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Ep 1384475 A1 Europäisches Patentamt *EP001384475A1* (19) European Patent Office Office européen des brevets (11) EP 1 384 475 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 31/352, C07D 311/76, 28.01.2004 Bulletin 2004/05 A61P 1/16, A23L 1/30, A23K 1/16 (21) Application number: 02713236.4 (86) International application number: (22) Date of filing: 28.03.2002 PCT/JP2002/003098 (87) International publication number: WO 2002/080904 (17.10.2002 Gazette 2002/42) (84) Designated Contracting States: • KAYAHASHI, Shun, AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Tsukuba Research Laboratories MC NL PT SE TR Tsukuba-shi, Ibaraki 305-0841 (JP) Designated Extension States: • HASHIZUME, Erika, AL LT LV MK RO SI Tsukuba Research Laboratories Tsukuba-shi, Ibaraki 305-0841 (JP) (30) Priority: 05.04.2001 JP 2001106600 • NAKAGIRI, Ryusuke, Tsukuba Research Laboratories (71) Applicant: KYOWA HAKKO KOGYO CO., LTD. Tsukuba-shi, Ibaraki 305-0841 (JP) Chiyoda-ku, Tokyo 100-8185 (JP) (74) Representative: Casalonga, Axel et al (72) Inventors: BUREAU D.A. CASALONGA - JOSSE • SAKAI, Yasushi, Paul-Heyse-Strasse 33 Foods & Liquors Research Laborat. 80336 München (DE) Inashiki-gun, Ibaraki 300-0398 (JP) (54) LIVER FUNCION PROTECTING OR AMELIORATING AGENT (57) A liver function protecting or improving agent which comprises a compound represented by the formula (I) {in the formula (I), R1,R2,R3,R4,R5,R6,R7,R8and R9 may be the same or different, and represent hydrogen, halogen, hydroxy, alkoxy or alkyl; and RA represents the formula (II) EP 1 384 475 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 384 475 A1 [in the formula (II) , R10 and R11 may be the same or different, and represent hydrogen or halogen, or R10 and R11 together represent a binding] or the formula (III) [in the formula (III), R12 represents hydrogen, halogen, hydroxy, alkoxy, cyano or alkyl, R13 and R14 may be the same or different, and represent hydrogen or halogen, or R13 and R14 together represent a binding]} or a glycoside thereof or a pharmaceutically acceptable salt thereof. 2 EP 1 384 475 A1 Description Technical Field 5 [0001] The present invention relates to a liver function protecting or improving agent, a food and drink or a feed for protecting or improving liver functions, and an additive for foods and drinks or additives for feeds having liver function protecting or improving activity. Background of the Invention 10 [0002] The liver is an important organ which has various functions such as metabolic regulation and storage of sugar, protein and lipid which are three major nutrients, and decomposition and detoxification of substances unnecessary to the living body. These functions suffer acute or chronic disorders due to an excessive intake of alcohol, viral infection, bad eating habits, stress, smoking, etc. The advance of these disorders results in diseases such as acute hepatitis, 15 chronic hepatitis, hepatic cirrhosis, alcoholic fatty liver, hepatitis B and liver cancer. [0003] When liver cells are damaged by virus, alcohol, etc., enzymes such as aspartate aminotransferase (glutamic- oxaloacetic transaminase, hereinafter abbreviated as GOT) and alanine aminotransferase (glutamic-pyruvic transam- inase, hereinafter abbreviated as GPT) in the cells leak into the blood, which raise the values indicating the activities of these enzymes. Accordingly, the levels of GOT and GPT activities in the blood are known as indices of the levels 20 of the liver function disorders. [0004] Known drugs used for the prevention or treatment of the liver function disorders include antiviral agents such as acyclovir, immunosuppressive agents, glutathione and the like. Foods and drinks which are recognized to be effective for protecting, strengthening and improving the liver functions include for example, turmeric, milk thistle, sesame lignan, oyster extract, liver extract and the like. 25 [0005] However, a strong need consistently exists for the development of pharmaceutical agents which are effective in prevention or treatment of liver diseases, and of health foods and drinks or animal feeds which enable prevention or treatment of hepatopathy by daily intake. [0006] In connection with stilbenoid compounds, anti-allergic activities, anti-oxidative activities and anti-bacterial activities have been conventionally investigated on compounds isolated from Hydrangeae Dulcis Folium which is a 30 herbal medicine [Summary of Lectures at the 2nd Symposium on Medicines and Foods, p. 85, 1999, Nihon Yakuyou Shokuhin Gakkai Zyunbi Iinkai (Japanese Society of Medicated Foods, Preparatory Committee)], and the like. [0007] Reports have been made as follows on in vitro activities of the stilbenoid compounds. [0008] In regard to the anti-allergic activities, it is reported that release of histamine from mast cells induced by compound 48/80 or calcium ionophore A23187 is suppressed by thunberginol A - G (50% inhibitory concentration: 9.4 35 -92µM), but is not suppressed by phyllodulcin or phyllodulcin 8-O-glucoside, hydrangenol, hydrangenol 8-O-glucoside, hydramacrophyllol A and B at 100 µM [Bioorganic & Medicinal Chemistry, 7, 1445 (1999)]. [0009] The extract of Hydrangeae Dulcis Folium (2000 mg/kg) is reported to suppress rat skin passive anaphylaxis through oral administration [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)]. In addition, it is re- ported that phyllodulcin 8-O-glucoside (300 and 500 mg/kg), hydrangenol (500 mg/kg), hydrangenol 8-O-glucoside 40 (300 and 500 mg/kg), thunberginol A (300 and 500 mg/kg), thunberginol F (300 and 500 mg/kg) suppress rat skin passive anaphylaxis through oral administration, but phyllodulcin (300 and 500 mg/kg) does not suppress rat skin passive anaphylatic reaction [Biological & Pharmaceutical Bulletin, 22(8), 870 (1999)]. [0010] In connection with the anti-oxidative activities, it is reported that: as to DPPH (1,1-Diphenyl 2-Picrylhydrazyl) radical capturing capacity, the extract of Hydrangeae Dulcis Folium exhibits 50% capturing action at 0.099 mg, while 45 phyllodulcinexhibits this activityat 0. 208 mg, andhydrangenol at 1.074 mg; as to linoleic acid oxidation (iron rhodanate method), phyllodulcin exhibits more potent suppressive activity than α-tocopherol or BHA (Butylated Hydroxyanisole) , while hydrangenol exhibits a weak suppressive activity thereto; and as to NADP (Nicotinamide Adenine Dinucleotide Phosphate) H dependent lipid peroxidation in rat liver microsome, phyllodulcin exhibits a suppressive activity at a similar level to α-tocopherol, while hydrangenol exhibits a weak suppressive activity thereto [Natural Medicine, 49(1), 50 84(1995)]. [0011] In regard to anti-bacterial activity, it is reported that phyllodulcin at 1000 ppm exhibits a proliferation suppres- sive activity on Staphylococcus aureus and Staphylococcus epidemidis (Japanese Published Unexamined Patent Ap- plication No. 43460/93), and phyllodulcin and hydrangenol exhibit an anti-bacterial activity on Bacteroides melanino- genicus and Fusobacterium nucleatum with the minimum growth inhibitory concentration of 1. 25 - 2.5 ppm (Japanese 55 Published Unexamined Patent Application No. 92829/94). [0012] In regard to differentiation-inducing activity on leukocyte [Chemical & Pharmaceutical Bulletin, 48(4), 566 (2000)], isocoumarins such as thunberginol A (active at 100 µM) are reported to have more potent activity in vitro than dihydroisocoumarin such as phyllodulcin or hydrangenol (active at 300 µM). In addition, hydrangenol is reported to 3 EP 1 384 475 A1 have a hyaluronidase inhibitory activity [Planta Medica, 54, 385 (1988)]. [0013] Moreover, it is reported that the extract of Hydrangeae Dulcis Folium (500 mg/kg) exhibits a cholagogic activity in an in vitro test, however, phyllodulcin (200 mg/kg) and hydrangenol (200 mg/kg) do not exhibit this activity [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)]. 5 [0014] Furthermore, it is reported that the extract of Hydrangeae Dulcis Folium (200 and 400 mg/kg, oral adminis- tration) suppresses rat gastric ulcer induced by ethanol hydrochloride, however, phyllodulcin (75 mg/kg, oral adminis- tration) and hydrangenol (75 mg/kg, oral administration) do not suppress the ulcer [Journal of the Pharmaceutical Society of Japan, 114(6), 401 (1994)] 10 Disclosure of the Invention [0015] An object of the present invention is to provide a liver function protecting or improving agent, a food and drink or a feed for protecting or improving liver functions, and an additive for foods and drinks or an additive for feeds for protecting or improving liver functions. 15 [0016] The present invention relates to the following (1) to (15) . (1) A liver function protecting or improving agent which comprises a compound represented by the formula (I) 20 25 30 35 {in the formula (I), R1,R2,R3,R4,R5,R6,R7,R8and R9 may be the same or different, and represent hydrogen, halogen, hydroxy, alkoxy or alkyl; and RA represents the formula (II) 40 45 [in the formula (II), R10 and R11 may be the same or dif ferent , and represent hydrogen or halogen, or R10 and R11 together represent a binding] or the formula (III) 50 55 4 EP 1 384 475 A1 5 10 [in the formula (III), R12 represents hydrogen, halogen, hydroxy, alkoxy, cyano or alkyl, R13 and R14 may be the same or different, and represent hydrogen or halogen, or R13 and R14 together represent a binding]} or a glycoside thereof [hereinafter referred to as compound (I)] or a pharmaceutically acceptable salt thereof. (2) The liver function protecting or improving agent according to (1), wherein R1,R3,R5,R8and R9 represent 15 hydrogen. (3) The liver function protecting or improving agent accordingto (1) or (2) , wherein R2 represents hydrogen or hydroxy, R4 represents hydroxy, R6 and R7 may be the same or different, and represent hydrogen, hydroxy or alkoxy. (4) The liver function protecting or improving agent according to any one of (1) to (3), wherein RA represents the 20 formula (II). (5) The liver function protecting or improving agent according to any one of (1) to (3) , wherein RA represents the formula (III).
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