Prophylactic or therapeutic agent for diseases associated with abnormal bone metabolism

A technology of abnormal bone metabolism and preventive medicine, which is applied in the field of diseases, and N-hydroxybenzamidine derivatives or their salts shown in activity, especially in the treatment of osteoporosis, which can solve the problems that are not easy to find and have better effects. Treatment or prevention methods, diminished efficacy, etc.

Inactive Publication Date: 2012-03-21
TEIJIN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although both are representative drugs for the treatment of osteoporosis, it has been reported that in the results of preclinical and clinical trials, the curative effect of combined administration is weakened compared with that of each alone (non-patent literature 3, 4)
In addition, with regard to active vitamin D or its prodrug, it has also been reported that in combination with vitamin K, which has an action of fixing calcium in bone, similar to the above-mentioned PTH and bisphosphonic acid, the results of clinical trials Among them, the curative effect of combined administration was weakened compared with that of each alone (Non-Patent Document 5)
[0008] From the above examples, it is not easy to find a better treatment or prevention method using existing or new osteoporosis treatment drugs

Method used

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  • Prophylactic or therapeutic agent for diseases associated with abnormal bone metabolism
  • Prophylactic or therapeutic agent for diseases associated with abnormal bone metabolism
  • Prophylactic or therapeutic agent for diseases associated with abnormal bone metabolism

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] N-Hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentyloxy}-benzamidine (compound 1) and 1α, 25-dihydroxyvitamin D 3 Effect on cell proliferation of ROS17 / 2.8 cells ( figure 1 ,Table 2)

[0180] ROS17 / 2.8 cells were divided into 2×10 4 Plates / well density were seeded in 96-well plates. As the medium, αMEM medium supplemented with 10% fetal calf serum (hereinafter referred to as 10% FCS-αMEM) was used. After culturing overnight, the medium was removed from each well, and then αMEM medium supplemented with 0.5% fetal bovine serum (hereinafter referred to as 0.5% FCS-αMEM) was added. After culturing for about 6 hours, the medium was removed from each well, and a solution containing DMSO and ethanol (hereinafter referred to as solution 1), compound 1 solution and ethanol (hereinafter referred to as solution 2), 1α,25-dihydroxyvitamin D 3 solution and DMSO (hereinafter referred to as solution 3), or compound 1 solution and 1α, 25-dihydroxyvitamin D 3...

Embodiment 2

[0187] N-hydroxy-4-5-[4-(2-dipropylamino-5-ethyl-1,3-thiazol-4-yl)phenoxy]pentyloxy-benzamidine (compound 11) and 1α, 25-Dihydroxyvitamin D 3 Effect on cell proliferation of ROS17 / 2.8 cells ( figure 2 ,table 3)

[0188] ROS17 / 2.8 cells were divided into 5×10 3 Plates / well density were seeded on 96-well plates. 10% FCS-αMEM was used as the medium. After culturing overnight, the medium was removed from each well, and 0.5% FCS-αMEM was added. After culturing for about 6 hours, the medium was removed from each well, and a solution containing DMSO and ethanol (hereinafter referred to as solution 1), a solution of Compound 11 and ethanol (hereinafter referred to as solution 5), 1α, 25-dihydroxyvitamin D 3 solution and DMSO (hereinafter referred to as solution 3), or compound 11 solution and 1α, 25-dihydroxyvitamin D 3 10% FCS-αMEM of the solution (hereinafter referred to as solution 6). Preparation of 10% FCS-αMEM containing Solution 1 was performed by diluting DMSO and e...

Embodiment 3

[0194] N-hydroxybenzamidine derivatives (hereinafter referred to as test compounds) shown in Table 1 and 1α,25-dihydroxyvitamin D were studied 3 Effect on the cell proliferation of ROS17 / 2.8 cells (table 4, table 5)

[0195] 100 μL of a solution containing DMSO and ethanol (hereinafter referred to as solution 7), a solution of the test compound and ethanol (hereinafter referred to as solution 8), 1α,25-dihydroxyvitamin D 3 solution and DMSO (hereinafter referred to as solution 9), or test compound solution and 1α, 25-dihydroxyvitamin D 3 10% FCS-αMEM of the solution (hereinafter referred to as solution 10). Take 5×10 3 ROS17 / 2.8 cells were inoculated at a density of 1 / 100 μL / well. Evaluation of test compound and 1α,25-dihydroxyvitamin D after incubation for about 48 hours by MTT method 3 Effect on cell proliferation of ROS17 / 2.8 cells. That is, after about 44 hours of cell culture, MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide 2mg / mL), an...

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PUM

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Abstract

Disclosed is a therapeutic or prophylactic agent for diseases associated with abnormal bone metabolism, particularly osteoporosis, which is more effective than conventional therapeutic or prophylactic agents. Specifically disclosed is a combination of an N-hydroxybenzamidine derivative represented by formula (I) or a salt thereof and active vitamin D or a prodrug thereof, which has a superior therapeutic or prophylactic effect on diseases associated with abnormal bone metabolism, particularly osteoporosis, compared with that achieved by the administration of the N-hydroxybenzamidine derivative or a salt thereof or the active vitamin D or a prodrug thereof alone.

Description

technical field [0001] The present invention relates to a drug for the treatment or prevention of diseases caused by abnormal bone metabolism, in particular to a drug for the prevention or treatment of osteoporosis, in particular to a drug containing N-hydroxybenzamidine derivatives represented by formula (I). Drugs or their salts, and active vitamin D or its prodrugs as active ingredients for diseases caused by abnormal bone metabolism, especially osteoporosis therapeutic or preventive drugs. Background technique [0002] The N-hydroxybenzamidine derivative represented by formula (I) or a salt thereof has a bone resorption inhibitory effect and a bone formation promoting effect, and is expected to be used as a therapeutic or preventive drug for osteoporosis. N-hydroxybenzamidine derivatives represented by formula (I) or salts thereof are disclosed in Patent Document 1, 2, 3 or 4. [0003] One of the N-hydroxybenzamidine derivatives shown in formula (I), i.e. N-hydroxyl-4-{...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/593A61K31/426A61P1/02A61P3/14A61P19/00A61P19/02A61P19/08A61P19/10A61P29/00A61P35/00A61P35/04
CPCA61K31/426A61K31/593A61P1/02A61P3/14A61P19/00A61P19/02A61P19/08A61P19/10A61P29/00A61P35/00A61P35/04A61P43/00
Inventor 落合锐士中山保典李振洙黄渊河郑德均
Owner TEIJIN PHARMA CO LTD
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