Novel compounds capable of inducing osteogenic differentiation

Abstract

The present invention relates to a novel compound capable of inducing the osteogenic differentiation of stem cells, and more specifically, to a compound of chemical formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and a composition for inducing the osteogenic differentiation of stem cells comprising the said compound, its stereoisomer or a pharmaceutically acceptable salt thereof. The novel nutrin-based compound according to the present invention induces the degradation of MDM2 and efficiently promotes the differentiation of mesenchymal matrix cells, thereby exhibiting excellent ability to induce the osteogenic differentiation of stem cells.

Claims

[Claim 1] Compounds of chemical formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (I) In the above formula, R is 【change】 、 【change】 、 【change】 、 【change】 or 【change】 in, The aforementioned X is C, O, or N, and n is one integer from 1 to 5. The aforementioned Z is one integer between 1 and 10. The aforementioned m is one integer between 1 and 10. Is Y-W equal to C≡C, or are both Y and W equal to C, or is Y equal to C and W equal to O? The aforementioned v is one integer from 1 to 4, The aforementioned A is C or N, The term l is an integer from 1 to 8, and the compound, its stereoisomer, or its pharmaceutically acceptable salt is one such integer. [Claim 2] The aforementioned R is The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein X is C or O, and n is one integer from 1 to 3. [Claim 3] The aforementioned R is The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein Z is one integer from 2 to 8. [Claim 4] The aforementioned R is The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein m is one integer from 3 to 9. [Claim 5] The aforementioned R is The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein Y-W is C≡C, or both Y and W are C, or Y is C, W is O, and v is one integer from 1 to 3. [Claim 6] The aforementioned R is The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein A is C or N, and l is one integer from 1 to 4. [Claim 7] A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising one or more selected from the group configured as follows: 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)pentyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(8-((2-(2,6-dioxo-opiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)octyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(11-((2-(2,6-dioxopyridine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)undecyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl))oxy)ethoxy)ethyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(2-(2-(2-((2-(2,6-dioxo-opiperidine-3-yl))-1,3-dioxoisoindorine-)4-yl)oxy)ethoxy)ethoxy)ethoyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(2-(2-(2-(2-((2-((2-(2,6-dioxopiperidine-3-yl))-1,3-dioxo)isoindoline-4-yl)oxy))ethoxy)ethoxy)-ethoxy)ethyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl))oxy)acetamide)ethyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(5-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl))oxy)acetamide)pentyl-1)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(8-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl))oxy)acetamide)octyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(6-(2-(2,6-dioxopipericin-3-yl)-1,3-dioxoisoindorin-4-yl)hexa-5-in-1-yl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)non-8-in-1-yl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(12-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)dodeca-11-in-1-yl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)octyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)methyl)phenyl)buto-3-in-1-yl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)methyl)phenyl)butyl)acetamide; 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)nonyl)acetamide; and 2-(4-(cis-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazine-1-yl)-N-(2-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)methyl)benzyl)oxy)ethyl)acetamide. [Claim 8] A composition for inducing osteogenic differentiation of stem cells, comprising a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [Claim 9] The pharmaceutical composition according to claim 8, characterized in that it is formulated into one dosage form selected from the group consisting of injections, oral preparations, patches, liquids, capsules, granules, tablets, powders, sprays, ointments, gelling agents, mucosal administration preparations, and suppositories. [Claim 10] The pharmaceutical composition according to claim 8, further comprising a pharmaceutically acceptable carrier. [Claim 11] The pharmaceutical composition according to claim 8, characterized in that the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once a day or two to three times a week in a daily dose of 1 μg / kg to 100 mg / kg.

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