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(12) Patent Application Publication (10) Pub. No.: US 2003/0153538A1 Kuno Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0153538A1 Kuno Et Al US 2003.0153538A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0153538A1 Kuno et al. (43) Pub. Date: Aug. 14, 2003 (54) ANTITUMORAGENT (30) Foreign Application Priority Data (75) Inventors: Noriyasu Kuno, Yokosuka-Shi (JP); Gou Shinohara, Yokosuka-Shi (JP); Jul. 31, 2000 (JP)...................................... 2OOO-23O254 Toshiyuki Inui, Yokosuka-Shi (JP) Nov. 30, 2000 (JP)...................................... 2OOO-366297 Correspondence Address: Publication Classification BURNS, DOANE, SWECKER & MATHIS, L.L.P. P.O. Box 1404 (51) Int. Cl. ................................................. A61K 31/56 Alexandria, VA 22313-1404 (US) (52) U.S. Cl. ............................................ 514/169; 514/557 (73) Assignee: The Nisshin OilliO, Ltd. (21) Appl. No.: 10/355,201 (57) ABSTRACT (22) Filed: Jan. 31, 2003 The present invention relates to an antitumor agent, which Related U.S. Application Data comprises, as an effective component, a compound Selected from the group consisting of maslinic acid, erythrodiol, (63) Continuation of application No. PCT/JP01/06393, uVaol, betulinic acid, betulin and physiologically acceptable filed on Jul. 25, 2001. salts thereof or derivatives thereof. US 2003/O153538A1 Aug. 14, 2003 ANTITUMORAGENT well (Cancer Letters, 1986, 30: 143-151 or Japanese Un Examined Patent Publication (hereunder referred to as “J.P. BACKGROUND OF THE INVENTION KOKAI”) No. Sho 63-57519). With respect to tumor cells, which have already been developed, urSolic acid is known to 0001. The present invention relates to an orally and/or have a cell-metastasis-inhibitory effect although the tumor parenterally administered antitumor agent comprising, as an cell-proliferation-inhibitory effect and tumor cell-killing (or effective component, at least one member Selected from the necrosis) action have not yet been confirmed (J.P. KOKAI group consisting of Specific 5-membered ring-containing No. Hei 9-143076). Up to date, however, it has never been triterpenes and physiologically acceptable Salts thereof or known that specific 5-membered ring-containing triterpenes derivatives thereof. and physiologically acceptable Salts thereof or derivatives 0002 Recently, the mortality rate of cancer or tumor has thereof including those, which have been known to have basically been apt to increase in Japan (in 1997), while it has carcinogenic promoter-inhibitory activity possess, for basically been Switched off to reducing tendency, at long instance, a tumor cell-proliferation-inhibitory effect, a tumor last, in the United States of America (in 1995), but the cancer cell-necrosis effect and a tumor cell-metastasis-inhibitory or tumor has still taken the Second place as the cause of effect. death. DISCLOSURE OF THE INVENTION 0.003 Contrary to this, the mechanism of the cancer development has been elucidated in the molecular level due 0008. It is an object of the present invention to provide an to the recent intensive and extensive investigations and orally and/or parenterally administered anti-V agent com studies. The fruits of these efforts or studies make it clear prising, as an effective component, at least one member that various chemical Substances can control various Steps of Selected from the group consisting of Specific 5-membered the cancer-developing processes and they have been ring-containing triterpenes and physiologically acceptable employed as pharmaceutical agents having antitumor Salts thereof or derivatives thereof and a method for using actions. the Same. More particularly, it is an object of the present 0004. These antitumor agents show their effects in accor invention to provide an antitumor agent having a tumor dance with different mechanisms, respectively and there cell-proliferation-inhibitory effect, a tumor cell-necrosis fore, they permit effective treatments by Successfully com effect and a tumor cell-metastasis-inhibitory effect as well as bining them. Moreover, if a drug has continuously been a method for using the same. used, it has been pointed out that a problem of So-called 0009. The inventors of this invention have conducted tolerance arises. If taking into consideration the foregoing, various Studies to achieve the foregoing objects, have found the existence of a wide variety of antitumor agents is quite that Specific 5-membered ring-containing triterpenes and desirable. physiologically acceptable Salts thereof or derivatives 0005 Furthermore, there have conventionally been used thereof possess excellent tumor cell-proliferation-inhibitory, various kinds of chemical Substances as antitumor agents tumor cell-necrosis (or killing) and tumor cell-metastasis possessing antitumor actions. They have, on the one hand, inhibitory effects and have thus completed the present Strong antitumor actions, but on the other hand, they have invention. Such a Side effect that they have harmful or injurious actions 0010 More specifically, the present invention relates to on not only the tumor cells, but also the normal cells. For this an antitumor agent comprising, as an effective component, reason, it is quite obvious that desirable antitumor agents one or at least two members Selected from the group should have a lower cytotoxicity and high Safety. consisting of maslinic acid, erythrodiol, urSolic acid, uVaol, 0006. On the other hand, the 5-membered ring-containing betulinic acid, betulin and physiologically acceptable Salts triterpenes belong to a kind of triterpenes, they are usually thereof or derivatives thereof, preferably relates to an anti 5-membered ring-containing compounds each consisting of tumor agent having a tumor cell-proliferation-inhibitory Six isoprene units in the molecule and the number of carbon effect, preferably relates to an antitumor agent having a atoms thereof is fundamentally 30, but the number of carbon tumor cell-killing effect and preferably relates to an antitu atoms included in the triterpenes may vary through the mor agent having a tumor cell-metastasis-inhibitory effect. rearrangement, oxidation, elimination or alkylation in the 0011. In addition, the present invention preferably relates processes for the biosynthesis of the Same. Moreover, they to an antitumor agent comprising, as an effective compo are in general classified on the basis of their skeletons and nent, maslinic acid and/or a physiologically acceptable Salt examples thereof include oleanane type triterpenes, urSane thereof, preferably relates to an antitumor agent having a type triterpenes, lupane type triterpenes, hopane type triter tumor cell-proliferation-inhibitory effect, preferably relates penes, Serratane type triterpenes, friedelane type triterpenes, to an antitumor agent having a tumor cell-killing effect and taraxerane type triterpenes, taraxastane type triterpenes, preferably relates to an antitumor agent having a tumor multi-furolane type triterpenes and germanicane type triter cell-metastasis-inhibitory effect. peneS. 0012. In this connection, the maslinic acid, erythrodiol, 0007. They in general have an anti-inflammatory effect urSolic acid, uVaol, betulinic acid and betulin used in the and an anti-carcinogenic promoter activity and therefore, it present invention may be those extracted from naturally has been known that they may be used as prophylactic occurring raw materials or may be any commercially avail medicine (Bulletin of the Society of Oil Chemistry in Japan, able reagents. In addition, the physiologically acceptable 2000, 49: 571) Moreover, in this respect, it has already been Salts and derivatives thereof may likewise be those extracted known that oleanolic acid, erythrodiol, glycyrrhetic acid or from naturally occurring raw materials or may be any the like have a carcinogenic promoter-inhibitory activity, as Synthesized products prepared through Synthetic reactions US 2003/O153538A1 Aug. 14, 2003 using Such extract as raw materials. In particular, it is 0018 Moreover, the present invention preferably relates preferred to use those isolated from naturally occurring raw to an antitumor agent comprising, as an effective compo materials. nent, maslinic acid and/or a physiologically acceptable Salt thereof. 0013 Moreover, the present invention relates to a method 0019 Maslinic acid is a compound present in, for of using, as an antitumor agent, at least one member Selected instance, olives, hops, peppermints, pomegranates, clove, from the group consisting of maslinic acid, erythrodiol, Sage and jujubes and the physiologically acceptable Salts urSolic acid, uVaol, betulinic acid, betulin and physiologi thereof are those derived from the group: -COOH in the cally acceptable salts thereof or derivatives thereof. In chemical formula (I) and the kinds of Salts are not restricted particular, the present invention likewise relates to a method to specific ones and may be those commonly used in foods of using at least one member Selected from the group and beverages or medical compositions. consisting of maslinic acid, erythrodiol, urSolic acid, uvaol, betulinic acid, betulin and physiologically acceptable Salts 0020. The term “comprising, as an effective component” thereof or derivatives thereof, for achieving at least one of used herein means that an antitumor agent contains an the following effects: a tumor cell-proliferation-inhibitory effective component in Such an amount Sufficient for achiev effect, a tumor cell-killing effect and a tumor cell-metastasis ing the desired tumor cell-proliferation-inhibitory, tumor inhibitory effect, as well as a method of using at least
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