Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-25
2004-05-04
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S183000
Reexamination Certificate
active
06730687
ABSTRACT:
TECHNICAL FIELD
The present invention relates to substituted benzylthiazolidine-2,4-dione derivatives effective for the prevention and/or therapy of metabolic diseases such as diabetes and hyperlipidemia as agonists of peroxisome proliferator-activated receptor (abbreviated as PPAR) being nuclear receptor, in particular, as agonists of human PPAR, 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 nuclear 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). Thereamong, the PPAR&agr; is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, particularly high expression is recognized in the liver, (Endo-crinology, 1995, 137, 354), positively or negatively controlling the expressions of genes related 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 related to the metabolisms of cholesterol and neutral lipid. The PPAR&bgr; is expressed ubiquitously in the tissues or organisms, including nerve cells. At present, the physiological significance of PPAR&bgr; is unclear. The PPAR&ggr; is highly expressed in the adipocytes and contributed to the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR play specific functions in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPAR&agr; exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPAR&agr; and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing action of cholesterol. while the statins have weak decreasing action of free fatty acids and triglycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function.
On the other hand, it is ascertained that the major intracellular target proteins of Troglitazone, Pioglitazone and Rosiglitazone, a series of thiazolidine-2,4-dione derivatives that are therapeutic drugs for type II diabetes (noninsulin-dependent diabetes) and exhibit blood sugar-decreasing action, improving action on hyperinsulinemia, etc. is PPAR&ggr;, and these drugs increase the transactivation of PPAR&ggr; (Endocrinology, 1996, 137, 4189, Cell., 1995, 83, 803, Cell., 1995, 83, 813). Hence, PPAR&ggr;-activator (agonist) that can augment the transactivation of PPAR&ggr; is important as antidiabetic drug.
As described, when considering the role of transcription factor called PPAR on the function on adipocytes and the controlling mechanisms of glucose metabolism and lipid metabolism, if a compound that binds directly to as a ligand of PPAR, in particular, human PPAR and can activate human PPAR could be created, it would be reasonable to expect the medicinal use as a compound that exhibits blood glucose-decreasing action and/or decreasing action of lipids (both of cholesterol and neutral lipid) in blood due to very specific mechanism.
For compounds having an affinity to PPAR&agr; as ligands of PPAR&agr;, HETE (hydroxyeicosatetraenoic acid) produced via oxidation with cytochrome P-450 and eicosanoides in HEPE (hydroxyeicosapentaenoic acid) groups, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB., being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
Moreover, with Toroglitazone, the occurrence of serious adverse effect on liver is reported rarely, hence the development of a therapeutic drug for type II diabetes with effectiveness and high safety is being sought.
Now, as compounds with similar structure to the inventive substituted benzylthiazolidine-2,4-dione derivatives, thiazolidine-2,4-dione derivatives in Japanese Unexamined Patent Publication Nos. Sho 55-22636, Sho 60-51189, Sho 61-85372, Sho 61-286376, Hei 1-131169, Hei 2-83384, Hei 5-213913, Hei 8-333355, Hei 9-48771 and Hei 9-169746, European Patent Open No. 0441605, WO-92/07839, etc. are known. However, all of these compounds are thiazolidine-2,4-dione derivatives with different structure from the inventive compounds.
With regard to patents etc. reporting the agonistic effect on PPAR&agr;, WO-97/25042, WO-97/36579, etc. are reported, but all of these have different structure from the inventive compounds and the transactivation function of PPAR&agr; is also never satisfied in strength.
Both the hyperlipidemia and the diabetes are risk factors of arterosclerosis and, from a viewpoint of the prevention of arterosclerosis, in particular, coronary arterosclerosis, the development of a therapeutic drug for metabolic diseases with effectiveness and high safety is desired clinically.
DISCLOSURE OF THE INVENTION
As a result of diligent studies paying an attention to such specific role on the lipid metabolism of human PPAR, aiming at the creation of structurally novel drug with effectiveness and high safety as a therapeutic drug for diabetes and a therapeutic drug for hyperlipidemia, the inventors have found that novel substituted benzylthiazolidine-2,4-dione derivatives represented by a following general formula (1) have excellent transactivation function on human PPAR, and exhibit the blood glucose-decreasing action and the lipid-decreasing action, leading to the completion of the invention.
Namely, the invention relates to substituted benzylthiazolidine-2,4-dione derivatives represented by a general formula (1)
[wherein the bond mode of A denotes —CH
2
CONH—, —NHCONH—, —CH
2
CH
2
CO— or —NHCOCH
2
—, and B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoro-methoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents], their medicinally acceptable salts and their hydrates.
The 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 (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), aluminum salt, and other pharmacologically acceptable salts are mentioned.
Moreover, the compounds represented by the general formula (1) in the invention sometimes include optical isomers based on thiazolidine-2,4-dione ring portion, but all of such isomers and their mixtures are to be included in the scope of the invention.
Furthermore, for the compounds represented by the general formula (1), the existence of various tautomers is considered. These are, for example, as shown in the following formulae.
[wherein the bond mode of A denotes —CH
2
CONH—, —NHCONH—, —CH
2
CH
2
CO— or —NHCOCH—, and B denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have subs
Miyachi Hiroyuki
Murakami Koji
Nomura Masahiro
Tanase Takahiro
Tsunoda Masaki
Anderson Rebecca
Kyorin Pharmaceutical Co. Ltd.
McKane Joseph K.
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