Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-03-18
2004-03-16
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S563000, C562S426000, C562S430000, C562S442000, C562S451000, C564S152000, C564S154000, C564S156000
Reexamination Certificate
active
06706763
ABSTRACT:
TECHNICAL FIELD
The present invention relates to o-anisamide derivatives effective for the prevention and/or therapy of metabolic diseases such as hyperlipidemia and diabetes, in which peroxisome proliferator-activated receptor (PPAR) being intranuclear receptor, in particular, human PPAR participates, as agonistic drugs thereon, their addition salts, processes for preparing them, and medicinal compositions containing these compounds.
BACKGROUND TECHNOLOGIES
The peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor that belongs to intranuclear receptor superfamily similarly to steroid receptor, retinoid receptor, thyroid receptor, etc., and three isoforms (&agr; type, &bgr;(or &dgr;) type and &ggr; type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). There among, the PPAR&agr; is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, particularly in the liver, high expression is recognized (Endocrinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and triglyceride. Moreover, the PPAR&ggr; is highly expressed in the fat cells and takes part in the differentiation of fat cells (J. Lipid Res., 1996, 37, 907), and so on. In such way, each isoform of PPAR is fulfilling a specific function in the particular organs and tissues.
Additionally, it is reported that a knock-out mouse of PPAR&agr; exhibits hyper triglyceridemia with ageing and becomes obesity mainly by increased white adipocytes (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARa and lowering action of lipids (cholesterol and triglyceride) in blood is suggested strongly. Similarly, it is ascertained that the major intracellular target proteins of Troglitazone, Pioglitazone and Rosiglitazone being thiazolidine-2,4-dione derivatives that exhibit blood glucose-lowering action and improving action on hyperinsulinemia are PPAR&ggr;s, and they increase the transcriptional activity of PPAR&ggr; (Endocrinology, 1996, 137, 4189, Cell., 1995, 83, 803 and 813). Hence, the relevance between activation of PPAR&ggr; and glucose-lowering action is suggested strongly.
When considering such functions of transcriptional factor called PPAR, for a compound that activates human PPAR, medicinal use aiming at the lowering action of lipids (cholesterol and triglyceride) in blood and/or the blood glucose-lowering action can be expected.
For compounds having an affinity to PPAR&agr; as ligands of PPAR&agr;, eicosanoides, in particular, 8-hydroxyeicosatetraenoic acid (8-HETE) and 8-hydroxyeicosapentaenoic acid (8-HEPE) are reported (Proc. Natl. Acad. Sci., 1997, 94, 312).
However, these endogenous unsaturated fatty acid derivatives are unstable and difficult to be offered as medicinal drugs, and, at the same time, they have different structure from the inventive compounds. Moreover, compounds having agonistic action on PPAR&agr; are reported in WO-97/25042, WO-97/36579, etc., but all of these have different structure from the inventive compounds and, at the same time, the effect of agonistic action is also never satisfied in strength. For compounds having agonistic action on PPAR&ggr;, a series of thiazolidine-2,4-dione derivatives are known in Japanese Unexamined Patent Publication Nos. Sho 60-51189, Sho 61-267580, Hei 1-131169, etc. However, all have different structure from the inventive compounds.
It is pointed out that the hyperlipidemia and the diabetes are principal diseases that modern times have to tackle and, at the same time, these become risk factors and link up with the atherosclerotic diseases, in particular, coronary atherosclerotic disease. Hence, from a viewpoint of the therapy or prevention thereof, the development of a therapeutic drug for metabolic diseases being effective and having high safety based on new action is desired strongly.
DISCLOSURE OF THE INVENTION
As a result of diligent studies paying an attention to the specific roles on the lipometabolism, adipocyte differentiation, of human PPAR, and aiming at the creation of structurally novel drug with high effectiveness and safety as a therapeutic drug for metabolic diseases, the inventors have found that o-anisamide derivatives represented by a following general formula (1) have excellent agonistic action on human PPAR and are useful as therapeutic drugs for metabolic diseases, leading to the completion of the invention.
Namely, the invention relates to o-anisamide derivatives represented by a general formula (1)
[wherein R denotes a carboxyl group, carboxymethyl group or CH
2
CHXCOY (here X denotes a mercapto group or S(O)nMe (n=0, 1 or 2) and Y denotes an amino group or hydroxyl group)], their medicinally acceptable salts and their hydrates.
The medicinally acceptable salts of the compounds represented by the general formula (1) in the invention are of common use and metal salts, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.) and aluminum salt are mentioned.
Moreover, the compounds, R being CH
2
CHXCOY, in the general formula (1) of the invention include optically active substances based on asymmetric carbon, and further, in the case of X being SOMe group, they include stereoisomers based on their three dimensions, but all of these isomers and mixtures are to be included in the scope of the invention.
According to the invention, compounds (1), being said general formula (1), can be prepared through processes shown in following diagram.
Namely, compounds represented by a general formula (1-a) can be prepared by condensation, leaving carboxyl group as it is or after converted it to reactive derivative according to usual method in the process shown in the diagram above.
In the case of conducting the reaction by leaving carboxylic acid as it is, the reaction can be performed in an inert solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and further in the presence or absence of additive. As the condensing agent, for example, dicyclohexylcarbodiimide,l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphonate, diphenylphosphoryl azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned.
In the case of using reactive derivative, the reaction can be performed in an inert solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base. As the reactive derivative, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like can be mentioned. The reaction can be performed at a reaction temperature of −20° C. to 100° C., preferably 0° C. to room temperature.
Compounds represented by a general formula (1-b) can be prepared by oxidation using usual oxidizing agent, followed by, if need be, hydrolysis. Namely, in the case of R1 being formyl group, the reaction can be performed using usual oxidizing agent, for example, chromium oxide, potassium permanganate, silver oxide or peroxide, but the oxidation using Jones reagent that uses chromic acid is preferable. The reaction temperature is preferable to be u
Awano Katsuya
Komuro Masakatsu
Murakami Koji
Satoh Hiroya
Kyorin Pharmaceutical Co. Ltd.
Richter Johann
Zucker Paul A.
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