-to-carbon triple bond hydrocarbon groups.

The term "cycloalkyl" means a monocyclic or polycyclic alkyl radical having at least 3 carbon atoms and typically 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-, wherein the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n -Butoxy, isobutoxy, 2 ° butoxy and 3 ° butoxy, or 2-methoxyethoxy.

The term “C ₁ to C ₅ alkylcycloalkyl” means that any one of the C ₁ to C ₅ alkyl groups is substituted on the cycloalkyl group and the hybrid group is attached to the nucleus at the alkyl end.

The term “C ₁ to C ₆ heterocycloalkyl” means a heterocycloalkyl group having 2 to 6 carbon atoms, preferably 3 to 5 carbon atoms, and N which may be attached via heteroatoms or carbon atoms At least one heteroatom selected from O and / or S.

The term "aryl" means an aromatic hydrocarbon group having a single (such as phenyl) or fused ring system (such as naphthalene, anthracene, phenanthrene, etc.). Typical aryl groups are aromatic carbocyclic rings having 6, 7, 8, 9 or 10 carbon atoms, for example phenyl, naphthyl, tetrahydronaphthyl or indenyl, hydroxy, amino, halogen, nitro, Cyano, C ₁ to C ₄ alkyl, C ₂ to C ₄ alkenyl, C ₂ to C ₄ alkynyl, C ₁ to C ₄ alkoxy, C ₁ to C ₄ dialkylamino, meaning as defined above It may be optionally substituted with one or more substituents selected from the alkyl moiety having. Preferred aromatic hydrocarbon groups are phenyl.

The term "C ₃ to C ₉ heteroaryl" means a substituted or unsubstituted aromatic group having 3, 4, 5, 6, 7, 8 or 9 carbon atoms and is at least selected from N, 0 and / or S One heteroatom, for example imidazolyl, thiadiazolyl, pyridyl, (benzo) thienyl, (benzo) furyl, quinolyl, tetrahydroquinolyl, quinoxalyl or indolyl. Substituents on the heteroaryl group may be selected from the groups of substituents listed for the aryl group. Heteroaryl groups may be attached via carbon atoms or heteroatoms as necessary.

The term “C ₆ to C ₁₀ aryloxy” means an aryl group containing 6, 7, 8, 9 or 10 carbon atoms as defined above, attached to an oxygen atom. C ₃ to C ₉ heteroaryloxy groups are analogs of C ₆ to C ₁₀ aryloxy groups comprising at least one heteroatom selected from N, O or S.

The term "halo" means fluoro, chloro, bromo, or iodo.

The term "amino", alone or in combination, refers to a primary, secondary or tertiary amino group bonded via a nitrogen atom, and two similar or different alkyl or cycloalkyl substituents or two secondary amino groups including alkyl or cycloalkyl substituents. Tertiary amino groups comprising two nitrogen substituents together form a ring, for example --NH ₂ , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or pyri; Ferridino and the like, and preferably amino, dimethylamino and diethylamino, with particular preference being primary amino.

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

The term "nitro", alone or in combination, refers to a -NO ₂ group.

The term “heterocyclic group” refers to 1, 2 or 3 hetero members having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms and selected from the group consisting of nitrogen, oxygen or sulfur. Refers to a radical or group derived from a monocyclic or polycyclic saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus containing a molecule.

The term "substituent" is a "do not interfere" substituent. By "non-interfering" is meant that the group occupies the indicated location and is chemically suitable and stable to play the indicated or intended role. Inappropriate flags are therefore excluded from the definition of "no interference."

The compounds of formula (I) and derivatives thereof may also be labeled with isotopes (such as ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

"Prodrug" is a compound that can be converted into a compound of the present invention by the reaction of enzymes, gastric juice, etc. under physiological conditions in vivo, specifically, the compound of the present invention in the reaction of enzymatic oxidation, reduction, hydrolysis, etc. It refers to a compound which can be converted or a compound which can be converted to the compound of the present invention when hydrolysis or the like occurs by gastric juice or the like.

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

The phrase “therapeutically effective amount” refers to treating or preventing a particular disease, disorder, or disorder; Or ameliorate or eliminate one or more symptoms of a particular disease, disorder, or disorder; Or an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, disorder, or disorder described herein.

The use of the term C ₁ -C _n is used to denote each of C ₁ , C ₂ , C ₃ , ... C _n . Therefore, C ₁ -C ₂₀ is C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C _1O , C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ , and C ₂₀ , respectively. C ₁ -C ₁₃ includes each of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ . C ₂ -C ₁₃ is a formula containing each of C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ .

It will be apparent to those skilled in the art that any modification may be made to both the material and the method without departing from the object and interest of the present invention. The following general terms used in the following examples are explained below:

a) All operations are carried out at room temperature or at ambient temperature and in the 1825 ° C range.

b) The reaction process is monitored by thin layer chromatography (TLC) and the reaction time is provided for illustrative purposes only.

c) The melting point is not calibrated and the melting point is provided for the material produced as described, and polymorphism may lead to the separation of materials having different melting points in some formulations.

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

e) Yields are shown for illustrative purposes only.

f) The delta (δ) values for the main diagnostic protons, given in parts per million (ppm) compared to tetramethylsilane (TMS) as an internal standard measured at 300 MHz or 400 MHz using the indicated solvents, when presented. Is presented in the form of.

g) Chemical symbols have the usual meaning: The following abbreviations have also been used: v (volume), w (weight), B> p. 9 boiling point), Mp. (Melting point), L (liters), ml (milliliters), gms (grams), mg (milligrams), mol (mols), mmole (millimoles), eq (equivalents), ° C (degrees Celsius), conc. ), SiO ₂ (silicon dioxide), Na ₂ SO ₄ (sodium sulfate).

h) The intermediate used in the following examples was from Sigma.

Lipase

Three members of the human triacylglycerol lipase family have already been described: pancreatic lipase, lipoprotein lipase, and liver lipase (Goldberg, IJ, Le, N. -A., Ginsberg, HN, Krauss, RM, and Lindgren, FT). (1988) J. Clin. Invest. 81,561-568; Goldberg, IJ, Le, N., Paterniti JR, Ginsberg, HN, Lindgren, FT, and Brown, WV (1982) J. Clin. Invest. 70, 1184- 1192; Hide, WA, Chan, L., and Li, W.-H. (1992) J. Lipid. Res. 33,167-178). Pancreatic lipases mainly contribute to the hydrolysis of food lipids. Although variants of pancreatic lipase have already been described, their physiological roles have not been measured (Giller, T., Buchwald, P., Blum-Kaelin, D., and Hunziker, W. (1992) J. Biol. Chem 267,16509-16516).

Lipases encoded by these lipase genes are approximately 450 amino acids in length and contain leader signal peptides to facilitate secretion. Lipase proteins consist of two basic domains (Winkler, K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Amino terminal domains contain catalytic sites, while carboxyl domains are believed to contribute to substrate binding, cofactor binding, and interaction with cellular receptors (Wong, H., Davis, R. C. Nikazy, J.). , Seebart, KE, and Schotz, MC (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. C, Thuren, T., Goers, JW, Nikazy, J., Waite, M., and Schotz, MC (1994) J. Biol. Chem. 269, 10319-10323; Chappell, DA, Inoue, L, Fiy, GL, Pladet, MW, Bowen, SL, Iverius, P.-H., Lalouel, J.-M. and Strickland, DK (1994) J. Biol. Chem. 269, 18001-18006). The overall level of amino acid homology between members of the family is 22-65%, with regions of high homology corresponding to structural homology linked to enzyme function being local.

Members of the triacylglycerol lipase family share many conserved structural features. One such feature is the "GXSXG" motif, whose central serine residue is one of three residues comprising a "catalytic triad" (Winkler, K., D'Arcy, A.). and Hunziker, W. (1990) Nature 343, 771-774; Faustinella, F., Smith, L. C. and Chan, L. (1992) Biochemistry 31,7219-7223). Conserved aspartate and histidine residues make up the remainder of the catalytic triad. A short distance of 19 to 23 amino acids (“lid region”) forms an amphiphilic helix structure and covers the catalytic region of the enzyme (Winkler, K., D'Arcy, A., and Hunziker, W (1990) Nature 343, 771-774). Comparison between hepatic lipase and lipoprotein lipase demonstrated that the difference in phospholipase activity of triacylglycerol lipase and enzyme is mediated in part by this lead region (Dugi, KA, Dichek HL, and Santamarina-Fojo, S. (1995) J. Biol. Chem. 270, 25396-25401). Triacylglycerol lipases have varying degrees of heparin binding activity. Lipoprotein lipase has the highest affinity for heparin, and this binding activity has been mapped to the stretch of positively charged residues of the amino terminal domain (Ma, Y., Henderson, HE, Liu, M.-S. , Zhang, H., Forsythe, IJ, Clarke-Lewis, L, Hayden, MR, and Brunzell, JDJ Lipid Res. 35, 2049-2059).

Gene sequences encoding human pancreatic lipase, liver lipase and lipoprotein lipase have already been reported (GenBank Accession Nos. M93285, J03540, and M15856, respectively). The messenger RNAs of human liver lipase and pancreatic lipase are approximately 1.7 and 1.8 kilobases in length, respectively. Two mRNA transcripts of 3.6 and 3.2 kilobases were generated from the human lipoprotein lipase gene (Ranganathan, G., Ong, JM, Yukht, A., Saghizadeh, M., Simsolo, RB, Pauer, A., and Kern, PA (1995) J. Biol. Chem. 270, 7149-7155).

Lipase  Compounds affecting activity

The present invention relates to compounds of the formula (I) and derivatives thereof, such as polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers, carbamates of such compounds, For all solvent compounds and hydrates and all salts thereof:

Where

R ₁ and R ₂ are each C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ( Independently selected from the group consisting of O) C ₁ -C ₆ alkyl, OC (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl, and OC (O) aryl, Wherein each group described above is one to six independently selected from hydrogen, halo, nitro, amino, cyano, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups Substituents may be optionally included. But according to the invention R ₁ and R ₂ are not methyl, methoxy, ethyl, ethoxy, phenyl, and hydroxy.

In another embodiment, the present invention provides a compound of formula (II) and derivatives thereof, such as polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers of such compounds , Carbamate, all its solvent compounds and hydrates, and all their salts:

Where

R ₁ and R ₂ are each C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ( O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cyano, It may optionally contain 1 to 6 substituents independently selected from isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups. But according to the invention R ₁ and R ₂ are not methyl, ethyl, and phenyl.

In another embodiment, the present invention provides a compound of formula (III) and derivatives thereof, such as polymorphs, isomers and precursors thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers of such compounds , Carbamate, all its solvent compounds and hydrates, and all their salts:

Where

R ₁ and R ₂ are each hydrogen, C ₁ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, Independently selected from the group consisting of C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cya It may optionally contain 1 to 6 substituents independently selected from no, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups.

In one embodiment the compound of formula (III) is independently selected from C (O) aryl, C (O) alkylaryl, C (O) haloaryl, C (O) nitroaryl, or C (O) alkoxyaryl R ₁ and R ₂ .

Another embodiment relates to a compound of Formula (III) wherein R ₁ and R ₂ are methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl , Iodophenylcarbonyl, fluorophenylcarbonyl, nitrophenylcarbonyl, methoxyphenylcarbonyl, or ethoxyphenylcarbonyl.

A further embodiment relates to compounds of formula (III), wherein R ₁ and R ₂ are 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2 -Chlorophenylcarbonyl, 3-chlorophenylcarbonyl, 4-chlorophenylcarbonyl, 2-bromophenylcarbonyl, 3-bromophenylcarbonyl, 4-bromophenylcarbonyl, 2-iodophenylcarbon Carbonyl, 3-iodophenylcarbonyl, 4-iodophenylcarbonyl, 2-fluorophenylcarbonyl, 3-fluorophenylcarbonyl, 4-fluorophenylcarbonyl, 2-nitrophenylcarbonyl, 3 -Nitrophenylcarbonyl, 4-nitrophenylcarbonyl, 2-methoxyphenylcarbonyl, 3-methoxyphenylcarbonyl, and 4-methoxyphenylcarbonyl.

The present invention therefore also encompasses prodrugs of the compounds of the invention. The term “prodrug” includes a compound that is converted in vivo to produce a compound of formula (I), (II) or (III). Information on the use of precursor drugs can be found in the literature ("Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, by T. Higuchi and W. Stella, and in Bioreversible Carriers in Drug Design Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987).

Also included herein are suitable active metabolites of compounds that fall within the category of formula (I), (II) or (III), which exist in any suitable form.

The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All suitable optical isomeric and stereoisomeric forms of the compounds of the invention and their mixtures, including racemic mixtures, form part of the invention. The invention also includes all geometric and positional isomers. For example, if a compound of the invention is included in a double bond or fused ring, cis- and trans-forms, and mixtures thereof, are also included within the scope of the invention. In the context of such compounds, the present invention suitably includes racemic compounds, single enantiomeric forms, single diastereomeric forms, or mixtures thereof. Moreover, such compounds may also exist in tautomeric forms. The present invention therefore relates to the use of all such suitable tautomeric forms and mixtures thereof. Diastereomeric mixtures can be separated into individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers convert the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (such as a chiral adjuvant such as a chiral alcohol or mosher acid chloride), separate the diastereomers, and then separate the individual diastereomers. By conversion (such as hydrolysis) to the corresponding pure regioisomers, or by dissolution in racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by using chiral stationary phases. Can be separated by chromatographic separation. In addition, certain compounds of the present invention may be atropisomers (such as substituted biaryls), which are also considered part of the present invention. Enantiomers can also be separated by the use of chiral HPLC columns.

Moreover, certain compounds of the present invention may exist in polymorphic form. The scope of the invention includes all polymorphs of the compounds according to the invention, which form a further aspect of the invention. It is to be appreciated that the present invention includes any and all racemic mixtures, optically active polymorphic and stereoisomeric forms, or mixtures thereof, and that such forms or forms have properties useful for the treatment of the diseases indicated herein.

The present invention further comprises the same isotopically-labelled compounds of the invention as those cited herein, wherein one or more atoms have an atomic mass or mass number that is different from the atomic mass or mass number commonly found in nature. Include the fact that it is replaced by an atom. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example ² H, ³ H, ¹¹ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl. Certain isotopically labeled compounds of the invention (such as those labeled with ³ H and ⁴ C) are useful for analyzing compounds and / or substrate tissue distribution. Tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and removal. Furthermore, substitution with heavier isotopes such as deuterium (ie ² H) may provide certain therapeutic advantages that will result in greater metabolic stability (such as increased half-life or reduced unit dose requirements in vivo). Therefore, it may be desirable in some situations. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F are useful for positron emission tomography (X-ray tomography) (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by substituting isotopically labeled reagents for reagents that are not isotopically labeled by procedures similar to those described in the Examples below.

One aspect of the invention is to provide a process for the preparation of compounds of formula (I), (II) or (III). Those skilled in the art will recognize from the disclosure herein that the most preferred compounds of the present invention are prepared using any suitable known method. Compounds of formula (I), (II) or (III) as described above, and R ₁ , R ₂ can be conveniently prepared according to schematic I, unless otherwise noted.

The examples provided herein further illustrate the preparation of the compounds of the present invention. Moreover, those skilled in the art will further understand the method of modifying schematic I from the present disclosure, and the examples described below to make any particular compound of formula (I), (II) or (III) of the present invention as needed. You will know. It should be noted that Schematic I is provided for illustrative purposes only and illustrates a possible route for synthesizing a compound of formula (I), (II) or (III) and does not limit the invention. Those skilled in the art will appreciate that other synthetic routes may also be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are represented in Scheme I, illustrated below, it will be appreciated that suitable substitutions may be readily made to provide various derivatives and reaction conditions. Many of the compounds prepared by the methods described below may also be further modified in the light of the disclosure using conventional chemistry known to those skilled in the art.

Schematic I

 Schematic I is formula (I), (II) starting from 2,5-dihydroxy-3-undecyl-1,4-benzoquinone or its oxime, or substituted oxime, or a suitable salt or analog thereof Or a general protocol for preparing compounds of (III). The starting materials -2,5-dihydroxy-3-undecyl-1,4-benzoquinone- are alkyl chlorides or acyl chlorides, or aryl chlorides or aroyl chlorides, or substituted aryl chlorides or substituted aroyl chlorides Reaction under controlled conditions such as for a period of about 1 hour to about 24 hours at a temperature of about 10 ° C. to about 40 ° C., in the presence of a suitable aromatic base (eg pyridine) in a suitable inert halogenated solvent (eg dichloromethane) Thus a compound of formula (I), (II) or (III) is obtained in crude form. Conventional separation and purification methods and / or techniques known to those skilled in the art can be used to isolate and purify the compounds of the present invention. Such techniques will be well known to those skilled in the art, for example all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using conventional adsorbents such as silica gel, and thin layer chromatography), recrystallization, and differential (Ie liquid-liquid) extraction techniques.

Lipase  Related diseases and ailments

One aspect of the present invention is to provide a compound of formula (I), (II) or (III) and derivatives thereof for use as a therapeutically active substance.

Compounds of the invention as disclosed above are useful for reducing or inhibiting the activity of lipase gene family enzymes for the treatment, amelioration or prevention of lipase gene family enzyme mediated diseases. Compounds are useful for reducing or inhibiting the metabolism, uptake, and accumulation of fat present at various levels, including body fluid, cell and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. Therefore, the compounds of the present invention and derivatives thereof, including the compositions thereof, are not limited to those that are overweight or obese, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other heart Metabolism, uptake, and accumulation of lipids present at various levels, including body fluid, cell, and tissue levels, for the treatment, amelioration, or prevention of diseases mediated by lipase gene family enzymes, including vascular diseases, and other metabolic diseases Useful for reducing or inhibiting the activity of enzymes of the lipase gene family involved in.

In another aspect, the compounds of the present invention and derivatives thereof, including the compositions thereof, are useful for preventing or treating cellular and tissue damage caused by microbial pathogens that secrete lipases.

In another aspect, the compounds of the present invention and derivatives thereof, including compositions thereof, are also useful for skin, hair care or cosmetic preparations.

One embodiment of the invention is the metabolism, uptake, and accumulation of fat present at various levels in the body, including body fluids, cells, and tissue levels by inhibiting or reducing the activity of enzymes belonging to the lipase gene family in mammals, including humans. By reducing or suppressing, including, but not limited to, overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases, and other metabolic diseases A method of treating diseases, disorders and / or disorders mediated by lipase gene family enzymes, the method of which is effective for the mammal of a compound of formula (I), (II) or (III) or a derivative thereof Administering a therapeutic amount.

In another embodiment, the present invention provides a method for treating or preventing cell and tissue damage caused by microbial pathogens that secrete lipase by inhibiting or reducing the activity of enzymes belonging to the lipase gene family in mammals, including humans. The method comprises administering to said mammal an effective therapeutic amount of a compound of formula (I), (II) or (III) or a derivative thereof.

Thus, one embodiment of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II) or (III) or a derivative thereof and a pharmaceutically acceptable inert adjuvant, diluent or carrier. It is to provide a composition. Or in the alternative, the pharmaceutical composition may comprise at least one additional pharmaceutically active agent. Further active pharmaceutical agents can be selected from chemically synthesized compounds or those derived from natural origin with the desired pharmacological activity.

Formulation

The compounds of formula (I), (II) or (III) or derivatives thereof may be administered parenterally (e.g. intravenously, intramuscularly, By subcutaneous, intrastem, or infusion techniques), topically (such as powders, ointments or dropping agents), transdermally, into a reservoir, intravaginally, intraperitoneally, intravesically, rectally. In another aspect of the invention, the compounds of the present invention and at least one other pharmaceutically active agent may be administered separately or in a pharmaceutical composition comprising them both. In general, such administration is preferably oral. However, if the subject to be treated cannot be swallowed, oral administration is otherwise ineffective or undesirable and parenteral or transdermal administration would be appropriate.

The compounds of formula (I), (II) or (III) or derivatives thereof can be administered in the form of any modified release, controlled release or release formulation over time (Langer, Science 249: 1527-1533 ( 1990). In one embodiment, a pump may be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al, Surgery 88: 507 ( And Saudek et al, N. Engl. J. Med. 321: 574 (1989)). In other embodiments, polymeric materials may be used (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 the compound of formula (I), (II) or (III) or a derivative thereof to be administered to a mammal, including a human or an animal, for the purpose as mentioned above is not specifically limited. Rather, it is very variable and subject to the etiology, condition, symptoms, or age of the subject and the judgment of the attending physician or veterinarian. The general range of effective dosages of the compounds of the invention is from about 0.001 mg to about 100 mg per kg body weight of the subject per day. The effective dosage of the compound of the present invention in the preferred range is about 0.01 mg to about 50 mg per kg body weight of the subject per day. The amount is selected based on a variety of factors, such as the composition to be administered, the site of the cell to be treated, the age, health, sex, and weight of the patient or animal to be treated, and the like. Useful amounts range from 1, 5, 15, 20, 25, 30, 40, 60, 150, 200 milligrams, 1 gm, 2 gm, 3 gm, and 10 milligrams to 100 grams, 50 milligrams to 5 grams, and 100 milligrams per unit dose. 10 grams, 250 milligrams to 2.5 grams, 500 milligrams to 1.25 grams, and the like. Although it may be practical to administer a daily dose of a compound of the invention, in part, at various times of the day, in any given case, the amount of the compound of the invention may be a compound of the invention, a precursor drug, an isomer or a pharmaceutically acceptable It will depend on factors such as the solubility of the salt to be used, the formulation used and the route of administration (eg, transdermally, parenterally, or topically).

A unit dose of a compound of the invention may be administered to a human by any suitable route, with oral administration being preferred. Individual oral dosage forms are, for example, tablets or capsules and should contain about 0.1 mg to about 100 mg of the compound of the present invention in a suitable pharmaceutically acceptable vehicle, diluent or carrier. Unit doses for intravenous administration are generally in the range of about 0.1 mg to about 10 mg per single dose as needed. For intranasal or inhaler administration, unit doses are generally formulated as about 0.1% to about 1% (w / v) solution. In practice, the physician will determine the actual unit dose that will be most suitable for the individual patient, which will depend on the particular patient's age, weight and response, for example. The unit dose is an example of an average case and, of course, there may be individual cases where more or less unit dose ranges are possible, and such unit doses of the compounds of the present invention also fall within the scope of the present invention.

Other preferred embodiments of the invention include, but are not limited to, overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases, and other metabolic diseases Providing a compound of formula (I), (II) or (III) or a derivative thereof for the manufacture of a pharmaceutical formulation for the prevention and treatment of diseases, diseases and / or disorders mediated by lipase gene family enzymes, including It is. Pharmaceutical formulations comprising a compound of formula (I), (II) or (III) or derivatives thereof may be prepared in conventional manner known to those skilled in the art using one or more pharmaceutically acceptable diluents, carriers, or vehicles. Can be formulated.

Pharmaceutical formulations that can be used in the present invention for oral administration include tablets, chewable tablets, controlled release tablets, capsules, dragees, granules, powders, pills, microcapsules, elixirs, syrups, and suspensions.

Generally, tablets can be prepared by methods known in the pharmaceutical art by direct compression, by wet granulation, or by dry granulation. Their formulations usually include diluents, binders, lubricants and disintegrants as well as the compounds of the present invention. Typical diluents are, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride and powdered sugars. Powdered cellulose derivatives can also be used. Typical tablet binders include materials such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, such as acacia gum, alginates, methylcellulose, polybitylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also act as binders.

Lubricants are generally needed in tablet formulations to prevent tablets and punches from sticking to the die. Lubricants are selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants include substances which, when wet, destroy tablets and release the compounds, precursors, isomers or pharmacologically acceptable salts of the invention. They include starch, clay, cellulose, algin, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose and sodium lauryl sulfate It can also be used. Tablets are sometimes coated with sugars as flavors and sealants, or with film-forming protective agents to modify the dissolution properties of the tablets. The compounds of the present invention are also chewable tablets, which can now be formulated by using large amounts of tasty substances, such as mannitol, in formulations, as is well known in the art.

As discussed above, the effects of the compounds of the present invention may be delayed, prolonged or time bound by appropriate formulations. For example, slowly soluble pellets of the compounds of the present invention can be prepared and incorporated into tablets or capsules. The technique can be improved by making pellets of various different degradation rates and subsequently filling the mixture of these pellets in capsules. Tablets or capsules may be coated with a film that is not subject to degradation for a predictable period of time.

Capsules can be prepared by mixing the compound of the invention with a suitable diluent and filling the capsule in the appropriate amount. Typical diluents include inert powder materials such as many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, granulated flour and similar edible powders.

Liquid formulations for oral administration may take the form of, for example, solutions, syrups or suspensions, or the formulation may be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid formulations include suspension / viscosity enhancers (such as sorbitol syrup, methyl cellulose or hydrogenated edible fats); Emulsifiers (such as lecithin or acacia); Non-aqueous vehicles (such as almond oil, oily esters or ethyl alcohol, triglycerides of medium chain length); And pharmaceutically acceptable additives such as preservatives (such as methyl or propyl p-hydroxybenzoate or sorbic acid).

For parenteral administration, the compounds of the invention may be formulated in injectable form, including using conventional catheterization techniques or infusion. Injectable formulations may, for example, be presented in unit dosage forms of ampoules or multi-dose containers with an added preservative. The compositions may take such forms in suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation preparations such as suspensions, stabilizers and / or dispersants. Injectable solutions or suspensions are, according to the known art, suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersions or Can be formulated with wetting and suspending agents such as sterile, blends, fixed oils such as synthetic mono- or diglycerides, and fatty acids such as oleic acid and surfactants such as hydroxypropyl cellulose, Properly adjusted and buffered. Oily solutions are generally suitable for intraarticular, intramuscular and subcutaneous injection purposes. Such aqueous solutions are suitable for intravenous injection purposes. Alternatively, the active ingredient may be in powder form, which may be reconstituted prior to use with a suitable vehicle, such as pyrogen-free sterile water. Parenteral preparations can also be prepared to act for long periods of time by dissolving or suspending the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the invention in oily or emulsified vehicles that can only be slowly dispersed in serum.

For intranasal administration or administration by inhalation, the compounds of the present invention are conveniently pressurized using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. From the container or inhaler the patient is delivered in the form of a solution or suspension from a pump spray container which is compressed or pumped or provided as an aerosol spray. In the case of a pressurized aerosol, the unit dose unit may be measured by providing a valve to deliver a metered amount. Pressurized containers or inhalers may contain solutions or suspensions of the active compounds. When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well known in the art of pharmaceutical formulations, and include benzyl alcohol or other suitable preservatives, absorption accelerators to enhance bioavailability, fluorocarbons, and And / or as a solution in saline using other solubilizers or dispersants known in the art. Capsules and cartridges (for example made of gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention with a powder suitable for an inhalation base such as lactose or starch.

The compounds of the present invention may also be administered topically, which may be by cream, jelly, plaster, lotion, gel, paste, ointment or the like according to standard pharmaceutical practice. Compounds of the invention can also be administered transdermally (such as by using a patch).

Any suitable formulation for transdermal application comprising a compound of the present invention may be used, and such formulation is generally an absorbent pharmacologically pharmacological agent for promoting and assisting the passage of the compound through a suitable transdermal carrier, such as the skin of a subject. Will contain acceptable solvents. For example, a suitable transdermal device may comprise a bandage form having a backing member and a reservoir containing a compound of the present invention. Such bandaged transdermal devices may further comprise a suitable carrier, a rate-controlling barrier, and means for securing the transdermal device to the subject's skin.

If it is desired for the compound of the invention to be administered as a suppository, any suitable base may be used. Cocoa butter is a traditional suppository base, which can be modified by adding wax to increase its melting point. Suppository bases which can be mixed with water are in particular polyethylene glycols of various molecular weights, which are widely used.

In another embodiment, the compounds of the present invention may be mixed in food, or in beverages.

The compounds of the present invention can also be administered to mammals other than humans. The method of administration and the unit dose to be administered to such mammals will depend, for example, on the species of the animal and the disease or disorder to be treated. The compounds of the present invention may be used in any suitable manner, such as orally, parenterally or transdermally, compounds of the invention, prodrugs, isomers or pharmaceutically acceptable salts and suitable diluents such as carbon wax or carnuba wax, and examples For example, any suitable form prepared by dispersing the compound of the present invention in a pharmaceutically acceptable oil, such as peanut oil, sesame oil or corn oil, together with a lubricant, liquid potion or paste, such as capsules, cyclics, tablets, The pellet may be administered to the animal. The compounds, prodrugs, isomers or pharmaceutically acceptable salts of the invention may also be administered to the animal as a graft. Such formulations are prepared according to standard veterinary practice in a conventional manner. Alternatively, the compounds of the present invention can be administered with a water supply, for example in the form of liquid or water soluble concentrates. The compounds of the invention can also be administered in animal feed, for example, in the pharmaceutical compositions of the invention, for example concentrated feed additives or premixes are usually suitable carriers before they are mixed with normal animal feed. Can be prepared together with. The carrier promotes uniform distribution of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the invention in the final feed, for example with a premix. Suitable carriers include, but are not limited to, liquids such as water, oils such as soybean oil, corn oil, cottonseed oil, or volatile organic solvents, and solids such as alfalfa, soybean oil, cottonseed oil, linseed oil, corn sacks oil, corn oil. , Small portions of feed containing molasses, urea and bone or various suitable coarse grain flour, and mineral mixtures.

In another aspect of the invention a biological assay is performed to demonstrate potent inhibition of lipase using the compounds of formulas (I), (II) and (III).

The following examples illustrate embodiments of the invention. However, it is to be appreciated that embodiments of the invention are not limited to the specific details of these embodiments, and that other variations thereof will be known to those skilled in the art or will be apparent to the disclosure of the invention.

Example  1: starting material: 2,5-dihydroxy-3- Undecyl -1,4- Benzoquinone  Extraction and separation

Structure # 1: -2,5-dihydroxy-3-undecyl-p-benzoquinone (embelin)

The powdered fruit of Emelia Rives was extracted successively with petroleum ether, chloroform, ethyl acetate, methanol and water. Crystallization was repeated for the chloroform extract using petroleum ether as the crystallization solvent. The crystallization step was repeated to increase yield. The mother liquor was fractionated by silica gel column chromatography (100-200 mesh) using petroleum ether-chloroform as elution solvent (gradient solvent) to further improve yield. All fractions were monitored on a silica gel TLC plate (silica gel 60 F ₂₅₄ , Merck) using n-propanol: n-butanol: ammonia liquor (6: 1: 3) as the TLC solvent system. Based on TLC, similar fractions were pooled together and concentrated under reduced pressure. The compound was repeatedly crystallized in petroleum ether to give 140 g (3.5%) of extract. About 50 g of the extract was refluxed in petroleum ether (500 ml) until the extract was dissolved in the solvent. The solution was cooled to rt and filtered. The procedure was repeated until a compound of the desired purity was obtained. The resulting compound showed the following properties: ¹ H NMR (300 MHz, CDCl ₃ ) δ: 0.87 (m, 3H), 1.0-1.75 (m, 18H), 2.43 (m, 2H), 5.99 (s, 1H ), 7.66 (bs, 2 H). TOF MS ES: 295 (M + H). Mp. 142-143 degreeC.

Example  2: 2,5-di-O- (3- Fluorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 2: Synthesis of 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 3-fluoro benzoyl chloride (1.35 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.96 g, 52.7%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 0.87 (t, 3H, J = 6.9 Hz), 1.0-1.6 (m, 18H), 2.5 (t, 2H, J = 7.6 Hz), 6.8 (s, 1H) , 7.3-8.0 (m, 8 H). TOF MS ES: 539 (M + H). Mp. 73.2-75.6 ° C.

Example  3: 2,5-di-O- (4- tert - Butylphenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 3: Synthesis of 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 4-tert-Butyl benzoyl chloride (1.67 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.47 g, 28.3%).

¹ H NMR (300 MHz, CDCl ₃ ) 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 (s, 1H) , 7.4-8.2 (m, 8 H). TOF MS ES: 615 (M + H). Viscous mass.

Example  4: 2,5-di-O- (2- Fluorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 4: Synthesis of 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 2-fluoro benzoyl chloride (1.35 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.96 g, 52.7%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 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- Bromophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 5: Synthesis of 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 2-bromobenzoyl chloride (1.9 g, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, then left to 30 ° C., and stirring continued for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to afford the crude compound by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Purification gave a pure mass (1.56 g, 69.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 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) , 7.4-8.2 (m, 8 H). TOF MS ES: 680 (25, M ⁺ + Na), 682 (100, M ⁺ + 2 + Na), 684 (25, M ⁺ + 4 + Na). Mp. 77.1-78.6 ° C.

Example  6: 2,5-di-O- (3- Bromophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 6: Synthesis of 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 3-Bromobenzoyl chloride (1.9 g, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (10-20% EtOAc in hexane). Pure chunks were obtained (1.4 g, 62%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.87 (t, 3H, J = 7.2 Hz), 1.0-1.8 (m, 18H), 2.51 (t, 2H, J = 7.2 Hz), 6.8 (s, 1H) , 7.4-8.4 (m, 8 H). TOF MS ES: 680 (5, M ⁺ + Na), 682 (20, M ⁺ + 2 + Na), 684 (5, M ⁺ + 4 + Na). Mp. 98.2-99.6 ° C.

Example  7: 2,5-di-O- (3- Chlorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 7: Synthesis of 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 3-Chlorobenzoyl chloride (1.5 gm, 8.50 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). To a pure mass (1.25 g, 64.4%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 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) , 7.4-8.2 (m, 8 H). 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- Chlorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 8: Synthesis of 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 2-Chlorobenzoyl chloride (1.5 gm, 8.50 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.14 g, 58.7%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 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- Chlorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 9: Synthesis of 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 4-chlorobenzoyl chloride (1.5 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.21 g, 62.4%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 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) , 7.3-8.1 (m, 8 H). TOF MS ES: 593 (10, M ⁺ + Na), 595 (3, M ⁺ + 2 + Na). Mp. 110.2-112 ° C.

Example  10: 2,5-di-O- (4- Bromophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 10: Synthesis of 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 4-Bromobenzoyl chloride (1.9 g, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.49 g, 66.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.8 (t, 3H, J = 6.8 Hz), 1.0-1.8 (m, 18H), 2.5 (t, 2H, J = 7.6 Hz), 6.7 (s, 1H) , 7.6-8.2 (m, 8H). TOF MS ES: 680 (5, M ⁺ + Na), 682 (20, M ⁺ + 2 + Na), 684 (5, M ⁺ + 4 + Na). Mp. 124.4-126.7 ° C.

Example  11: 2,5-di-O- (3- Nitrophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 11: Synthesis of 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 3-nitrobenzoyl chloride (1.6 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.95 g, 47%).

¹ H NMR (300 MHz, CDCl ₃ ) 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) , 7.6-8.6 (m, 8 H). TOF MS ES: 593 (M + H). Mp. 112.6-114.4 ° C.

Example  12: 2,5-di-O- (4- Methylphenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 12: Synthesis of 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (0.41 mL, 5.1 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.15 g, 0.5 mmol) in dichloromethane (20 mL). 4-Toluoyl chloride (0.23 g, 1.53 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (84 mg, 32%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 0.85 (m, 3H), 1.0-1.8 (m, 18H), 2.44 (m, 8H), 6.74 (s, 1H), 7.25-8.25 (m, 8H). TOF MS ES: 553 (10O, M ⁺ + Na). Mp. 94.8-96.2 ° C.

Example  13: 2,5-di-O- (3- Methylphenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 13: Synthesis of 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (0.55 mL, 6.8 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.5 g, 1.7 mmol) in dichloromethane (20 mL). 3-Toluoyl chloride (0.654gm, 4.25mmol) was added to this solution at 15-20 占 폚, stirred, and stood at 30 占 폚, and stirring was continued for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.64 g, 71%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 0.85 (t, 3H, J = 7.5 Hz), 1.0-1.5 (m, 18H), 2.3-2.5 (m, 8H), 6.75 (s, 1H), 7.30- 7.61 (m, 5 H), 7.9-8.10 (m, 3 H). TOF MS ES: 553 (100, M ⁺ + Na). Mp. 80.4-81.7 ° C.

Example  14: 2,5-di-O- (2- Nitrophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 14: Synthesis of 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 2-nitrobenzoyl chloride (1.6 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.95 g, 47%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.86 (t, 3H, J = 6.5 Hz), 1.1-1.6 (m, 18H), 2.6 (t, 2H, J = 8.0 Hz), 6.9 (s, 1H) , 7.7-8.1 (m, 8 H). TOF MS ES: 615 (100, M ⁺ + Na). Mp. 72.2-73.8 ° C.

Example  15: 2,5-di-O- ( Phenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 15: Synthesis of 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (0.3 mL, 4.08 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.3 g, 1.02 mmol) in dichloromethane (20 mL). Benzoyl chloride (0.26 gm, 2.55 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.285 g, 56.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.85 (m, 3H), 1.10-1.68 (m, 18H), 2.50 (m, 2H), 6.77 (s, 1H), 7.42-7.64 (m, 6H), 8.11-8.22 (m, 4 H). TOF MS ES: 525 (100, M ⁺ + Na). Mp. 98.2-99.6 ° C.

Example  16: 2,5-di-O- (4- Fluorophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 16: Synthesis of 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 4-Fluorobenzoyl chloride (1.35 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.85 g, 46.4%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.86 (t, 3H, J = 6.7 Hz), 1.0-1.7 (m, 18H), 2.5 (t, 2H, J = 7.3 Hz), 6.7 (s, 1H) , 7.1-7.2 (m, 4H), 8.1-8.2 (m, 4H). Mp. 95.8-97.7 ° C.

Example  17: 2,5-di-O- (3- Methoxyphenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 17: Synthesis of 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, 3.4 mmol) in dichloromethane (20 mL). 3-methoxybenzoyl chloride (1.45 g, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.32 g, 69%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.87 (t, 3H, J = 7.0 Hz), 1.1-1.7 (m, 18H), 2.5 (t, 2H, J = 7.9 Hz), 3.9 (s, 6H) , 6.8 (s, 1 H), 7.2-7.7 (m, 8 H). TOF MS ES: 585 (100, M ⁺ + Na). Mp.77.1-78.6 ° C.

Example  18: 2,5-di-O- (4- Methoxyphenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 18: Synthesis of 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 4-methoxybenzoyl chloride (1.45 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and stood at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (1.37 g, 71.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.87 (t, 3H, J = 6.7 Hz), 1.1-1.7 (m, 18H), 2.5 (t, 2H, J = 7.6 Hz), 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- Iodophenylcarbonyl ) -3- Undecyl -1,4- Benzoquinone

Structure # 19: Synthesis of 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone

Pyridine (1.1 mL, 13.6 mmol) was added to a stirred solution of 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3.4 mmol) in dichloromethane (20 mL). 2-iodobenzoyl chloride (2.26 gm, 8.5 mmol) was added to this solution at 15 to 20 ° C., stirred, and allowed to stand at 30 ° C., followed by stirring for 3 hours (TLC). The organic layer was extracted with dichloromethane, washed with water and brine, dried over Na ₂ SO ₄ , concentrated and the resulting crude compound was purified by SiO ₂ column chromatography (EtOAc in 10-20% hexane). Pure chunks were obtained (0.89 g, 35%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 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. 64.2-67.6 ° C.

Example  20: Lipase  Assay for Inhibitory Activity

Preparation of Test Samples: Structures # 1 to # 19 were dissolved in 1 mL of DMSO to obtain 10 mM stock solution, vigorously rotated to melt and stored at 4 ° C. Various concentrations of working samples were prepared in 0.2 M phosphate buffer, pH8.0. This sample was used as a test sample for all further analysis.

Lipase Analysis: Lipase analysis was performed with a slight modification of the method described by Winkler and Stuckman (Winkler, UK & Stuckmann, M. Glycogen, hyaluronate, and some other polysaccharides greatly enhance the formation of exolipase by Serratia marcescens. J. Bacteriol. 138: 663-670 (1979)). The assay was designed using the 96-well format. The substrate used in this analysis was p-nitro phenol palmitate (Sigma, Cat. No. N-2752). 4.5 mg of p-nitro phenol palmitate was dissolved in 200 μl of N, N-dimethyl formamide (Sigma, Cat. No. N-4551) and the volume was made up to 10 ml using phosphate buffer at 0.1 M pH8.0. Pancreatic lipase (Sigma, Cat # L-3126) samples were prepared by dissolving this enzyme in a concentration of 5 mg / ml in 0.1 M phosphate buffer. The reaction mixture is 150 μl of substrate solution; 40 μl of phosphate buffer (pH 8.0, 0.2M), and 10 μl of lipase solution. The reaction mixture was incubated at 37 ° C. and the optical density after incubation was measured at 405 nm. Enzyme activity is expressed in the form of international units (IU).

Lipase Activity: One enzyme unit of lipase is defined as the amount of 1 nm free phenol released from the substrate per ml and per minute (p-nitro phenol palmitate) under standard assay conditions (Winkler and Stuckmann, 1979; Yadav RP, Saxena RK). , Gupta R, Davidson WS., Purification and Characterization of Region-Specific Lipases from Aspergillus Tereus, Biotechnol.Appl. Biochem. (1998) 28, (243-249)). It is derived from the standard graph of p-nitro phenol (Sigma, 104-8).

Lipase Inhibition Assay: Enzyme inhibition assays were performed in a dose dependent manner. The concentrations of the synthetic analogs investigated were 100 μM and 200 μM. The assay was similar to the assay described above, except 40 μl of test sample was used in place of phosphate buffer in the control. Optical density was measured at 0 hours and after incubation at 37 ° C.

Enzyme Inhibition: Enzyme inhibition is briefly expressed in terms of relative activity and percentage inhibition based on changes in international units (IU).

Table 1: Effect of Compounds of Structures # 1 to # 19 on Pancreatic Lipase Inhibition

Sample % Suppression (200μM) % Suppression (100μM) Control Standard (No Inhibitor) 0.00 0.00 Structure # 1 69.46 67.87 Structure # 2 97.91 99.16 Structure # 3 99.16 99.54 Structure # 4 99.96 99.62 Structure # 5 100.00 100.00 Structure # 6 100.00 100.00 Structure # 7 100.00 100.00 Structure # 8 100.00 100.00 Structure # 9 100.00 98.40 Structure # 10 97.02 87.49 Structure # 11 97.95 97.38 Structure # 12 99.12 88.49 Structure # 13 100.00 100.00 Structure # 14 61.31 65.88 Structure # 15 100.00 100.00 Structure # 16 100.00 89.55 Structure # 17 96.46 78.31 Structure # 18 94.08 55.64 Structure # 19 100.00 29.18

Example  21: IC ₅₀ Measure

Preparation of Test Samples: Synthetic analogs were dissolved in 1 mL of DMSO to obtain 10 mM stock solution. The sample was melted by vigorous rotation and stored at 4 ° C. Various concentrations of working samples were prepared in 0.2 M phosphate buffer, pH8.0. This sample was used as a test sample for all further analysis.

Lipase Inhibition Assay: Enzyme inhibition assays were performed in a dose dependent manner. The concentration of the synthetic analogs investigated was 6.25 μM to 200 μM. The assay was similar to the assay described above, except 40 μl of test sample was used in place of phosphate buffer in the control. Optical density was measured at 0 hours and after incubation at 37 ° C. Enzyme activity was measured in International Units (IU).

Lipase Activity: One enzyme unit of lipase is defined as the amount of 1 nm free phenol released from the substrate per ml and per minute (p-nitro phenol palmitate) under standard assay conditions. It is derived from the standard graph of p-nitro phenol (Sigma, 104-8).

IC ₅₀ Calculations: The IC ₅₀ of each analog was calculated from the dose dependency graph (6.25 μM to 200 μM) of each analog of each concentration. The% inhibition of lipase was then measured as 50% of two near straight points (50% inhibition above and below). IC ₅₀ values were derived from linear regression. Derived values are based on interpolated data.

Table 2: IC ₅₀ of Compounds of Structures # 1 to # 19 for Pancreatic Lipase Inhibition

IC ₅₀ (μM) Structure # 1 21.94 Structure # 2 <6.25 Structure # 3 <6.25 Structure # 4 7.78 Structure # 5 10.98 Structure # 6 13.51 Structure # 7 16.72 Structure # 8 20.61 Structure # 9 22.80 Structure # 10 23.69 Structure # 11 26.97 Structure # 12 41.34 Structure # 13 44.68 Structure # 14 45.32 Structure # 15 55.57 Structure # 16 72.81 Structure # 17 81.91 Structure # 18 94.22 Structure # 19 129.39

Example  22: inhibition of lipid absorption

Four-week-old male Wistar rats (weight range: 150-200 g) fasted overnight were used for inhibiting lipid absorption. Mice were divided into two groups of 6 animals each and 100 μl of blood was collected from the orbit for estimation of the plasma lipid profile at 0 hours. A 1 ml fat rich liquid diet was administered as PO (par orally) by gavage. In addition, 100 μg of test compound (2,5-di-O-aroyl-3-undecyl-1,4-benzoquinone derivative structure # 1-# 19) dissolved in 500 μl of vehicle was orally added to the experimental group. The control group received the same volume of vehicle.

100 μl of blood was collected 1 hour after feeding for the evaluation of total triglycerides. The results are shown in the table below. The experimental group had significantly lower levels of triglycerides.

Table 3: Triglyceride Levels

group Triglycerides (mg / dL) Time (O) Time (1) Group-1 (Control) One 77 79.5 127 135.1 2 72 160 3 54 171 4 66 63 5 79 90 6 129 200 Group-2 (Experiment: Structure # 2-# 19) 7 64 70.6 74 66.5 8 42 48 9 66 91 10 106 67 11 76 50 12 70 69

Example  23: inhibition of cellular uptake of lipids

Mouse macrophage cell lines (J774A.1) were plated in 6-well culture plates (1 × 10 ⁵ cells / well) in Dulbecco's Minimum Essential Medium (DMEM) containing 10% fetal bovine serum. 100 μg of oxidized low density lipoprotein (LDL) was added to each well. Three plates of one of the compounds (Structures # 1 to # 19) (10 μM) were added to the wells in each plate and the three wells were maintained as controls. The experiment was terminated after 48 hours. Cells were stained with oil red and counterstained with hematoxylin and observed under a microscope. Compared with the control, treatment with structures # 2 to # 19 significantly inhibited uptake of LDL by macrophages.

All publications and patent applications cited herein are hereby incorporated by reference as indicating that each individual publication and patent application is specifically and individually incorporated by reference.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art should, without departing from the spirit or scope of the appended claims, with particular modifications and variations in light of the teachings of the invention. It will be readily appreciated that the present invention can be made.

The compounds of the present invention and derivatives thereof reduce or inhibit the metabolism, uptake, and accumulation of fat at various levels including body fluid, cell, and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. Can be used.

Claims (41)

A compound of formula (I), and a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable ester, ether of the compound, precursor drug, isomer or polymorph , Carbamate, oxime, all its solvent compounds and hydrates and all salts:

Where R ₁ and R ₂ are each hydrogen, C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, Independent from the group consisting of C (O) C ₁ -C ₆ alkyl, OC (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl and O- (C (O) aryl Wherein each group described above is independently selected from hydrogen, halo, nitro, amino, cyano, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups It may optionally contain 1 to 6 substituents, wherein R ₁ and R ₂ are not methyl, methoxy, ethyl, ethoxy, phenyl, and hydroxy. A compound of formula (II): and a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable ester, ether of the compound, precursor drug, isomer or polymorph , Carbamate, oxime, all its solvent compounds and hydrates and all salts:

Where R ₁ and R ₂ are each C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ( O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cyano, May optionally contain 1 to 6 substituents independently selected from isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups, wherein R ₁ and R ₂ are methyl , Ethyl, and phenyl. A compound of formula (III), and a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable ester of said compound, precursor drug, isomer or polymorph, Ethers, carbamates, oximes, all their solvent compounds and hydrates and all salts:

Where R ₁ and R ₂ are each hydrogen, C ₁ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₁₃ alkylamine, C ₁ -C ₁₃ arylamine, C ₁ -C ₅ alkylcycloalkyl, C ₁ -C ₅ alkylcycloalkenyl, Independently selected from the group consisting of C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, and C (O) aryl, wherein each group described above is hydrogen, halo, nitro, amino, cya It may optionally contain 1 to 6 substituents independently selected from no, isocyano, thio, C ₁ -C ₆ alkyl, cycloalkyl, aryl, alkoxy, and aryloxy groups. The group of claim 1, wherein R ₁ and R ₂ are composed of C (O) aryl, C (O) alkylaryl, C (O) haloaryl, C (O) nitroaryl, and C (O) alkoxyaryl A compound of formula (II), its precursor drug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and all salts, which are selected independently from each other. According to claim 1, wherein R ₁ and R ₂ is methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl, iodophenylcarbonyl, fluorine A compound of formula (II), a prodrug thereof, geometrical form thereof, characterized in that it is independently selected from the group consisting of rophenylcarbonyl, nitrophenylcarbonyl, methoxyphenylcarbonyl, and ethoxyphenylcarbonyl Optical isomers, polymorphs thereof, all solvates and hydrates thereof and all salts. The compound of claim 1, wherein R ₁ and R ₂ are 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2-chlorophenylcarbonyl, 3-chloro Phenylcarbonyl, 4-chlorophenylcarbonyl, 2-bromophenylcarbonyl, 3-bromophenylcarbonyl, 4-bromophenylcarbonyl, 2-iodophenylcarbonyl, 3-iodophenylcarbonyl , 4-iodophenylcarbonyl, 2-fluorophenylcarbonyl, 3-fluorophenylcarbonyl, 4-fluorophenylcarbonyl, 2-nitrophenylcarbonyl, 3-nitrophenylcarbonyl, 4-nitro Compound of formula (II), a precursor thereof, characterized in that it is independently selected from phenylcarbonyl, 2-methoxyphenylcarbonyl, 3-methoxyphenylcarbonyl, or 4-methoxyphenylcarbonyl Geometric or optical isomers thereof, polymorphs thereof, all solvent compounds and hydrates thereof and all salts. Compounds, their precursors, their geometric or optical isomers, their polymorphs, all their solvent compounds and hydrates and all salts, characterized in that they are selected from the group consisting of: a. 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; b. 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iii) 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iv) 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; v) 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vi) 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vii) 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; viii) 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; ix) 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; x) 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xi) 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xii) 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiii) 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiv) 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xv) 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvi) 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvii) 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xviii) 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone. A compound of formula (I) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, a precursor drug, an isomer or a polymorph A pharmaceutical composition comprising an ester, ether, carbamate, oxime, all solvent compounds and hydrates thereof and all salts thereof, and a pharmaceutically acceptable inert adjuvant, diluent or carrier. A compound of formula (I) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, a precursor drug, an isomer or a polymorph A pharmaceutical composition comprising an ester, ether, carbamate, oxime, all solvent compounds and hydrates thereof, and all salts, and at least one additional pharmaceutically active agent. A compound of formula (I) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, a precursor drug, an isomer or a polymorph Compositions for skin or hair care or cosmetic preparations comprising esters, ethers, carbamates, oximes, all solvent compounds and hydrates thereof, and all salts, and inert aids, diluents or carriers. A compound of formula (II) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, a precursor drug, an isomer or a polymorph A pharmaceutical composition comprising an ester, ether, carbamate, oxime, all solvent compounds and hydrates thereof and all salts thereof, and a pharmaceutically acceptable inert adjuvant, diluent or carrier. A compound of formula (II) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, precursor drug, isomer or polymorph A pharmaceutical composition comprising an ester, ether, carbamate, oxime, all solvent compounds and hydrates thereof, and all salts, and at least one additional pharmaceutically active agent. A compound of formula (II) according to claim 1, a precursor drug thereof, a derivative thereof, a geometric or optical isomer thereof, a polymorph thereof, and a pharmaceutically acceptable compound of the compound, a precursor drug, an isomer or a polymorph Compositions for skin or hair care or cosmetic preparations comprising esters, ethers, carbamates, oximes, all solvent compounds and hydrates thereof, and all salts, and inert aids, diluents or carriers. A compound selected from the group consisting of: or a precursor drug thereof, a geometric or optical isomer thereof, a polymorph thereof, a solvent compound and a hydrate thereof and all salts thereof, and a pharmaceutically acceptable inert adjuvant, diluent or Pharmaceutical compositions comprising a carrier: i) 2,5-dihydroxy-3-undecyl-p-benzoquinone ii) 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iii) 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iv) 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; v) 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vi) 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vii) 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; viii) 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; ix) 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; x) 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xi) 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xii) 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiii) 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiv) 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xv) 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvi) 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvii) 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xviii) 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xix) 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone. A compound selected from the group consisting of: or a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, a solvent compound and a hydrate thereof, and all salts, and at least one additional pharmaceutically acceptable Pharmaceutical compositions comprising the active agent: i) 2,5-dihydroxy-3-undecyl-p-benzoquinone ii) 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iii) 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iv) 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; v) 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vi) 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vii) 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; viii) 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; ix) 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; x) 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xi) 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xii) 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiii) 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiv) 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xv) 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvi) 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvii) 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xviii) 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xix) 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone. A compound selected from the group consisting of the following compounds, or a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, a solvent compound and a hydrate thereof and all salts and a medicament comprising an inert adjuvant, diluent or carrier Pharmaceutical composition: i) 2,5-dihydroxy-3-undecyl-p-benzoquinone ii) 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iii) 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iv) 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; v) 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vi) 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vii) 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; viii) 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; ix) 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; x) 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xi) 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xii) 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiii) 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiv) 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xv) 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvi) 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvii) 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xviii) 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xix) 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone. A method of treating, ameliorating or preventing a disease or condition mediated by a lipase gene family enzyme, Administering to the mammal a therapeutically effective amount of a compound of formula (I) according to claim 1 to a degree that treats, ameliorates or prevents the disease or condition sufficient to inhibit or reduce the activity of enzymes belonging to the lipase gene family. Way of doing. The method of claim 1, wherein treating, ameliorating, or preventing the disease comprises reducing or inhibiting metabolism, absorption, and accumulation of fat at various levels, including body fluids, cells, and tissues of a mammal. Way. 2. The disease according to claim 1, wherein the disease is selected from the group consisting of overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease, and metabolic disease How to. The method of claim 1, wherein the method comprises treating or preventing cell or tissue damage caused by a microbial pathogen that secretes lipase. The method of claim 1, wherein the method comprises treatment of a skin, hair or cosmetic disease. The method of claim 1, wherein inhibiting or reducing the activity of enzymes belonging to the lipase gene family is sufficient to reduce or inhibit metabolism, uptake, and accumulation of fat in body fluids, cells, and tissues. The method of claim 1, wherein the compound is administered by a method selected from the group consisting of oral, topical, intranasal, intravenous, transdermal, intramucosal, and inhalation. A method of treating, ameliorating or preventing a disease or condition mediated by a lipase gene family enzyme, Administering a therapeutically effective amount of a compound of formula (II) according to claim 1 to a mammal to such an extent that the disease or condition is treated, ameliorated or prevented, the method being sufficient to inhibit or reduce the activity of enzymes belonging to the lipase gene family. Way of doing. The method of claim 1, wherein treating, ameliorating or preventing the disease comprises reducing or inhibiting metabolism, absorption, and accumulation of fat at various levels, including body fluids, cells, and tissues of a mammal. . 2. The disease according to claim 1, wherein the disease is selected from the group consisting of overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease, and metabolic disease How to. The method of claim 1, wherein the method comprises treating or preventing cell or tissue damage caused by a microbial pathogen that secretes lipase. The method of claim 1, wherein the method comprises treatment of a skin, hair or cosmetic disease. The method of claim 1, wherein inhibiting or reducing the activity of enzymes belonging to the lipase gene family is sufficient to reduce or inhibit metabolism, uptake, and accumulation of fat in body fluids, cells, and tissues. The compound of claim 1, wherein R ₁ and R ₂ in formula (II) are C (O) aryl, C (O) alkylaryl, C (O) haloaryl, C (O) nitroaryl, and C (O) And independently selected from the group consisting of alkoxyaryl. A compound according to claim 1, wherein R ₁ and R ₂ in formula (II) are methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl, iodo And phenylcarbonyl, fluorophenylcarbonyl, nitrophenylcarbonyl, methoxyphenylcarbonyl, and ethoxyphenylcarbonyl. A compound according to claim 1, wherein R ₁ and R ₂ in formula (II) are 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2-chlorophenylcarbon Carbonyl, 3-chlorophenylcarbonyl, 4-chlorophenylcarbonyl, 2-bromophenylcarbonyl, 3-bromophenylcarbonyl, 4-bromophenylcarbonyl, 2-iodophenylcarbonyl, 3- Iodophenylcarbonyl, 4-iodophenylcarbonyl, 2-fluorophenylcarbonyl, 3-fluorophenylcarbonyl, 4-fluorophenylcarbonyl, 2-nitrophenylcarbonyl, 3-nitrophenylcarbon And independently selected from carbonyl, 4-nitrophenylcarbonyl, 2-methoxyphenylcarbonyl, 3-methoxyphenylcarbonyl, or 4-methoxyphenylcarbonyl. The method of claim 1, wherein the compound is administered by a method selected from the group consisting of oral, topical, intranasal, intravenous, transdermal, intramucosal, and inhalation. A method for treating, ameliorating or preventing a disease or condition mediated by a lipase gene family enzyme, The method comprises a compound selected from the group consisting of the following compounds, or a precursor drug thereof, its geometric or optical isomers, its polymorphs, all its solvent compounds and hydrates and all salts belonging to the lipase gene family A method comprising administering to a mammal to the extent that the disease or condition is treated, ameliorated or prevented in a therapeutically effective amount sufficient to inhibit or reduce the activity of the enzyme: i) 2,5-dihydroxy-3-undecyl-p-benzoquinone ii) 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iii) 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; iv) 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; v) 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vi) 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; vii) 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; viii) 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; ix) 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; x) 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xi) 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xii) 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiii) 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xiv) 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xv) 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvi) 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xvii) 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xviii) 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone; xix) 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone. The method of claim 1, wherein treating, ameliorating or preventing the disease comprises reducing or inhibiting metabolism, absorption, and accumulation of fat at various levels, including body fluids, cells, and tissues of a mammal. . 2. The disease according to claim 1, wherein the disease is selected from the group consisting of overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease, and metabolic disease How to. The method of claim 1, wherein the method comprises treating or preventing cell or tissue damage caused by a microbial pathogen that secretes lipase. The method of claim 1, wherein the method comprises treatment of a skin, hair or cosmetic disease. The method of claim 1, wherein inhibiting or reducing the activity of enzymes belonging to the lipase gene family is sufficient to reduce or inhibit metabolism, uptake, and accumulation of fat in body fluids, cells, and tissues. The method of claim 1, wherein the compound is administered by a method selected from the group consisting of oral, topical, intranasal, intravenous, transdermal, intramucosal, and inhalation. A method according to the foregoing claims substantially described herein in connection with embodiments and figures.