Method of treating or preventing osteoporosis comprising administering to a patient in need thereof an effective amount of pharmacuetical composition comprising benzamidine derivative or it's salt, and bisphosphonate

A method of treating osteoporosis comprising administering to a patient in need thereof an effective amount of pharmaceutical composition comprising the following compounds (a) and (b) for the purpose of using simultaneously, separately, or sequentially as active ingredients:

• (a) a benzamidine derivative represented by the following Formula 1 or salt thereof, and
• (b) bisphosphonate represented by the following Formula 2,
• wherein R1 is C1˜C6 alkyl which is unsubstituted or substituted with pyridinyl;
• straight or branched C1˜C6 alkyl which is substituted with
• unsubstituted or substituted with hydroxy;
• C3˜C6 cycloalkyl;
• phenyl;
• benzyl;
• pyridinyl which is unsubstituted or substituted with C1˜C6 alkyl;
• guanidino;
• NR6R7;
• CH2NR6R7;
• group which is substituted with straight or branched C1˜C6 alkyl;
• or
• (wherein A is C1˜C6 alkyl, and m is an integer of 2 to 6);
• R2 is hydrogen;
• straight or branched C1˜C6 alkyl which is unsubstituted or substituted with NR8R9;
• C3˜C6 cycloalkyl;
• phenyl;
• benzyl;
• C2˜C6 alkenyl;
• carbonyl which is substituted with NR8R9;
• amino;
• dimethylamino;
• morpholinyl;
• thiomorpholinyl;
• 4-methylpiperazinyl;
• or straight or branched C1˜C6 alkyl which is substituted with hydroxy, C1˜C6 alkoxy, halogen, C3˜C6 cycloalkyl,
• imidazolyl, or pyrrolidinyl;
• R3 and R4 are each independently hydrogen;
• halogen;
• hydroxy;
• C1˜C6 alkyl which is unsubstituted or substituted with halogen;
• C3˜C6 cycloalkylamino;
• C1˜C6 alkoxy;
• C1˜C6 alkanoyloxy;
• C2˜C6 alkenyloxy;
• phenyl-C1˜C6 alkoxy;
• phenoxy;
• C2˜C6 alkenoyloxy or phenyl-C1˜C6 alkanoyloxy;
• C3˜C6 cycloalkyloxy which is substituted with one group selected from carboxy, esterified carboxy and amidated carboxy;
• or an aminooxy group;
• R5 is hydrogen or hydroxy group;
• R6 and R7 are each independently hydrogen;
• C1˜C6 alkyl which is unsubstituted or substituted with one group selected from hydroxy, C1˜C6 alkoxy, pyridine and
• phenyl;
• benzyl;
• pyridinyl;
• carbonyl which is substituted with one group selected from C1˜C6 alkyl, hydroxy, C1˜C6 alkyl substituted with hydroxy, C1˜C6 alkoxy, phenyl, benzyl, pyridine and
• or C1˜C6 alkanesulfonyl;
• R8 and R9 are each independently hydrogen;
• C1˜C6 alkyl which is unsubstituted or substituted with one group selected from hydroxy, C1˜C6 alkoxy, morpholine, imidazole and NR6R7;
• C1˜C6 alkoxy;
• C3˜C6 cycloalkyl;
• phenyl;
• benzyl;
• pyridinyl;
• morpholine;
• carbonyl which is substituted with one group selected from C1˜C6 alkyl, C1˜C6 alkoxy, phenyl, benzyl, pyridine and
• carbonyl which is substituted with C1˜C6 alkyl substituted with one group selected from halogen, C1˜C6 alkoxy and imidazole;
• or C1˜C6 alkanesulfonyl;
• R10 and R11 are each independently hydrogen, C1˜C2 alkyl, C1˜C3 alkoxy or halide;
• X1-X2-X3 is
• Y is O, S, NR6 or CH2 group;
• and
• n is an integer of 0, 1 and 2,
• wherein R12 is methyl, chloro, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 4-chlorophenylthio, 3-pyridylmethyl, (imidazo[1,2-a]pyridine-3-yl)methyl, 2-(N-methyl-N-n-pentyl)aminoethyl, cycloheptylamino, (1-imidazolyl)methyl or 1-pyrrolidinylethyl,
• R13 is hydrogen, chloro or hydroxy group,
• M is hydrogen or sodium, and
• Z is any number, preferably an integer of 0 to 7.