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(12) Patent Application Publication (10) Pub. No.: US 2010/0216747 A1 Ochiai Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0216747 A1 Ochiai Et Al US 2010O216747A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0216747 A1 Ochiai et al. (43) Pub. Date: Aug. 26, 2010 (54) PREVENTIVE AGENT OR THERAPEUTIC Related U.S. Application Data AGENT FOR DISEASE CAUSED BY (60) Provisional application No. 60/935,262, filed on Aug. ABNORMAL BONE METABOLISM 2, 2007. (75) Inventors: Eiji Ochiai, Hino-shi (JP); Miyuki Publication Classification Nishiga, Hino-shi (JP); Kenichiro (51) Int. Cl. Takagi, Hino-shi (JP); Yoshiaki A6II 3/663 (2006.01) Azuma, Hino-shi (JP) A63/675 (2006.01) A6IP 9/08 (2006.01) Correspondence Address: (52) U.S. Cl. .............. 514/89: 514/108: 514/107: 514/94. SUGHRUE MION, PLLC 2100 PENNSYLVANIA AVENUE, N.W., SUITE (57) ABSTRACT 8OO An object of the present invention is to provide a preventive WASHINGTON, DC 20037 (US) drug and a therapeutic drug for diseases caused by abnormal bone metabolism, especially osteoporosis, which is more (73) Assignee: TEIJIN PHARMA LIMITED, effective than conventional drugs. Combined use of N-hy Chiyoda-ku, Tokyo (JP) droxy-4-5-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phe noxylpentoxy-benzamidine, or a salt thereof; and at least (21) Appl. No.: 12/671,414 one compound selected from the group consisting of etidronic acid, clodronic acid, pamidronic acid, tiludronic (22) PCT Filed: Aug. 1, 2008 acid, risedronic acid, minodronic acid, ibandronic acid, Zoledronic acid, and salts thereof can exert higher bone (86). PCT No.: PCT/UP2008/063864 resorption inhibitory effect and provide a preventive effect and a therapeutic effect for diseases caused by abnormal bone S371 (c)(1), metabolism, especially osteoporosis as compared with (2), (4) Date: Apr. 26, 2010 administration of the respective agents respectively. Patent Application Publication Aug. 26, 2010 Sheet 1 of 3 US 2010/0216747 A1 Figure 1 Effect of combined use of Compound A (10M) and s risedronic acid (3 x 10M) s (5 4. O 8 20 s 9 100 80 2 60 t 40 g 2O added and concentration PBS Risedronic acid 3 x 10M Comparative Comparative Comparative Example 1-1 Example 1-2 Example 1-3 Example 1 Patent Application Publication Aug. 26, 2010 Sheet 2 of 3 US 2010/0216747 A1 Figure 2) SSG Effect of combined use of Compound A (10M) and 9. s risedronic acid (3 x 10M) g O NS. O O S. -- 3.d 8n s d bO GD c) H d R DMSO Compound A 10M DMSO Compound A O'M Compound added and concentration PBS Risedronic acid 3 x 10'M Comparative Comparative Comparative Example 2-1 Example 2-2 Example 2-3 Example 2 Patent Application Publication Aug. 26, 2010 Sheet 3 of 3 US 2010/0216747 A1 Figure 3 Effect of combined use of Compound A (10M) and clodronic acid (10M) 140 120 OO 80 60 40 20 O Compound DMSO Compound A OM DMSO Compound A 10M added and awa-no-mimesms concentration PBS Clodronic acid Comparative Comparative Comparative 1 OM- 5 Example 3-1 Example 3-2 Example 3-3 Example 3 US 2010/0216747 A1 Aug. 26, 2010 PREVENTIVE AGENT OR THERAPEUTIC 0006 Patent Document 1: Japanese Unexamined Patent AGENT FOR DISEASE CAUSED BY Application Publication No. 2004-537549 ABNORMAL BONE METABOLISM 0007 Non-patent Document 1: Lee Sung-eun, Synthesis and Biological Activity of Natural Products and Designed New Hybrid Compounds for the Treatment of LTB4 Related TECHNICAL FIELD Disease, Graduate School of Pusan National University, 0001. The present invention relates to a preventive or Department of Science, Doctoral dissertation, 1999.8 therapeutic agent for diseases caused by abnormal bone 0008. Non-patent Document 2: R Samad fam et al., Endo metabolism, particularly to a preventive or therapeutic agent crinology, Vol. 148, No. 6, 2007 for osteoporosis, and specifically to a preventive or therapeu 0009. Non-patent Document 3: DM Blacket al., The New tic agent for diseases caused by abnormal bone metabolism, England Journal of Medicine, Vol. 349, No. 13, 2003 especially osteoporosis, containing, as active ingredients, N-hydroxy-4-5-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl) DISCLOSURE OF THE INVENTION phenoxylpentoxy-benzamidine, or a salt thereof, and at least Problems to be Solved by the Invention one compound selected from the group consisting of 0010. An object of the present invention is to provide a etidronic acid, clodronic acid, pamidronic acid, tiludronic drug or a therapeutic or preventive method that is more effec acid, risedronic acid, minodronic acid, ibandronic acid, tive as a therapeutic or preventive agent and a therapeutic or Zoledronic acid, and salts thereof. preventive method for diseases caused by abnormal bone metabolism, especially osteoporosis than existing drugs. 0011. The present inventors have keenly studied ingredi BACKGROUND ART ents that are effective as a therapeutic or preventive agent for 0002 N-hydroxy-4-5-4-(5-isopropyl-2-methyl-1,3- diseases caused by abnormal bone metabolism, especially thiazol-4-yl)phenoxylpentoxy-benzamidine represented by osteoporosis, and found that combined use of specific drugs, formula (I) or a salt thereof has a bone resorption inhibitory each of which can be used alone, can provide a therapeutic or effect and a bone formation promoting effect, and is expected preventive agent or a therapeutic or preventive method for diseases caused by abnormal bone metabolism, especially as a therapeutic or preventive agent for osteoporosis. osteoporosis that has extremely high efficacy. 0012. In other words, the present invention is a preventive Formula 1 ortherapeutic agent or a preventive or therapeutic method for diseases caused by abnormal bone metabolism, especially osteoporosis, containing as active ingredients, the following X. N -OH (a) and (b): S ea I0013 (a) N-hydroxy-4-5-4-(5-isopropyl-2-methyl-1,3- NH2 thiazol-4-yl)phenoxylpentoxy-benzamidine or a salt thereof, and 1n 1a1n 0014 (b) at least one compound selected from the group consisting of etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, minodronic acid, 0003 N-hydroxy-4-5-4-(5-isopropyl-2-methyl-1,3- ibandronic acid, Zoledronic acid, and salts thereof. thiazol-4-yl)phenoxylpentoxy-benzamidine, or a salt 0015. Further, the present invention is a preventive or thereof is disclosed in Patent Document 1 and Non-patent therapeutic agent for diseases caused by abnormal bone Document 1. metabolism, especially osteoporosis, containing as active 0004 Etidronic acid, clodronic acid, pamidronic acid, ingredients (a) and (b), in a form of a combination drug or tiludronic acid, risedronic acid, minodronic acid, ibandronic independent single drugs. acid, Zoledronic acid, or salts thereof are considered to act specifically on activated osteoclasts and Suppress bone Effect of the Invention resorption by Suppressing their activity, and used as therapeu 0016. The present invention is a preventive or therapeutic tics agent for diseases caused by abnormal calcium metabo drug or a preventive or therapeutic method for diseases lism Such as osteoporosis and the like. caused by abnormal bone metabolism, especially osteoporo 0005. A large number of therapeutic agents for osteoporo sis, wherein N-hydroxy-4-5-4-(5-isopropyl-2-methyl-1,3- sis are currently available. Therapeutic effects of combined thiazol-4-yl)phenoxylpentoxy-benzamidine, or a salt use of these agents are varied, however. For example, a com thereof, and at least one compound selected from the group bination of PTH (parathyroid hormone) and a certain bispho consisting of etidronic acid, clodronic acid, pamidronic acid, sphonic acid is known to cancel their therapeutic effect each tiludronic acid, risedronic acid, minodronic acid, ibandronic other. Although both agents are representative therapeutic acid, Zoledronic acid, and salts thereof; are administered in agents for osteoporosis, it has been reported as the results of combination, by which an extremely strong preventive or a preclinical study and a clinical study that their effects were therapeutic effect can be obtained as compared with the effect reduced when they were administered in combination as obtained by either ingredient alone. compared with the effects obtained when they were admin istered alone, respectively (Non-patent Documents 2 and 3). BRIEF DESCRIPTION OF DRAWINGS It is not easily conceivable to discover a therapeutic or pre 0017 FIG. 1 is a graph showing an inhibitory effect on the ventive method having higher efficacy using an existing or number of formed osteoclast-like cells of a solvent, N-hy novel therapeutic agent for osteoporosis, as is also considered droxy-4-5-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phe from this example. noxylpentoxy-benzamidine (Compound A) and risedronic US 2010/0216747 A1 Aug. 26, 2010 acid that were used respectively or in combination of two of Zoledronic acid, and salts thereof. The combined use provides them in the experimental system in which osteoclast-like cells a stronger effect than the use of the respective ingredients were formed by adding 1C.25(OH), D to mouse bone mar alone as a preventive or therapeutic agent or a preventive or row-derived cells and culturing the cells for 7 days. therapeutic method for osteoporosis. 0018 FIG. 2 is a graph showing the inhibitory effect on the 0025 Among etidronic acid, clodronic acid, pamidronic number of formed osteoclast-like cells of a solvent, N-hy acid, tiludronic acid, risedronic acid, minodronic acid, iban droxy-4-5-4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phe dronic acid, Zoledronic acid, or a salt thereof used in the noxylpentoxy-benzamidine (Compound A) and risedronic present invention, clodronic acid or risedronic acid is prefer acid that were used respectively or in combination of two of able, and risedronic acid is more preferable. When these are them in the experimental system in which osteoclast-like cells used in combination with N-hydroxy-4-5-4-(5-isopropyl were formed by adding 1C.25(OH), D to mouse bone mar 2-methyl-1,3-thiazol-4-yl)phenoxylpentoxy-benzamidine, row-derived cells and culturing the cells for 7 days.
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