JP2009505953A - Compounds for the treatment of lipase-mediated diseases - Google Patents

Abstract

Novel benzoquinone-derived compounds and polymorphs and prodrugs thereof, geometrical or optical isomers thereof, pharmaceutically acceptable esters, ethers, carbamates, oximes of such compounds, polymorphs, prodrugs and isomers Provided. Processes for preparing the compounds of the present invention, as well as pharmaceutical compositions containing such compounds and their active polymorphs, prodrugs, isomers, or pharmaceutically acceptable salts, esters, and lipase genes Diseases and conditions mediated by the family (including overweight, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, diabetes, atherosclerosis, other cardiovascular diseases, metabolic syndrome Their use for reducing or inhibiting the activity of the lipase gene family to treat, ameliorate or prevent), including metabolic disorders, and their use for skin, hair and cosmetics are provided.

Description

(Technical field of the invention)
The present invention relates to novel heterocyclic compounds of the benzoquinone series that affect the activity of enzymes of the lipase gene family. The present invention has pharmaceutical compositions containing such benzoquinone-derived compounds, processes for preparing such benzoquinone-derived compounds, and selective activity against diseases and conditions mediated by genes of the lipase family. Related to pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates thereof.

(Background of the Invention)
In many developed and developing countries, the tendency to adopt diets that contain high fat content and low fiber concentration continues to increase, accompanied by a sedentary lifestyle that does not involve intense labor Yes. Such excessive intake of fat, when accompanied by a reduced conversion of fat to energy due to a lifestyle often sitting, in the body at various levels, including body fluids, cells and tissues May cause fat accumulation. As a result, there is a steadily increasing population with increased risk of metabolic disorders (eg, overweight or obesity) that progress to various related disorders such as diabetes, cardiovascular disorders, metabolic syndrome and hypertension .

  In general, the first treatment option for individuals suffering from such metabolic disorders (specifically, overweight or obesity) involves taking a low-fat diet and regular exercise. However, such treatment therapies cannot be adequately protected, and therefore treatment with therapeutic drugs is required as the disease progresses.

  Accordingly, various studies are directed to developing drugs that are safe and effective to prevent and treat clinical manifestations caused as a result of fat accumulation in body fluids, cells and tissues. Therefore, there is a continuing need to reduce fat absorption and accumulation in the body in some manner.

  One way to prevent or reduce fat accumulation is by reducing or inhibiting agents that help digest and absorb fat at various levels in the body. Enzymes belonging to the lipase gene family are most important in lipid metabolism, absorption and transport.

  Liver lipases and lipoprotein lipases are multifunctional proteins that mediate the binding, uptake, catabolism and remodeling of lipoproteins and phospholipids. Lipoprotein lipase and liver lipase function in peripheral tissues and liver, respectively, while bound to the luminal surface of endothelial cells. Both enzymes are involved in reversible cholesterol transport, which is the transfer of cholesterol from peripheral tissues to the liver, either for excretion from the body or for recirculation. It is known that genetic defects in both liver lipase and lipoprotein lipase are responsible for familial disorders of lipoprotein metabolism. Defects in lipoprotein metabolism lead to a variety of serious metabolic disorders, including hypercholesterolemia, hyperlipidemia and atherosclerosis.

  The enzymes of the lipase gene family are involved in a wide range of metabolic pathways ranging from lipid digestion, absorption, fatty acid uptake, lipoprotein transport to inflammation as well (Non-patent Document 1).

  Pancreatic lipase is one of the important enzymes in lipid metabolism. Pancreatic lipase is synthesized by pancreatic acinar cells that are secreted into the intestinal lumen and helps intestinal absorption of long-chain triglyceride fatty acids (Non-Patent Document 2; Non-Patent Document 3).

  The action of triacylglycerol lipase is considered to suppress atherogenesis since these enzymes reduce the triacylglycerol level in serum and promote HDL formation (Non-patent Document 4). Lipoprotein lipase is the main enzyme responsible for the distribution and utilization of triglycerides in the body. Lipoprotein lipase hydrolyzes triglycerides in both chylomicrons and VLDL. Liver lipase hydrolyzes triglycerides in IDL and HDL and is involved in lipoprotein remodeling. Liver lipase also functions as a phospholipase and hydrolyzes phospholipids in HDL.

  Various lipase members function in the metabolism of circulating lipoproteins. Liver lipase plays a role in the uptake of HDL cholesterol (Non-Patent Document 5). Liver lipase is synthesized exclusively in the liver where liver lipase is mainly found (Non-patent Document 6).

  A third member of the lipase gene family, lipoprotein lipase (LPL), is distributed in various tissues, with the highest concentration present in adipose tissue and muscle. This lipase binds to the capillary endothelium and functions in the capillary endothelium to supply the underlying tissues with fatty acids derived from the circulating chylomicron and VLDL triglyceride-rich cores (7). ). In this process, LPL converts these lipoproteins into remnant particles and HDL particles. Accumulating evidence suggests that LPL produced in the vascular wall by macrophages may promote the development of atherosclerosis by enhancing lipid accumulation within the lesion. . LPL has been shown to be involved in the pathogenesis of atherosclerosis (Non-patent Document 8). Several groups have also proposed that both LPL and liver lipase also appear to act as ligands in the metabolism of plasma lipoproteins in addition to their conventional role as lipolytic enzymes (non- Patent Document 9; Non-Patent Document 10). Transgenic animals expressing human lipoprotein lipase or liver lipase have reduced levels of plasma triglycerides and increased levels of high density lipoprotein (HDL) (Non-Patent Document 11; Non-Patent Document 12).

  A more recently discovered member of the lipase gene family is endothelial lipase. The function of this lipase is currently uncertain, but is thought to have a role in HDL metabolism (Non-patent Document 13).

  Drugs that inhibit or reduce lipase activity at various levels in the body, along with the increasingly recognized potential of lipases in the fat metabolic pathway, treat diseases mediated by elevated levels of fat accumulation To be the first line of treatment.

  Lipase inhibitors marketed as anti-obesity drugs include Orlistat (XENICAL (registered trademark)) described in Patent Document 1. U.S. Patent No. 6,057,051 relates to Orlistat and related compounds and their use in inhibiting pancreatic lipase and treating hyperlipidemia and obesity. Orlistat only inhibits intestinal lipases (eg, gastric lipase, pancreatic lipase, and carboxylester lipase, especially pancreatic lipase) in the intestinal lumen by preventing the lipase from interacting with its lipid target, Stop digestion. However, Orlistat does not appear to have an effect on lipases other than intestinal lipases that are also recognized as having a role in catalyzing lipid hydrolysis (eg, liver lipase or endothelial lipase). Yes (Non-Patent Document 14). Orlistat also tends to cause unpleasant (relatively harmful) side effects (eg, diarrhea) with a high frequency of occurrence.

Various compounds that inhibit the activity of liver lipase and / or endothelial lipase are disclosed in US Pat. These compounds are primarily aimed at increasing HDL levels by inhibiting the activity of liver lipase and / or endothelial lipase and are not intended to target intestinal lipase or other lipases.
US Pat. No. 4,598,089 European Patent Application No. 129748 International Publication No. 2004094393 Pamphlet Wong Howard et al., 2002, The Lipase Gene family, Journal of Lipid Research, Vol. 43: 993-999 Verger, R.A. 1984, Pancreatic Lipases, Lipases (B. Borgstrom and HL Blockman, Elsevier, New York, 83-150) Lowe, M.C. E. 1997, Molecular mechanisms of rat and human pancreatic triglycerides liposomes, J. MoI. Nutr. 127: 549-557 Olivecrona, G. et al. And Olivecrona, T .; (1995), Curr. Opin. Lipid. 6: 291-305 Olivecrona, T .; Et al., 1993, Lipoprotein Lipase and Hepatic Lipase, Curr. Opin. Lipidol. 4: 187-196 Hixenbaugh, E .; A. Et al., 1989, Hepatic lipid in the rat ovary, J. et al. Biol. Chem. 264: 4222-4230 Olivecrona, T .; And G. Bengtsson-Olivecrona, 1993, Lipoprotein Lipase and hepatic Lipase, Curr. Opin. Lipidol. 4: 187-196 Mead JR et al., 1999, “Lipoprotein Lipase, a key role in atherosclerosis?”, FEBS Lett. , Nov 26, 462 (1-2): 1-6 Nykjaer, A .; 1993, The alpha 2-macroglobulin receptor / low density lipoprotein receptor-relevant protein binding the biodeposition of beta and the like. Biol. Chem. 268: 15048-15055 Krapp, A.M. S. Et al., 1996, Hepatic lipid mediates the uptake of chloromicrons and VLDL into cells via the LDL receptor-related protein (LRP), J. et al. Lipid Res. 37: 926-936 Shimada, M .; Et al. (1993), J. Am. Biol. Chem. 268: 17924-17929 Liu, M .; -S. Et al. (1994), J. Am. Biol. Chem. 269: 11417-11424 Jaye, M .; Et al., 1999, A novel enderal-derived lipid that modulates HDL metabolism, Nat. Genet. 21: 424-428 Dent ML, van der Veen EA, Lipase inhibition: A novel concept in the treatment of interest, Int. Obes. Relat. Metab. Disorder. 1993; 17: 241-244.

  Thus, the metabolism, absorption and accumulation of fat, including body fluids, cells and tissues in the body, by inhibiting or reducing the activity of all members of the lipase gene family of interest, rather than just a specific type of lipase It is desirable to develop new compounds that are useful in reducing or inhibiting at low levels.

  The plant benzoquinone embellin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), which is obtained from the dried fruit of Embellia ribes and is known as a contraceptive, is also an adipogenic enzyme, apple It has been reported to increase the activity of acid dehydrogenase, glucose-6-phosphate dehydrogenase and hydroxymethylglutaryl-CoA reductase, while essentially not affecting the activity of lipolytic enzymes (Gupta S. et al., Fitotalapia, 60 (4): 331-338 (1989)). Enveline is also used as a tapeworm repellent and is also used as having antitumor, anti-inflammatory and analgesic effects (Chitra et al., Chemotherapy, 40: 109 (1994)) and also X-linked inhibition of apoptosis It is used as a cell-permeable non-peptide inhibitor of the agent (XIAP) (Nikolovska-Coleska et al., J. Med. Chem. 47: 2430 (2004)).

(Summary of the Invention)
The present invention provides the following compounds of formula (I):

（式中、
Ｒ_１およびＲ_２はそれぞれが独立して、水素、Ｃ_３〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、Ｏ−Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリール、Ｃ（Ｏ）アリールおよびＯ−Ｃ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる）。
しかしながら、本発明によれば、Ｒ_１およびＲ_２は、メチル、メトキシ、エチル、エトキシ、フェニルおよびヒドロキシではない。

(Where
R ₁ and R ₂ are each independently 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 alkyl _{cycloalkenyl,} C 1 _{-C 13 alkylamine,} C 1 _{-C 13} arylamine, From the group consisting of C (O) C ₁ -C ₆ alkyl, O—C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl and O—C (O) aryl is selected; however, each of the group hydrogen, halo, nitro, amino, cyano, isocyano, thio, C ₁ -C ₆ al Group, may have optionally a cycloalkyl group, an aryl group, one to six substituents independently selected from alkoxy and aryloxy groups).
However, according to the invention, R ₁ and R ₂ are not methyl, methoxy, ethyl, ethoxy, phenyl and hydroxy.

  The invention also includes compounds of formula (I) and derivatives thereof, including polymorphs, isomers and prodrugs thereof, geometrical or optical isomers thereof, and pharmaceutically acceptable forms of such compounds. Esters, ethers, carbamates, all solvates and hydrates thereof, and all salts thereof).

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

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

（式中、
Ｒ_１およびＲ_２はそれぞれが独立して、Ｃ_３〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリールおよびＣ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる）。
しかしながら、本発明によれば、Ｒ_１およびＲ_２は、メチル、エチルおよびフェニルではない。

(Where
R ₁ and R ₂ are each independently 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 alkyl _{cycloalkenyl,} C 1 _{-C 13 alkylamine,} C 1 _{-C 13} arylamine, C ( O) selected from the group consisting of C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl and C (O) aryl; provided that each of said groups is hydrogen, halo group, nitro group, amino group, cyano group, isocyano group, _thio, C 1 -C ₆ alkyl group, a cycloalkyl group, an aryl group, an alkoxy group and aryl It can be optionally having one to six substituents independently selected from oxy groups).
However, according to the invention, R ₁ and R ₂ are not methyl, ethyl and phenyl.

  The invention also includes compounds of formula (II) and derivatives thereof, including polymorphs, isomers and prodrugs thereof, geometrical or optical isomers thereof, and pharmaceutically acceptable forms of such compounds. Esters, ethers, carbamates, all solvates and hydrates thereof, and all salts thereof).

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

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

（式中、
Ｒ_１およびＲ_２はそれぞれが独立して、水素、Ｃ_１〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリールおよびＣ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる）。

(Where
R ₁ and R ₂ are each independently 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 alkyl cycloalkenyl, Selected from the group consisting of C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl and C (O) aryl; provided that each of said groups is hydrogen, halo, nitro, amino group, cyano group, isocyano group, _thio, C 1 -C ₆ alkyl group, a cycloalkyl group, an aryl group, an alkoxy group and It can be optionally having one to six substituents independently selected from aryloxy group).

  The invention also includes compounds of formula (III) and derivatives thereof, including polymorphs, isomers and prodrugs thereof, geometrical or optical isomers thereof, and pharmaceutically acceptable forms of such compounds. Esters, ethers, carbamates, all solvates and hydrates thereof, and all salts thereof).

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

  The present invention further provides a process for preparing compounds of formula (I), formula (II) and formula (III) and derivatives thereof.

  The present invention relates to the activity of lipase gene family enzymes involved in lipid metabolism, absorption and accumulation in the body, including diseases mediated by lipase gene family enzymes (including overweight or obesity, hyperlipidemia, Treat, improve or treat hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases and other metabolic disorders) To prevent, the compounds of the invention (including polymorphs, prodrugs, isomers or pharmaceuticals thereof) that are useful in reducing or inhibiting at various levels, including body fluid level, cellular level and tissue level A pharmaceutically acceptable ester, ether, carbamate and oxime) Subjected to.

  The invention provides in a further aspect the use of compounds of formula (I), formula (II) and formula (III) and derivatives thereof for the preparation of skin care products, hair care products or cosmetics.

  In yet a further aspect, the present invention provides compounds of formula (I), formula (II) and formula (III) and derivatives thereof for preventing or treating cell and tissue damage caused by microbial pathogens that secrete lipases. Provide the use of.

  The present invention also provides a medicament comprising any of the compounds of formula (I), formula (II) and formula (III) and derivatives thereof, alone or in combination with suitable pharmaceutically acceptable excipients. Related to the formulation. Such formulations may inhibit the activity of lipase gene family enzymes involved in lipid metabolism, absorption and accumulation in the body in diseases mediated by lipase gene family enzymes (eg, overweight or obesity, hyperlipidemia). Fluid levels, cell levels and tissues to treat, ameliorate, or prevent hypercholesterolemia, hypertriglyceridemia, pancreatitis, diabetes, atherosclerosis, other cardiovascular diseases, metabolic syndrome and metabolic disorders) Useful in reducing or inhibiting at various levels, including levels.

  The present invention also includes compounds of formula (I), formula (II) and formula (III) and derivatives thereof in therapeutically effective amounts, alone or in combination with pharmaceutically acceptable adjuvants. A method for producing a pharmaceutical product is provided. The compounds of formula (I), formula (II) and formula (III) and their derivatives can be further combined with other active ingredients.

  The present invention further provides for the treatment of diseases mediated by enzymes of the lipase gene family in human or animal subjects with compounds of formula (I), formula (II) and formula (III) and derivatives thereof in therapeutically effective amounts. Related to how to treat.

  The invention and other objects, features and advantages of the invention will become more apparent in the following detailed description of the invention and the accompanying embodiments.

(Detailed description of the invention)
The present invention relates to novel methods and compositions used in reducing or inhibiting the activity of lipase gene family enzymes to treat, ameliorate or prevent diseases and conditions mediated by lipase gene family enzymes in an individual. Offer things.

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

  The term “lipase gene family of enzymes” as used herein includes liver lipase, intestinal lipase (including gastric lipase, pancreatic lipase and carboxyl ester lipase), endothelial lipase, phospholipase and other related lipases. However, it is not limited to these.

  The term “pharmaceutically acceptable” as used herein refers to a carrier, diluent, vehicle excipient or composition that is chemically and / or toxicologically compatible with its intake. Indicates a substance to be included with other ingredients that constitute a non-hazardous formulation.

  The term “alkyl”, whether alone or as part of another substituent, means a straight or branched monovalent hydrocarbon group, unless otherwise defined, eg, methyl, ethyl, n- It means propyl, isopropyl, n-butyl, tertiary butyl, sec-butyl, n-pentyl and n-hexyl.

  The term “alkenyl” used alone or in combination with other terms means a straight or branched monovalent hydrocarbon radical having the stated range of carbon atoms, for example vinyl, propenyl, crotonyl , Groups such as isopentenyl and various butenyl isomers.

  The term “alkynyl” used alone or in combination with other terms is a straight chain or branched acyclic carbon containing a carbon-carbon triple bond hydrocarbon group having the stated number range of carbon atoms. Means chain, means group.

  The term “cycloalkyl” refers to a cyclic alkyl group, whether monocyclic or polycyclic, having at least 3 carbon atoms, typically 3 to 7 carbon atoms. means. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

  The term “alkoxy”, alone or in combination, means a group of the formula alkyl-O—, wherein the term “alkyl” has the previously indicated meaning, eg methoxy, ethoxy , N-propoxy, isopropoxy, n-butoxy, isobutoxy, 2 ° butoxy and 3 ° butoxy, 2-methoxyethoxy and the like.

The term “C ₁ -C ₅ alkyl cycloalkyl” means that any of the C ₁ -C ₅ alkyl groups is substituted on the cycloalkyl group, and this composite group is attached to the nucleus at the alkyl terminus.

The term “C ₁ -C ₆ heterocycloalkyl” has 2 to 6 carbon atoms (preferably 3 to 5 carbon atoms) and is selected from N, O and / or S A heterocycloalkyl group containing at least one heteroatom, wherein the heterocycloalkyl group can be attached via a heteroatom or a carbon atom.

The term “aryl” means an aromatic hydrocarbon group having one ring system (eg, phenyl) or an aromatic hydrocarbon group having a condensed ring system (eg, naphthalene, anthracene, phenanthrene, etc.). Typical aryl groups include hydroxy, amino, halogen, nitro, _cyano, C 1 -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 2 -C _{4 alkynyl,} C 1 -C _{4 alkoxy,} C 1 -C ₄ 6, 7, 8, which may be optionally substituted with one or more substituents selected from dialkylamino, where these alkyl moieties have the same meaning as previously defined An aromatic carbocyclic ring having 9 or 10 carbon atoms (eg, with phenyl, naphthyl, tetrahydronaphthyl or indenyl, etc.). A preferred aromatic hydrocarbon group is phenyl.

The term “C ₃ -C ₉ heteroaryl” refers to three, four, five, like imidazolyl, thiadiazolyl, pyridyl, (benzo) thienyl, (benzo) furyl, quinolyl, tetrahydroquinolyl, quinoxalyl or indolyl, It means a substituted or unsubstituted aromatic group having 6, 7, 8, or 9 carbon atoms and containing at least one heteroatom selected from N, O and / or S. The substituents in the heteroaryl group can be selected from the group of substituents listed for the aryl group. A heteroaryl group can be attached via a carbon atom or a heteroatom, where feasible.

The term “C ₆ -C ₁₀ aryloxy” means an aryl group as defined above containing 6, 7, 8, 9 or 10 carbon atoms attached to an oxygen atom. . C ₃ -C ₉ heteroaryl group is, N, at least including one heteroatom selected from O or _S, which is an analog of the C 6 _{-C 10} aryloxy.

  The term “halo” means fluoro, chloro, bromo or iodo.

The term “amino”, whether alone or in combination, is a primary amino group, a secondary amino group or a tertiary amino group attached through a nitrogen atom, provided that the secondary amino group is an alkyl substituent. Or a cycloalkyl substituent and the tertiary amino group has two similar or different alkyl or cycloalkyl substituents, or two nitrogen substituents together form a ring) means, for example, -NH _2, methylamino, ethylamino, dimethylamino, diethylamino, methyl - and at ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino, particularly Preferred is primary amino.

  The term “cyano”, alone or in combination, means a —CN group.

The term “nitro”, alone or in combination, means a —NO ₂ group.

  The term “heterocyclic group” has 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms and is nitrogen, oxygen or A radical or group derived from a monocyclic or polycyclic saturated or unsaturated substituted or unsubstituted heterocyclic nucleus containing one, two or three heteroatoms selected from the group consisting of sulfur Show.

  The term substituent is a “non-interfering” substituent. “Non-interfering” means that the group occupies the indicated position and is suitable chemically and in terms of stability to perform the indicated or intended role. Is meant. Accordingly, unsuitable groups are excluded from the definition of “non-interfering”.

In addition, compounds of formula (I) and derivatives thereof can be labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

  A “prodrug” is a compound that can be converted to a compound of the present invention by a reaction such as an enzyme or gastric juice under physiological conditions in vivo, specifically, when it is oxidized, reduced or hydrolyzed by an enzyme, etc. The compound which can be converted into the compound of this invention or the compound which can be converted into the compound of this invention at the time of hydrolysis by gastric juice etc. is shown.

  “Polymorph” refers to a compound that exists in more than one form.

  The expression “therapeutically effective amount” treats or prevents a particular disease, condition or disorder, or attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. Or alternatively, an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, condition 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 to} C ₂₀ include 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 ₁₄ , C ₁₅ , C ₁₆ , C ₁₇ , C ₁₈ , C ₁₉ and C ₂₀ are included. Each of C _{1 to} C ₁₃ includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , and C _13. It is. C _{2 to} C ₁₃ include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ , C ₁₃ , etc. The same applies to.

It will be apparent to those skilled in the art that any modification to both the materials and the methods can be implemented without departing from the objects and advantages of the present invention. The following general terms as appearing in the examples are explained below:
a) All operations performed at room or ambient temperature ranged from 18 ° C to 25 ° C.

  b) The course of the reaction was followed by thin layer chromatography (TLC). The reaction times are shown for illustration only.

  c) Melting points are uncorrected and melting points are given for materials prepared as described. Polymorphism may lead to the isolation of materials with different melting points in some preparations.

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

  e) Yields are shown for illustration only.

  f) When given, the NMR data are the main features given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, measured at 300 MHz or 400 MHz using the indicated solvents. Is the form of the delta (δ) value for a typical proton.

g) Chemical symbols have their usual meanings: The following abbreviations are also used: v (volume), w (weight), Bp (boiling point), Mp (melting point), L (liter), ml (milliliter) ), Gm (gram), mg (milligram), mol (mol), mmole (mmol), eq (equivalent), ° C (degrees Centigrade), conc. (Concentrated), SiO ₂ (silicon dioxide), Na ₂ SO ₄ (sodium sulfate).

  h) The intermediates used in the examples below are obtained from Sigma.

Lipases Three members of the human triacylglycerol lipase family have 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, I.J., Le, N., Pateriti JR, Ginsberg, H. N., Lindgren, FT, and Brown, WW (1982), J. Clin. Invest. 70, 1184-1192, Hide, WA, Chan, L., and Li, W.-H. (1992), J. Lipid.Res.33, 167-178. . Pancreatic lipase is primarily involved in the hydrolysis of dietary lipids. Various variants of pancreatic lipase have been described, but their physiological role has not been elucidated (Giller, T., Buchwald, P., Blum-Kaelin, D. and Hunziker, W. (1992). ), J. Biol. Chem. 267, 16509-16516).

  The lipase polypeptides encoded by these lipase genes are about 450 amino acids in length and have a leader signal peptide to facilitate secretion. The lipase protein is composed of two major domains (Winkler, K., D'Arcy, A. and Hunziker, W. (1990), Nature 343, 771-774). The amino terminal domain contains a catalytic site, while the carboxyl domain is thought to be involved in substrate binding, cofactor association, and interaction with cellular receptors (Wong, H., Davis, R., et al.). C., Nikazy, J., Seebart, KE, and Schotz, MC (1991), Proc. Natl. Acad. Sci. USA 88, 11290-11294, van Tilbehurh, H., Roussel, A .; Lalouel, J.-M. and Cambilau, C. (1994), J. Biol. Chem. 269, 4626-4633; Wong, H., Davis, RC, Thuren, T., Goers, J .; W., Nikazy, J., Waite, M. and Schott, M. et al. C. (1994), J. Biol. Chem. 269, 10319-10323; Chappell, DA, Inoue, I., Fry, GL, Pradet, 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 among members of this family is between 22% and 65%, and local regions with high homology correspond to structural homology portions linked to enzyme function.

  Members of the triacylglycerol lipase family share several conserved structural features with each other. One such feature is the “GXSXG” motif, in which the central serine residue is one of the three residues that make up the “catalytic triad” (Winkler, K., D 'Arcy, A. and Hunziker, W. (1990), Nature 343, 771-774; Faustinella, F., Smith, LC and Chan, L. (1992), Biochemistry 31, 7219-7223). Conserved aspartic acid and histidine residues constitute the remainder of the catalytic triad. A short range of 19 to 23 amino acids (the “lid region”) forms an amphiphilic helical structure and covers the catalytic pocket of the enzyme (Winkler, K., D′ Arcy, A. and Hunziker, W.). 1990), Nature 343, 771-774). Comparison between liver lipase and lipoprotein lipase reveals that differences in the enzyme's triacylglycerol and phospholipase activities are mediated in part by this lid region (Dugi, KA, et al. , Dichek HL and Santamarina-Fojo, S. (1995), J. Biol. Chem. 270, 25396-25401). Triacylglycerol lipase has varying degrees of heparin binding activity. Lipoprotein lipase has the greatest affinity for heparin, and this binding activity is located in the spread of positively charged residues in the amino terminal domain (Ma, Y., Henderson, HE, Liu, M.-S., Zhang, H., Forsythe, I.J., Clarke-Lewis, I., Hayden, MR, and Brunzell, J.D., J. Lipid Res. 35, 2049-2059) .

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

Compounds affecting lipase activity The present invention relates to compounds of the following formula (I):

およびその誘導体（これには、その多形体、異性体およびプロドラッグ、その幾何異性体または光学異性体、ならびに、そのような化合物の医薬的に許容可能なエステル、エーテル、カルバメート、そのすべての溶媒和物および水和物ならびにそのすべての塩が含まれるが、これらに限定されない）に関連する：上記式において、Ｒ_１およびＲ_２はそれぞれが独立して、水素、Ｃ_３〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、Ｏ−Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリール、Ｃ（Ｏ）アリールおよびＯ−Ｃ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる。しかしながら、本発明によれば、Ｒ_１およびＲ_２は、メチル、メトキシ、エチル、エトキシ、フェニルおよびヒドロキシではない。

And derivatives thereof (including polymorphs, isomers and prodrugs thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers, carbamates, all solvents thereof, and the like) Including, but not limited to, hydrates and hydrates thereof): wherein R ₁ and R ₂ are each independently 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 alkyl _{cycloalkenyl,} C 1 _{-C 13 alkylamine,} C 1 _{-C 13} Ariruami , C _(O) C 1 -C _{6 alkyl, O-C (O) C} 1 ~C 6 alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl and O-C (O) group consisting of aryl selected is from; each However, the group of hydrogen, halo, nitro, amino, cyano, isocyano, thio, C ₁ -C ₆ alkyl group, a cycloalkyl group, an aryl group, an alkoxy group And optionally have 1 to 6 substituents independently selected from aryloxy groups. However, 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):

およびその誘導体（これには、その多形体、異性体およびプロドラッグ、その幾何異性体または光学異性体、ならびに、そのような化合物の医薬的に許容可能なエステル、エーテル、カルバメート、そのすべての溶媒和物および水和物ならびにそのすべての塩が含まれるが、これらに限定されない）に関連する：上記式において、Ｒ_１およびＲ_２はそれぞれが独立して、Ｃ_３〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリールおよびＣ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる。しかしながら、本発明によれば、Ｒ_１およびＲ_２は、メチル、エチルおよびフェニルではない。

And derivatives thereof (including polymorphs, isomers and prodrugs thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers, carbamates, all solvents thereof, and the like) Including, but not limited to, hydrates and hydrates thereof): wherein R ₁ and R ₂ are each independently 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 _alkyl, C 1 -C ₅ alkyl _{cycloalkenyl,} C 1 _{-C 13 alkylamine,} C 1 _{-C 13} arylamine, C O) C ₁ ~C ₆ alkyl, heterocycloalkyl, aryl is selected from the group consisting of alkyl aryl and C (O) aryl; with the proviso that each of the group hydrogen, halo, nitro, amino, cyano group, isocyano group, optionally having a thio, C ₁ -C ₆ alkyl group, a cycloalkyl group, an aryl group, one to six substituents independently selected from alkoxy and aryloxy radicals Can do. However, 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):

およびその誘導体（これには、その多形体、異性体およびプロドラッグ、その幾何異性体または光学異性体、ならびに、そのような化合物の医薬的に許容可能なエステル、エーテル、カルバメート、そのすべての溶媒和物および水和物ならびにそのすべての塩が含まれるが、これらに限定されない）に関連する：上記式において、Ｒ_１およびＲ_２はそれぞれが独立して、水素、Ｃ_１〜Ｃ_１３アルキル、Ｃ_１〜Ｃ_２０ハロアルキル、Ｃ_２〜Ｃ_１３アルケニル、Ｃ_２〜Ｃ_１３アルキニル、Ｃ_４〜Ｃ_６シクロアルキル、Ｃ_４〜Ｃ_６シクロアルケニル、Ｃ_１〜Ｃ_１３アルコキシアルキル、Ｃ_１〜Ｃ_１３アルキルアミン、Ｃ_１〜Ｃ_１３アリールアミン、Ｃ_１〜Ｃ_５アルキルシクロアルキル、Ｃ_１〜Ｃ_５アルキルシクロアルケニル、Ｃ（Ｏ）Ｃ_１〜Ｃ_６アルキル、ヘテロシクロアルキル、アリール、アルキルアリールおよびＣ（Ｏ）アリールからなる群から選択される；ただし、前記基のそれぞれは、水素、ハロ基、ニトロ基、アミノ基、シアノ基、イソシアノ基、チオ基、Ｃ_１〜Ｃ_６アルキル基、シクロアルキル基、アリール基、アルコキシ基およびアリールオキシ基から独立して選択される１個〜６個の置換基を場合により有することができる。

And derivatives thereof (including polymorphs, isomers and prodrugs thereof, geometric or optical isomers thereof, and pharmaceutically acceptable esters, ethers, carbamates, all solvents thereof, and the like) Including, but not limited to, hydrates and hydrates): wherein R ₁ and R ₂ are each independently 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 alkyl cycloalkenylene , C _(O) C 1 -C ₆ alkyl, heterocycloalkyl, aryl is selected from the group consisting of alkyl aryl and C (O) aryl; with the proviso that each of the group hydrogen, halo, nitro, amino group, cyano group, isocyano group, thio, C ₁ -C ₆ alkyl group, when a cycloalkyl group, an aryl group, one to six substituents independently selected from alkoxy and aryloxy radicals Can have.

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

In other embodiments, R ₁ and R ₂ are independently methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl, iodophenylcarbonyl, fluorophenylcarbonyl, nitrophenylcarbonyl Relates to compounds of formula (III) selected from methoxyphenylcarbonyl or ethoxyphenylcarbonyl.

In further embodiments, R ₁ and R ₂ are independently 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2-chlorophenylcarbonyl, 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-nitrophenylcarbonyl, 4-nitrophenylcarbonyl, 2-methoxyphenylcarbonyl, 3 It relates to a compound of formula selected from methoxy phenylcarbonyl and 4-methoxyphenyl carbonyl (III).

  Accordingly, the present invention also includes prodrugs of the compounds of the present invention. The term “prodrug” includes compounds that are converted in vivo to yield a compound of formula (I), formula (II), or formula (III). Information on the use of prodrugs can be found in T.W. Higuchi and W.H. “Pro-drugs as Novel Delivery Systems” by Stella (Volume 14 of AC Symposium Series 198) and Bioreversible Carriers in Drug Design, Ed P. Can be found.

  Suitable active metabolites of compounds within the scope of formula (I), formula (II) or formula (III) in any suitable form are also included in the present invention.

  The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All suitable optical isomers and stereoisomeric forms of the compounds of the invention and mixtures thereof (including racemic mixtures) form part of the invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if a compound of the present invention contains a double bond or a fused ring, the cis and trans forms, as well as the mixtures, are included within the scope of the present invention. For such compounds, the present invention includes the use of racemates, only one enantiomeric form, only one diastereomeric form, or mixtures thereof as appropriate. Moreover, such compounds may also exist as tautomers. The invention therefore relates to the use of all such suitable tautomers and mixtures thereof. Diastereomeric mixtures are separated into their individual diastereoisomers based on their physical and chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Can do. Enantiomers convert an enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (eg, a chiral auxiliary such as a chiral alcohol or Mosher acid chloride) and separate the diastereoisomers. By subsequent conversion of the individual diastereoisomers to the corresponding pure enantiomers (eg hydrolysis) or by resolution from racemic forms of recrystallization techniques, by synthesis from optically active starting materials, Separation can be achieved by chiral synthesis or by chromatographic separation using a chiral stationary phase. Similarly, some of the compounds of the present invention may be atropisomers (eg, substituted biaryl compounds) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

  Moreover, some compounds of the invention may exhibit polymorphism. The scope of the invention includes all polymorphic forms of the compounds according to the invention, which form a further aspect of the invention. The present invention encompasses any and all racemic, optically active, polymorphic and stereoisomeric forms, or mixtures thereof, which have properties that are useful in the treatment of the conditions indicated herein. You must understand that you have.

Furthermore, the present invention also includes the present invention except that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Included are isotopically-labeled compounds of the present invention that are identical to the compounds presented herein. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine isotopes (eg, ² H, ³ H, ¹¹ C, ¹³ 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 present invention (eg, compounds labeled with ³ H and ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ready preparation and detectability. Furthermore, substitution with heavier isotopes (eg, deuterium (ie, ² H), etc.) may have some therapeutic benefit resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). ), And thus may be preferred in some situations. Positron emitting isotopes (such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F) are useful for positron emission tomography (PET) studies to examine receptor occupancy of substrates. Isotopically-labeled compounds of the present invention are generally produced by procedures similar to those disclosed in the Examples hereinbelow, by using isotopically labeled reagents in place of isotopically unlabeled reagents. Can be prepared.

It is one aspect of the present invention to provide a process for preparing a compound of formula (I), formula (II) or formula (III). Those skilled in the art will understand from this disclosure how to prepare highly preferred compounds of the present invention using any suitable known method. Compounds of formula (I), formula (II) or formula (III) as described above, and R ₁ , R ₂ can be conveniently prepared according to Scheme I unless otherwise indicated.

  In addition, the examples provided herein illustrate the preparation of the compounds of the present invention. Moreover, one of ordinary skill in the art would prepare Scheme I, and the present specification to prepare any specific compound of formula (I), formula (II) or formula (III) of the present invention as desired. It will be understood from this disclosure how to modify the details of the examples described below. Scheme I is provided for illustrative purposes only, and illustrates a possible route for synthesizing compounds of formula (I), formula (II) or formula (III) and does not limit the invention. I have to understand that. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. Specific starting materials and reagents are shown in Scheme I, exemplified below, but suitable substitutions can readily be made to provide a variety of derivatives and reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry known to those skilled in the art.

  Scheme I:

スキームＩには、式（Ｉ）、式（ＩＩ）または式（ＩＩＩ）の化合物を、２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノンまたはそのオキシム、あるいは、置換されたオキシム、あるいは、その好適な塩またはアナログから出発して調製するための一般的なプロトコルが示される。出発物質の２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノンを、アルキルクロリドまたはアシルクロリド、あるいは、アリールクロリドまたはアロイルクロリド、あるいは、置換されたアリールクロリドまたは置換されたアロイルクロリドと、好適な不活性なハロゲン化溶媒（例えば、ジクロロメタン）において、好適な芳香族塩基（例えば、ピリジン）の存在下、制御された条件（例えば、約１０℃〜約４０℃の温度で約１時間〜約２４時間の期間など）のもとで反応させて、式（Ｉ）、式（ＩＩ）または式（ＩＩＩ）の化合物を粗生成物の形態で得る。当業者に知られている分離および精製の従来の方法および／または技術を、本発明の化合物を単離および精製するために使用することができる。様々なそのような技術が当業者には広く知られており、そのような技術には、例えば、すべてのタイプのクロマトグラフィー（高圧液体クロマトグラフィー（ＨＰＬＣ）、一般的な吸着剤（例えば、シリカゲルなど）を使用するカラムクロマトグラフィー、および、薄層クロマトグラフィー）、再結晶、および、示差的な（例えば、液−液）抽出技術が含まれ得る。

In Scheme I, a compound of formula (I), formula (II) or formula (III) is converted to 2,5-dihydroxy-3-undecyl-1,4-benzoquinone or its oxime, or a substituted oxime, or A general protocol for preparing starting from a suitable salt or analog thereof is shown. Starting material 2,5-dihydroxy-3-undecyl-1,4-benzoquinone with alkyl chloride or acyl chloride, or aryl chloride or aroyl chloride, or substituted aryl chloride or substituted aroyl chloride In a suitable inert halogenated solvent (eg, dichloromethane) in the presence of a suitable aromatic base (eg, pyridine) at controlled conditions (eg, at a temperature of about 10 ° C. to about 40 ° C. for about 1 hour). To give a compound of formula (I), formula (II) or formula (III) in the form of a crude product. Conventional methods and / or techniques of separation and purification known to those skilled in the art can be used to isolate and purify the compounds of the present invention. A variety of such techniques are well known to those skilled in the art and include, for example, all types of chromatography (high pressure liquid chromatography (HPLC), common adsorbents (eg silica gel Column chromatography and thin layer chromatography), recrystallization, and differential (eg, liquid-liquid) extraction techniques.

Diseases and conditions associated with lipases It is an aspect of the present invention to provide compounds of formula (I), formula (II) or formula (III) and derivatives thereof for use as therapeutically active substances. .

  The compounds of the present invention as disclosed above are useful for reducing or inhibiting the activity of lipase gene family enzymes to treat, ameliorate or prevent diseases mediated by lipase gene family enzymes. Such compounds reduce or inhibit fat metabolism, absorption and accumulation at various levels, including body fluid levels, cell levels and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family. Useful in doing. Accordingly, the compounds of the present invention and derivatives thereof (including compositions thereof) are able to reduce the level of lipase gene family enzymes involved in lipid metabolism, absorption and accumulation in the body by diseases mediated by lipase gene family enzymes ( This includes overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases and other metabolic disorders Useful in reducing or inhibiting at various levels, including but not limited to body fluid level, cell level and tissue level, to treat, ameliorate or prevent (including but not limited to).

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

  In another aspect, the compounds of the invention and derivatives thereof (including compositions thereof) are also useful for preparing skin care products, hair care products or cosmetics.

  Reduces fat metabolism, absorption and accumulation at various levels, including fluid, cellular and tissue levels in the body by inhibiting or reducing the activity of enzymes belonging to the lipase gene family in mammals (including humans) Or by inhibiting, conditions, diseases and / or disorders mediated by enzymes belonging to the lipase gene family (including overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, A method for treating hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases and other metabolic disorders, comprising the formula (I), formula ( II) or an effective therapeutic amount of a compound of formula (III) or a derivative thereof is administered to said mammal It is one embodiment of the present invention to provide a method comprising and.

  In another embodiment, the present invention is for preventing or treating cell damage and tissue damage caused by a microbial pathogen secreting lipase by inhibiting or reducing the activity of enzymes belonging to the lipase gene family in mammals. A method is provided comprising administering to said mammal an effective therapeutic amount of a compound of formula (I), formula (II) or formula (III) or a derivative thereof.

  Accordingly, a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) or a derivative thereof and a pharmaceutically acceptable inert adjuvant, diluent or carrier. Providing an object is one embodiment of the present invention. Alternatively, the pharmaceutical composition can comprise at least one additional pharmaceutically active agent. Further active pharmaceutical agents can be selected from chemically synthesized compounds having the desired pharmacological activity or compounds derived from natural sources.

Formulation The compound of formula (I), formula (II) or formula (III) or derivative thereof can be any conventional oral administration, oral administration, nasal administration, administration by inhalation spray in unit dosage form, parenteral administration (Eg, intravenous, intramuscular, subcutaneous, intrasternal, or by infusion technique), topical administration (eg, powder, ointment or drops), transdermal administration, in-vessel administration, intravaginal administration, intraperitoneal administration It can be administered intracapsular or rectal. In another aspect of the invention, the compound of the invention and the at least one other pharmaceutically active agent can be administered either separately or in a pharmaceutical composition comprising both. It is generally preferred that such administration be oral. However, if the subject being treated is unable to swallow or otherwise oral administration is impaired or undesirable, parenteral or transdermal administration may be appropriate.

  The compound of formula (I), formula (II) or formula (III) or derivative thereof can be administered in the form of any modified release formulation, controlled release formulation or sustained release formulation. (See, eg, Langer, Science 249: 1527-1533 (1990)). In one embodiment, a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgary 88: 507 (1980); and Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, polymeric materials can be used (Medical Applications of Controlled Release (Langer and Wise, Ed. 1974); Controlled Drug Bioavailability, Drug Product P, and Drug Product P, 198). 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). )checking).

  The dose of the compound of formula (I), formula (II) or formula (III) or a derivative thereof administered to a mammal (including a human or an animal) for the purpose as described above is not particularly limited. Rather, the dose administered varies widely and is subject to the pathology, condition, symptoms or age of the subject and the judgment of the attending physician or veterinarian. A general range of effective dosage rates of the compounds of the invention is from about 0.001 mg / kg subject body weight / day to about 100 mg / kg subject body weight / day. A preferred range of effective dosage rates for the compounds of the present invention is from about 0.01 mg / kg subject body weight / day to about 50 mg / kg subject body weight / day. The amount is selected based on various factors including the environment in which the composition is administered, the site of the cells to be treated, the age, health status, sex and weight of the patient or animal being treated. Useful amounts include 1 milligram, 5 milligram, 15 milligram, 20 milligram, 25 milligram, 30 milligram, 40 milligram, 60 milligram, 150 milligram, 200 milligram, 1 gm, 2 gm, 3 gm, and Range between 10 milligrams and 100 grams, range between 50 milligrams and 5 grams, range between 100 milligrams and 10 grams, range between 250 milligrams and 2.5 grams, 500 milligrams to 1.25 grams The range between and so on is included. While it may be practical to administer a daily dose of the compound of the invention in any given case, in portions at various times of the day, the amount of the compound of the invention Various such as solubility of compounds, prodrugs, isomers or pharmaceutically acceptable salts of the invention, formulations used, and routes of administration (eg, oral, transdermal, parenteral or topical) Depends on factors.

  Various dosages of the compounds of the invention can be administered to humans by any suitable route, with oral administration being preferred. Individual oral dosage forms (eg, tablets or capsules) generally should contain from about 0.1 mg to about 100 mg of a compound of the invention in a suitable pharmaceutically acceptable vehicle, diluent or carrier. Don't be. Dosages for intravenous administration are generally in the range of about 0.1 mg to about 10 mg per dose, as required. For intranasal or inhalation administration, the dosage is generally formulated as a solution from about 0.1% (w / v) to about 1% (w / v). In practice, the physician will determine the actual dosage that is most suitable for an individual patient, and the actual dosage will vary depending on, for example, the age, weight and response of the particular patient. The above dosages are exemplary of the average case, but it will be appreciated that there may be individual cases where larger or smaller dosage ranges are possible. Such dosages of the compounds of the invention are within the scope of the invention.

  Compounds of formula (I), formula (II) or formula (III) and derivatives thereof may be used to treat conditions, diseases and / or disorders mediated by enzymes of the lipase gene family (including overweight or obesity, hyperlipidemia) Prevention of hypertension, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, other cardiovascular diseases and other metabolic disorders) and Providing to produce a pharmaceutical formulation for treatment is another preferred embodiment of the present invention. A pharmaceutical formulation comprising a compound of formula (I), formula (II) or formula (III) or a derivative thereof is one of ordinary skill in the art using one or more pharmaceutically acceptable diluents, carriers or vehicles. Can be formulated in a conventional manner known in the art.

  For oral administration, pharmaceutical formulations that can be used in the present invention include tablets, chewable tablets, controlled release tablets, capsules, troches, granules, powders, pills, microcapsules, elixirs, syrups and suspensions. Contains turbidity.

  In general, tablets can be prepared by methods known in the pharmaceutical sciences by direct compression, wet granulation or dry granulation. Tablet formulations usually include diluents, binders, lubricants and disintegrants as well as the compounds of the invention. Common diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives can also be used. Common tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose and glucose. Natural and synthetic rubbers are also convenient and include gum arabic, alginate, methylcellulose and polyvinylpyrrolidone. Polyethylene glycol, ethyl cellulose and waxes can also serve as binders.

  Lubricants are generally necessary in tablet formulations to prevent tablets and tablet machine ridges from sticking in the mold. The lubricant is selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants include substances that swell when wetted to break the tablet and release the compound, prodrug, isomer, or pharmaceutically acceptable salt of the present invention. Disintegrants include starch, clay, cellulose, algin and gum. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, similar to sodium lauryl sulfate Can be used for Tablets are often coated with a fragrance and sugar as a sealant, or with a film-forming protective agent to adjust the dissolution characteristics of the tablet. The compounds of the present invention can also be formulated as chewable tablets by using large amounts of pleasant tasting substances such as mannitol in the formulation, as is well established in the art today.

  As discussed above, the effects of the compounds of the invention that are delayed, sustained, or limited in duration by proper formulation can be controlled. For example, slowly dissolving pellets of the compounds of the invention can be prepared and incorporated into tablets or capsules. This technique can be improved by making pellets of several different dissolution rates and subsequently filling the mixture with these pellets. Tablets or capsules can be coated with a film that prevents dissolution for a predictable period of time.

  Capsules can be prepared by mixing a compound of the invention with a suitable diluent and filling the capsule with the appropriate amount of the mixture. Typical diluents include inert powdered materials such as many different types of starch, powdered cellulose (especially crystalline cellulose and microcrystalline cellulose), sugars (eg fructose, mannitol and Sucrose, etc.), cereal flour and similar edible powders.

  Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or are provided as a dry product for constitution with water or other suitable vehicle before use. be able to. Such liquid preparations may be prepared using pharmaceutically acceptable additives such as suspending / viscosity enhancing agents (eg sorbitol syrup, methylcellulose or hydrogenated edible fat), emulsifiers (eg lecithin or Gum arabic), non-aqueous vehicles (eg tonsil oil, oily esters or ethyl alcohol, medium chain triglycerides) and preservatives (eg methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbic acid) and the like And can be prepared by conventional means.

  For parenteral administration, the compounds of the invention can be formulated in the form of injectables, including using conventional catheterization techniques or infusion. Formulations for injection can be provided in unit dosage forms, eg, in ampoules or multi-dose containers, with a preservative added. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can also be formulated (eg, suspending, stabilizing and / or dispersing agents). Can be contained. Injectable solutions or suspensions are suitable non-toxic diluents or solvents that are acceptable for parenteral administration (eg, mannitol, 1,3-butanediol, water, Ringer's solution, or isotonic sodium chloride solution). Or suitable dispersing or wetting agents and suspending agents (eg, sterile non-irritating fixed oils (including synthetic mono- or diglycerides) and fatty acids (including oleic acid) and interfaces Activators (such as hydroxypropylcellulose) can be used according to known techniques, and the pH of the solution is suitably adjusted and buffered if necessary. . In general, oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Such an aqueous solution is suitable for intravenous injection purposes. Alternatively, the active ingredient can be in powder form for reconstitution prior to use with a suitable vehicle (eg, sterile pyrogen-free water). Parenteral preparations can also contain the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention, optionally in oily or emulsified vehicles that allow them to be dispersed only slowly in the serum. It can be made to work longer by dissolving or suspending.

  For intranasal administration, or administration by inhalation, the compounds of the invention may be conveniently delivered from a pump spray container in the form of a solution or suspension that is pushed or pumped by the patient, Alternatively, the use of a suitable propellant (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas) is convenient as an aerosol spray presentation form from a pressurized container or nebulizer Well delivered. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a fixed amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound. When administered by nasal aerosol or inhalation, these compositions are known in the art as benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or Can be prepared according to techniques well known in the field of pharmaceutical formulation and prepared as a solution in physiological saline, using other stabilizers or dispersants. Capsules and cartridges for use in inhalers or insufflators (made from gelatin, for example) are suitable for the compounds of the invention and powders suitable for inhalation bases (eg lactose or starch) Etc.) and a powder mixture.

  The compounds of the present invention can also be administered topically, according to standard pharmaceutical practice, for example as a cream, jelly, salve, lotion, gel, paste and ointment. The compounds of the invention can also be administered transdermally (eg, by use of a patch).

  Any suitable formulation for transdermal application comprising a compound of the present invention can be used, and such formulation also generally facilitates the passage of the compound through the subject's skin, and To assist, a suitable transdermal carrier (eg, an absorbable pharmacologically acceptable solvent) is included. For example, a suitable transdermal device can include a dressing form having a backing member and a reservoir containing a compound of interest. Such bandage-type transdermal devices can further include a suitable carrier, a rate control barrier, and means for solidifying the transdermal device to the subject's skin.

  When it is desired to administer a compound of the invention as a suppository, any suitable base can be used. Cocoa butter is a traditional suppository base, which can be adjusted by the addition of waxes to increase its melting point. Water miscible suppository bases, particularly water miscible suppository bases containing polyethylene glycols of various molecular weights are widely used.

  In other embodiments, the compounds of the invention can be formulated into food or beverages.

  The compounds of the present invention can also be administered to mammals other than humans. The method of administration to such mammals and the dosage administered to such mammals will depend, for example, on the species of animal and the disease or disorder being treated. The compounds of the present invention may be combined in any suitable form, eg, with the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention together with a lubricant (eg, carbowax or In capsules, boluses, tablets, pellets, etc. prepared by mixing with carnuba wax, etc., or, for example, pharmaceutically acceptable oils (eg, peanut oil, sesame oil or corn oil) Etc.) and can be administered to animals in any suitable manner (eg, orally, parenterally or transdermally). The compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention can also be administered to animals as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. Alternatively, the compounds of the present invention can be administered to the water supply, for example, in the form of a liquid or water-soluble concentrate. In addition, the compounds of the present invention can be administered in animal feed, for example when included in the pharmaceutical composition of the present invention, eg, high concentrations of feed additives or premixes are generally suitable for this purpose. Can be prepared for mixing with normal animal feed together with a suitable carrier. Such carriers facilitate, for example, the uniform distribution of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention in the finished feed in which the premix is mixed. Suitable carriers include various liquids (eg, water, oil (eg, soybean oil, corn oil, cottonseed oil, etc.) or volatile organic solvents) and various solids (eg, alfalfa, soybean, cottonseed oil, linseed oil) , Corn cobs, corn, molasses, urea and bones and feeds including mineral mixtures or parts of various suitable baits).

  In another aspect of the invention, biological assays conducted using compounds of formula (I), formula (II) and formula (III) reveal potent inhibition of lipase.

  The following examples illustrate embodiments of the invention. However, embodiments of the invention will be described in the specific details of these examples, as various other changes thereof will be apparent to those skilled in the art or will be apparent to those skilled in the art in light of this disclosure. It must be understood that it is not limited.

  Example 1: Extraction and isolation of starting material (2,5-dihydroxy-3-undecyl-1,4-benzoquinone)

構造＃１：２，５−ジヒドロキシ−３−ウンデシル−ｐ−ベンゾキノン（エンベリン）
エンベリア・リベスの粉末化果実を、石油エーテル、クロロホルム、酢酸エチル、メタノールおよび水により順次抽出した。クロロホルム抽出物を、石油エーテルを結晶化溶媒として使用する反復した結晶化に供した。結晶化工程を繰り返して、収率を増大させた。母液を、石油エーテル−クロロホルムを溶出溶媒（グラジエント溶出）として使用してシリカゲルカラムクロマトグラフィー（１００〜２００メッシュ）によって分画化して、収率をさらに改善した。すべての分画物を、ｎ−プロパノール：ｎ−ブタノール：アンモニア溶液（６：１：３）をＴＬＣ溶媒系として用いてシリカゲルＴＬＣプレート（シリカゲル６０Ｆ_２５４、Ｍｅｒｃｋ）でモニターした。ＴＬＣに基づいて、類似する分画物をプールして一緒にし、減圧下で濃縮した。化合物を石油エーテルにおける反復した結晶化によって精製して、１４０ｇ（３．５％）の抽出物を得た。約５０ｇの抽出物を、抽出物が溶媒に溶解するまで石油エーテル（５００ｍｌ）中で還流した。溶液を室温に冷却し、ろ過した。上記手順を、所望する純度の化合物が得られるまで繰り返した。得られた化合物は、

Structure # 1: 2,5-dihydroxy-3-undecyl-p-benzoquinone (embelin)
The powdered fruit of Embellia Ribes was extracted sequentially with petroleum ether, chloroform, ethyl acetate, methanol and water. The chloroform extract was subjected to repeated crystallization using petroleum ether as the crystallization solvent. The crystallization process was repeated to increase the yield. The mother liquor was fractionated by silica gel column chromatography (100-200 mesh) using petroleum ether-chloroform as the elution solvent (gradient elution) to further improve the yield. All fractions were monitored on silica gel TLC plates (silica gel 60F ₂₅₄ , Merck) using n-propanol: n-butanol: ammonia solution (6: 1: 3) as the TLC solvent system. Based on TLC, similar fractions were pooled together and concentrated under reduced pressure. The compound was purified by repeated crystallization 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 room temperature and filtered. The above procedure was repeated until the desired purity of the compound was obtained. The resulting compound is

を示した。

showed that.

  Example 2: 2,5-di-O- (3-fluorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃２の合成；２，５−ビス−（３−フルオロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに３−フルオロベンゾイルクロリド（１．３５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．９６ｇ、５２．７％）。

Synthesis of structure # 2; 2,5-bis- (3-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 3-fluorobenzoyl chloride (1.35 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.96 g, 52.7%).

実施例３：２，５−ジ−Ｏ−（４−ｔｅｒｔ−ブチルフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 3: 2,5-di-O- (4-tert-butylphenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃３の合成；２，５−ビス−（４−ｔｅｒｔ−ブチルフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに４−ｔｅｒｔ−ブチルベンゾイルクロリド（１．６７ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．４７ｇ、２８．３％）。

Synthesis of structure # 3; 2,5-bis- (4-tert-butylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1. To a stirred solution of 0 gm, 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 4-tert-butylbenzoyl chloride (1.67 gm, 8.5 mmole) at 15 ° C. to 20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.47 g, 28.3%).

実施例４：２，５−ジ−Ｏ−（２−フルオロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 4: 2,5-di-O- (2-fluorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃４の合成；２，５−ビス−（２−フルオロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに２−フルオロベンゾイルクロリド（１．３５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．９６ｇ、５２．７％）。

Synthesis of structure # 4; 2,5-bis- (2-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 2-fluorobenzoyl chloride (1.35 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.96 g, 52.7%).

実施例５：２，５−ジ−Ｏ−（２−ブロモフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 5: 2,5-di-O- (2-bromophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃５の合成；２，５−ビス−（２−ブロモフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに２−ブロモベンゾイルクロリド（１．９ｇ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．５６ｇ、６９．６％）。

Synthesis of structure # 5; 2,5-bis- (2-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 2-bromobenzoyl chloride (1.9 g, 8.5 mmole) at 15 ° C.-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.56 g, 69.6%).

実施例６：２，５−ジ−Ｏ−（３−ブロモフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 6: 2,5-Di-O- (3-bromophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃６の合成；２，５−ビス−（３−ブロモフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに３−ブロモベンゾイルクロリド（１．９ｇ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．４ｇ、６２％）。

Synthesis of structure # 6; 2,5-bis- (3-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 3-bromobenzoyl chloride (1.9 g, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.4 g, 62%).

実施例７：２，５−ジ−Ｏ−（３−クロロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 7: 2,5-di-O- (3-chlorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃７の合成；２，５−ビス−（３−クロロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに３−クロロベンゾイルクロリド（１．５ｇｍ、８．５０ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．２５ｇ、６４．４％）。

Synthesis of structure # 7; 2,5-bis- (3-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3 To a stirred solution of .4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 3-chlorobenzoyl chloride (1.5 gm, 8.50 mmole) at 15 ° C.-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.25 g, 64.4%).

実施例８：２，５−ジ−Ｏ−（２−クロロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 8: 2,5-Di-O- (2-chlorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃８の合成；２，５−ビス−（２−クロロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに２−クロロベンゾイルクロリド（１．５ｇｍ、８．５０ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．１４ｇ、５８．７％）。

Synthesis of structure # 8; 2,5-bis- (2-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3 To a stirred solution of .4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 2-chlorobenzoyl chloride (1.5 gm, 8.50 mmole) at 15 ° C.-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.14 g, 58.7%).

実施例９：２，５−ジ−Ｏ−（４−クロロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 9: 2,5-di-O- (4-chlorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃９の合成；２，５−ビス−（４−クロロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに４−クロロベンゾイルクロリド（１．５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．２１ｇ、６２．４％）。

Synthesis of structure # 9; 2,5-bis- (4-chlorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, 3 To a stirred solution of .4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 4-chlorobenzoyl chloride (1.5 gm, 8.5 mmole) at 15 ° C. to 20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.21 g, 62.4%).

実施例１０：２，５−ジ−Ｏ−（４−ブロモフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 10: 2,5-di-O- (4-bromophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１０の合成；２，５−ビス−（４−ブロモフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに４−ブロモベンゾイルクロリド（１．９ｇ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．４９ｇ、６６．５％）。

Synthesis of structure # 10; 2,5-bis- (4-bromophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 4-bromobenzoyl chloride (1.9 g, 8.5 mmole) at 15 ° C. to 20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.49 g, 66.5%).

実施例１１：２，５−ジ−Ｏ−（３−ニトロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 11: 2,5-di-O- (3-nitrophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１１の合成；２，５−ビス−（３−ニトロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに３−ニトロベンゾイルクロリド（１．６ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．９５ｇ、４７％）。

Synthesis of structure # 11; 2,5-bis- (3-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 3-nitrobenzoyl chloride (1.6 gm, 8.5 mmole) at 15 ° C.-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.95 g, 47%).

実施例１２：２，５−ジ−Ｏ−（４−メチルフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 12: 2,5-di-O- (4-methylphenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１２の合成；２，５−ビス−（４−メチルフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（０．１５ｇ、０．５ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（０．４１ｍＬ、５．１ｍｍｏｌｅ）を加えた。これに４−トルオイルクロリド（０．２３ｇ、１．５３ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３．５時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（８４ｍｇ、３２％）。

Synthesis of structure # 12; 2,5-bis- (4-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.15 g, To a stirred solution of 0.5 mmole) in dichloromethane (20 mL) was added pyridine (0.41 mL, 5.1 mmole). To this was added 4-toluoyl chloride (0.23 g, 1.53 mmole) at 15 ° C. to 20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3.5 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (84 mg, 32%).

実施例１３：２，５−ジ−Ｏ−（３−メチルフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 13: 2,5-di-O- (3-methylphenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１３の合成；２，５−ビス−（３−メチルフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（０．５ｇ、１．７ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（０．５５ｍＬ、６．８ｍｍｏｌｅ）を加えた。これに３−トルオイルクロリド（０．６５４ｇｍ、４．２５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．６４ｇ、７１％）。

Synthesis of structure # 13; 2,5-bis- (3-methylphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.5 g, To a stirred solution of 1.7 mmole) in dichloromethane (20 mL) was added pyridine (0.55 mL, 6.8 mmole). To this was added 3-toluoyl chloride (0.654 gm, 4.25 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.64 g, 71%).

実施例１４：２，５−ジ−Ｏ−（２−ニトロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 14: 2,5-Di-O- (2-nitrophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１４の合成；２，５−ビス−（２−ニトロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに２−ニトロベンゾイルクロリド（１．６ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．９５ｇ、４７％）。

Synthesis of structure # 14; 2,5-bis- (2-nitrophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 2-nitrobenzoyl chloride (1.6 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.95 g, 47%).

実施例１５：２，５−ジ−Ｏ−（フェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 15: 2,5-Di-O- (phenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１５の合成；２，５−ビス−（フェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（０．３ｇ、１．０２ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（０．３ｍＬ、４．０８ｍｍｏｌｅ）を加えた。これにベンゾイルクロリド（０．２６ｇｍ、２．５５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．２８５ｇ、５６．８％）。

Synthesis of structure # 15; 2,5-bis- (phenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (0.3 g, 1.02 mmole) ) In dichloromethane (20 mL) was added pyridine (0.3 mL, 4.08 mmole). To this was added benzoyl chloride (0.26 gm, 2.55 mmole) at 15 ° C. to 20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.285 g, 56.8%).

実施例１６：２，５−ジ−Ｏ−（４−フルオロフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 16: 2,5-Di-O- (4-fluorophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１６の合成；２，５−ビス−（４−フルオロフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに４−フルオロベンゾイルクロリド（１．３５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．８５ｇ、４６．４％）。

Synthesis of structure # 16; 2,5-bis- (4-fluorophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 4-fluorobenzoyl chloride (1.35 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.85 g, 46.4%).

実施例１７：２，５−ジ−Ｏ−（３−メトキシフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 17: 2,5-di-O- (3-methoxyphenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１７の合成；２，５−ビス−（３−メトキシフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに３−メトキシベンゾイルクロリド（１．４５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．３２ｇ、６９％）。

Synthesis of structure # 17; 2,5-bis- (3-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 3-methoxybenzoyl chloride (1.45 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.32 g, 69%).

実施例１８：２，５−ジ−Ｏ−（４−メトキシフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 18: 2,5-di-O- (4-methoxyphenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１８の合成；２，５−ビス−（４−メトキシフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに４−メトキシベンゾイルクロリド（１．４５ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（１．３７ｇ、７１．７％）。

Synthesis of structure # 18; 2,5-bis- (4-methoxyphenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 g, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 4-methoxybenzoyl chloride (1.45 gm, 8.5 mmole) at 15-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (1.37 g, 71.7%).

実施例１９：２，５−ジ−Ｏ−（２−ヨードフェニルカルボニル）−３−ウンデシル−１，４−ベンゾキノン

Example 19: 2,5-di-O- (2-iodophenylcarbonyl) -3-undecyl-1,4-benzoquinone

構造＃１９の合成；２，５−ビス−（２−ヨードフェニルカルボニルオキシ）−３−ウンデシル−１，４−ベンゾキノン
２，５−ジヒドロキシ−３−ウンデシル−１，４−ベンゾキノン（１．０ｇｍ、３．４ｍｍｏｌｅ）のジクロロメタン（２０ｍＬ）における撹拌された溶液にピリジン（１．１ｍＬ、１３．６ｍｍｏｌｅ）を加えた。これに２−ヨードベンゾイルクロリド（２．２６ｇｍ、８．５ｍｍｏｌｅ）を１５℃〜２０℃で加え、撹拌し、これにより３０℃に達した。撹拌を３時間続けた（ＴＬＣ）。有機層をジクロロメタンにより抽出し、洗浄し（水、ブライン）、乾燥し（Ｎａ_２ＳＯ_４）、濃縮して粗製物にし、これをＳｉＯ_２カラムクロマトグラフィー（１０％〜２０％ＥｔＯＡｃ／ヘキサン）によって純粋な物質に精製した（０．８９ｇ、３５％）。

Synthesis of structure # 19; 2,5-bis- (2-iodophenylcarbonyloxy) -3-undecyl-1,4-benzoquinone 2,5-dihydroxy-3-undecyl-1,4-benzoquinone (1.0 gm, To a stirred solution of 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this was added 2-iodobenzoyl chloride (2.26 gm, 8.5 mmole) at 15 ° C.-20 ° C. and stirred to reach 30 ° C. Stirring was continued for 3 hours (TLC). The organic layer is extracted with dichloromethane, washed (water, brine), dried (Na ₂ SO ₄ ) and concentrated to a crude product which is purified by SiO ₂ column chromatography (10% -20% EtOAc / hexanes). Purified to pure material (0.89 g, 35%).

実施例２０：リパーゼ阻害活性についてのアッセイ
試験サンプルの調製：構造＃１〜構造＃１９を、１０ｍＭストック溶液を得るために１ｍＬのＤＭＳＯに溶解し、ボルテックス撹拌して溶解させ、４℃で保存した。様々な濃度の作業用サンプルを０．２Ｍリン酸塩緩衝液（約８．０のｐＨ）において調製した。このサンプルをすべてのさらなるアッセイのための試験サンプルとして使用した。

Example 20: Assay for Lipase Inhibitory Activity Test Sample Preparation: Structure # 1 to Structure # 19 were dissolved in 1 mL DMSO to obtain a 10 mM stock solution, vortexed and stored at 4 ° C. . Various concentrations of working samples were prepared in 0.2M phosphate buffer (pH of about 8.0). This sample was used as a test sample for all further assays.

  Lipase assay: The lipase assay was performed with modifications as described by Winkler and Stuckmann (1979) (Winkler, UK & Stuckmann, M., Glycogen, hyaluronate, and some other polysaccharids chemistry). exolipase by Serratia marcescens, J. Bacteriol. 138: 663-670 (1979)). The assay was designed using a 96 well format. The substrate used in this assay was p-nitrophenol palmitate (Sigma, Cat No. N-2752). 4.5 mg of p-nitrophenol palmitate is dissolved in 200 μl of N, N-dimethylformamide (Sigma, Cat No. D-4551) and the volume is made up to 10 ml with 0.1 M phosphate buffer (pH 8.0). I made it. Pancreatic lipase (Sigma, Cat No. L-3126) samples were prepared by dissolving the enzyme in 0.1 M phosphate buffer at a concentration of 5 mg / ml. The reaction mixture consisted of 150 μl substrate solution, 40 μl phosphate buffer (pH 8.0, 0.2 M) and 10 μl lipase solution. The reaction mixture was incubated at 37 ° C. and the optical density was measured at 405 nm after incubation. Enzymatic activity was expressed in the form of International Units (IU).

  Lipase activity: 1 enzyme unit of lipase can be obtained by using 1 nm of free phenol as standard assay conditions (Winkler and Stuckmann, 1979; Biotechnol.Appl.Biochem. (1998), 28, (243-249)) is defined as such an amount released from the substrate (p-nitrophenol palmitate) for 1 ml per minute. Free phenol is obtained from a standard graph of p-nitrophenol (Sigma, 104-8).

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

  Enzyme inhibition: Enzyme inhibition was expressed in terms of relative activity and percent inhibition based solely on changes in International Units (IU).

実施例２１：ＩＣ_５０の決定
試験サンプルの調製：合成アナログを、１０ｍＭストック溶液を得るために１ｍＬのＤＭＳＯに溶解した。サンプルをボルテックス撹拌して溶解させ、４℃で保存した。様々な濃度の作業用サンプルを０．２Ｍリン酸塩緩衝液（約８．０のｐＨ）において調製した。このサンプルをすべてのさらなるアッセイのための試験サンプルとして使用した。

Example 21: Determination of IC ₅₀ Test sample preparation: Synthetic analogs were dissolved in 1 mL DMSO to obtain a 10 mM stock solution. Samples were dissolved by vortexing and stored at 4 ° C. Various concentrations of working samples were prepared in 0.2M phosphate buffer (pH of about 8.0). This sample was used as a test sample for all further assays.

  Lipase inhibition assay: Enzyme inhibition assays were performed in a dose dependent manner. The concentration of the synthetic analog examined was 6.25 μM to 200 μM. This assay was similar to the assay described above, except that 40 μl of the test sample was used instead of phosphate buffer in the control. Optical density was measured at 0 hours and after incubation at 37 ° C. Enzyme activity was measured in terms 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 (p-nitrophenol palmitate) per minute per ml under standard assay conditions. Free phenol is obtained from a standard graph of p-nitrophenol (Sigma, 104-8).

  Percent inhibition: Enzyme inhibition was expressed in terms of% inhibition simply based on changes in International Units (IU).

IC ₅₀ calculation: The IC ₅₀ for each analog was manually calculated in concentration from the dose-dependent graph of each analog (6.25 μM-200 μM). In this case, the% inhibition of lipase was measured as 50% at two points close to a straight line (more than 50% inhibition and less than 50% inhibition). IC ₅₀ values were obtained from linear regression. The value obtained is based on the interpolated data.

実施例２２：脂質吸収の阻害
一晩絶食させた４週齢のオスのＷｉｓｔａｒラット（体重範囲：１５０グラム〜２００グラム）を脂質吸収研究のために使用した。ラットを、それぞれが６匹の２つの群に分け、１００μｌの血液を、０時間における血漿脂質プロフィールの推定のために眼窩静脈洞から採血した。１ｍｌの高脂肪液体餌を胃管法によってＰＯ（経口）投与した。加えて、実験群には、５００μｌのビヒクルに溶解された１００μｇの試験化合物（２，５−ジ−Ｏ−アロイル−３−ウンデシル−１，４−ベンゾキノン誘導体、構造＃１〜構造＃１９）が経口により与えられた。コントロール群には、同じ体積のビヒクルが与えられた。

Example 22: Inhibition of lipid absorption Four week old male Wistar rats (weight range: 150-200 grams) fasted overnight were used for lipid absorption studies. Rats were divided into two groups of 6 each, and 100 μl of blood was drawn from the orbital sinus for estimation of plasma lipid profile at 0 hours. 1 ml of a high fat liquid diet was administered PO (orally) by gavage. In addition, the experimental group contained 100 μg test compound (2,5-di-O-aroyl-3-undecyl-1,4-benzoquinone derivative, structure # 1 to structure # 19) dissolved in 500 μl vehicle. Given orally. The control group received the same volume of vehicle.

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

実施例２３：脂質の細胞取り込みの阻害
マウスのマクロファージ細胞株（Ｊ７７４Ａ．１）を、１０％ウシ胎児血清を含有するダルベッコ最少必須培地（ＤＭＥＭ）において６ウエル培養プレートに置床した（ウエルあたり１ｘ１０^５個の細胞）。１００μｇの酸化された低密度リポタンパク質（ＬＤＬ）をそれぞれのウエルに加えた。それぞれのプレートにおいて、化合物（構造＃１〜構造＃１９）の１つ（１０μＭ）を三連でウエルに加え、一方で、３つのウエルはコントロールとして維持された。実験を４８時間後に終了した。細胞をオイルレッドにより染色し、ヘマトキシリンにより対比染色し、顕微鏡で観察した。コントロールと比較したとき、構造＃２〜構造＃１９による処理はマクロファージによるＬＤＬの取り込みを著しく阻害した。

Example 23: Inhibition of lipid cellular uptake The mouse macrophage cell line (J774A.1) was plated in 6-well culture plates in Dulbecco's minimal essential medium (DMEM) containing 10% fetal calf serum (1 x 10 ⁵ per well). Cells). 100 μg of oxidized low density lipoprotein (LDL) was added to each well. In each plate, one of the compounds (Structure # 1 to Structure # 19) (10 μM) was added to the wells in triplicate, while three wells were maintained as controls. The experiment was terminated after 48 hours. Cells were stained with oil red, counterstained with hematoxylin, and observed with a microscope. Treatment with structure # 2 to structure # 19 markedly inhibited LDL uptake by macrophages when compared to controls.

  All publications and patent applications cited herein are hereby incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Incorporated into.

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, certain changes and modifications may be made to the invention without departing from the spirit or scope of the appended claims. It will be readily apparent to those skilled in the art in light of the teachings of the present invention.

Claims (41)

Compounds of formula (I) below:

Wherein R ₁ and R ₂ are each independently 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 alkyl cycloalkyl, C ₁ -C ₅ alkyl cycloalkenyl, C ₁ -C ₁₃ alkyl amine, C ₁ -C ₁₃ arylamine, C (O) C ₁ -C ₆ alkyl, O—C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl, C (O) aryl and O—C (O) aryl Wherein each of said groups is hydrogen, halo group, nitro group, amino group, cyano group, isocyano group, thio group, C ₁ -C Optionally having 1 to 6 substituents independently selected from ₆ alkyl groups, cycloalkyl groups, aryl groups, alkoxy groups and aryloxy groups; and R ₁ and R ₂ are methyl , Not methoxy, ethyl, ethoxy, phenyl and hydroxy)
Prodrugs, derivatives thereof, geometric or optical isomers, polymorphs thereof, and pharmaceutically acceptable esters, ethers, carbamates, oximes of the compounds, the prodrugs, the isomers or the polymorphs , All solvates and hydrates thereof and all salts thereof. Compound of formula (II) below:

Wherein R ₁ and R ₂ are each independently C ₃ -C ₁₃ alkyl, C ₁ -C ₂₀ haloalkyl, C ₂ -C ₁₃ alkenyl, C ₂ -C ₁₃ alkynyl, C ₄ -C ₆ cyclo Alkyl, C ₄ -C ₆ cycloalkenyl, C ₁ -C ₁₃ alkoxyalkyl, C ₁ -C ₅ alkyl cycloalkyl, C ₁ -C ₅ alkyl cycloalkenyl, C ₁ -C ₁₃ alkyl amine, C ₁ -C ₁₃ aryl Selected from the group consisting of amine, C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl and C (O) aryl; provided that each of said groups is hydrogen, halo group, nitro group , amino group, cyano group, isocyano group, _thio, C 1 -C ₆ alkyl group, a cycloalkyl group, an aryl group, Oyo alkoxy group Can be optionally having one to six substituents independently selected from aryloxy group; and, R ₁ and R ₂ are methyl, are not ethyl and phenyl)
Prodrugs, derivatives thereof, geometric or optical isomers, polymorphs thereof, and pharmaceutically acceptable esters, ethers, carbamates, oximes of the compounds, the prodrugs, the isomers or the polymorphs , All solvates and hydrates thereof and all salts thereof. The compound of claim 1 having the following formula (III):

Wherein R ₁ and R ₂ are each independently 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 alkyl amine, C ₁ -C ₁₃ aryl amine, C ₁ -C ₅ alkyl cycloalkyl, C ₁ -C ₅ Selected from the group consisting of alkylcycloalkenyl, C (O) C ₁ -C ₆ alkyl, heterocycloalkyl, aryl, alkylaryl and C (O) aryl; provided that each of said groups is hydrogen, halo group, nitro group, amino group, cyano group, isocyano group, _thio, C 1 -C ₆ alkyl group, a cycloalkyl group, an aryl group, an alkoxy And independently aryloxy group may have optionally from 1 to 6 substituents selected)
Prodrugs, derivatives thereof, geometric or optical isomers, polymorphs thereof, and pharmaceutically acceptable esters, ethers, carbamates, oximes of the compounds, the prodrugs, the isomers or the polymorphs , All solvates and hydrates thereof and all salts thereof. R ₁ and R ₂ are independently selected from the group consisting of C (O) aryl, C (O) alkylaryl, C (O) haloaryl, C (O) nitroaryl and C (O) alkoxyaryl 2. A compound of formula (II) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, all solvates and hydrates thereof and all salts thereof. R ₁ and R ₂ are independently methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl, iodophenylcarbonyl, fluorophenylcarbonyl, nitrophenylcarbonyl, methoxyphenylcarbonyl and ethoxy 2. A compound of formula (II) according to claim 1 selected from the group consisting of phenylcarbonyl, its prodrug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and Its all salt. R ₁ and R ₂ are independently 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2-chlorophenylcarbonyl, 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-nitrophenylcarbonyl, 4-nitrophenylcarbonyl, 2-methoxyphenylcarbonyl, 3-methoxyphenylcarbonyl The compound of formula (II) according to claim 1, selected from the group consisting of bonyl or 4-methoxyphenylcarbonyl, its prodrug, its geometric or optical isomer, its polymorph, all its solvates And hydrates and all their salts. The following compounds:
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;
vii) 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 selected from the group consisting of its prodrugs, its geometric or optical isomers, its polymorphs, all its solvates and hydrates and all its salts. A pharmaceutically acceptable compound of formula (I) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph A pharmaceutical composition comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and a pharmaceutically acceptable inert adjuvant, diluent or carrier. A pharmaceutically acceptable compound of formula (I) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph A pharmaceutical composition comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and at least one further pharmaceutically active agent. A pharmaceutically acceptable compound of formula (I) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph For preparing skin care products or hair care products or cosmetics comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and inert adjuvants, diluents or carriers Composition. A pharmaceutically acceptable compound of formula (II) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph A pharmaceutical composition comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and a pharmaceutically acceptable inert adjuvant, diluent or carrier. A pharmaceutically acceptable compound of formula (II) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph A pharmaceutical composition comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and at least one further pharmaceutically active agent. A pharmaceutically acceptable compound of formula (II) according to claim 1, a prodrug thereof, a geometric or optical isomer thereof, a polymorph thereof, said compound, said prodrug, said isomer or said polymorph For preparing skin care products or hair care products or cosmetics comprising possible esters, ethers, carbamates, oximes and solvates, hydrates and salts thereof and inert adjuvants, diluents or carriers Composition. The following compounds:
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 pharmaceutically acceptable inert compound with a compound selected from the group consisting of its prodrug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and all its salts A pharmaceutical composition comprising any adjuvant, diluent or carrier. The following compounds:
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;
At least one further pharmaceutically active compound selected from the group consisting of its prodrug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and all its salts A pharmaceutical composition comprising a drug. The following compounds:
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 its prodrug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and all its salts, and inert adjuvants, diluents Or a composition for preparing a skin care product or hair care product or cosmetic comprising a carrier. A method for treating, ameliorating or preventing a disease or condition mediated by an enzyme of the lipase gene family, wherein the activity of an enzyme belonging to the lipase gene family is inhibited to the extent that the disease or condition is treated, ameliorated or prevented A method comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) according to claim 1 sufficient to do or reduce. 2. The treatment, amelioration or prevention of a disease comprises reducing or inhibiting fat metabolism, absorption and accumulation at various levels including fluid levels, cellular levels and tissue levels in mammals. The method described in 1. The disease is selected from the group comprising overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease and metabolic disorders The method of claim 1, wherein: 2. The method of claim 1, comprising the treatment or prevention of cell or tissue damage caused by microbial pathogens that secrete lipases. 2. The method of claim 1, comprising treating a skin, hair or cosmetic condition. Inhibiting or reducing the activity of an enzyme belonging to the lipase gene family is sufficient to reduce or inhibit fat metabolism, absorption and accumulation in body fluids, cells and tissues. The method described. 2. 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 methods. A method for treating, ameliorating or preventing a disease or condition mediated by an enzyme of the lipase gene family, wherein the activity of an enzyme belonging to the lipase gene family is inhibited to the extent that the disease or condition is treated, ameliorated or prevented A method comprising administering to a mammal a therapeutically effective amount of a compound of formula (II) according to claim 1 sufficient to do or reduce. 2. The treatment, amelioration or prevention of a disease comprises reducing or inhibiting fat metabolism, absorption and accumulation at various levels including fluid levels, cellular levels and tissue levels in mammals. The method described in 1. The disease is selected from the group comprising overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease and metabolic disorders The method of claim 1, wherein: 2. The method of claim 1, comprising the treatment or prevention of cell or tissue damage caused by microbial pathogens that secrete lipases. 2. The method of claim 1, comprising treating a skin, hair or cosmetic condition. Inhibiting or reducing the activity of an enzyme belonging to the lipase gene family is sufficient to reduce or inhibit fat metabolism, absorption and accumulation in body fluids, cells and tissues. The method described. R ₁ and R ₂ of formula (II) independently of one another consist of C (O) aryl, C (O) alkylaryl, C (O) haloaryl, C (O) nitroaryl and C (O) alkoxyaryl The method of claim 1, wherein the method is selected from the group. In formula (II), R ₁ and R ₂ are independently of each other, methylphenylcarbonyl, ethylphenylcarbonyl, propylphenylcarbonyl, butylphenylcarbonyl, chlorophenylcarbonyl, bromophenylcarbonyl, iodophenylcarbonyl, fluorophenylcarbonyl, nitrophenylcarbonyl 2. The method of claim 1, wherein the method is selected from the group consisting of: methoxyphenylcarbonyl and ethoxyphenylcarbonyl. R ₁ and R _{2 in} formula (II) are independently of each other 2-methylphenylcarbonyl, 3-methylphenylcarbonyl, 4-methylphenylcarbonyl, 4-ter-butylphenylcarbonyl, 2-chlorophenylcarbonyl, 3-chlorophenyl. Carbonyl, 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-nitrophenylcarbonyl, 2-methoxyphenylcarbonyl, 3- Butoxy selected from phenylcarbonyl or the group consisting of 4-methoxyphenyl carbonyl method of claim 1. 2. 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 methods. A method for treating, ameliorating or preventing a disease or condition mediated by an enzyme of the lipase gene family, comprising:
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;
Treating or ameliorating said disease or condition with a compound selected from the group consisting of its prodrug, its geometric or optical isomer, its polymorph, all its solvates and hydrates and all its salts Or administering to a mammal in a therapeutically effective amount sufficient to inhibit or reduce the activity of an enzyme belonging to the lipase gene family to a degree that prevents it. 2. The treatment, amelioration or prevention of a disease comprises reducing or inhibiting fat metabolism, absorption and accumulation at various levels including fluid levels, cellular levels and tissue levels in mammals. The method described in 1. The disease is selected from the group comprising overweight or obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, hyperglycemia, atherosclerosis, metabolic syndrome, cardiovascular disease and metabolic disorders The method of claim 1, wherein: 2. The method of claim 1, comprising the treatment or prevention of cell or tissue damage caused by microbial pathogens that secrete lipases. 2. The method of claim 1, comprising treating a skin, hair or cosmetic condition. Inhibiting or reducing the activity of an enzyme belonging to the lipase gene family is sufficient to reduce or inhibit fat metabolism, absorption and accumulation in body fluids, cells and tissues. The method described. 2. 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 methods. A process as claimed in the above claims substantially as herein described with reference to the examples and figures.