RU2020136560A - Acylated derivative of GLP-1 - Google Patents

Claims (32)

1. A derivative of the GLP-1(7-37) analog or a pharmaceutically acceptable salt thereof, wherein the GLP-1(7-37) analog contains the amino acid sequence of the following formula: HX ₈ EGTFTSDVSSX ₁₉ LEEX ₂₃ AARX ₂₇ FIX ₃₀ WLVX ₃₄ GX ₃₆ X ₃₇ (SEQ ID NO: 39), where X ₈ is selected from V; X ₁₉ is Y or K; X ₂₃ is Q or K; X ₂₇ is E or K; X ₃₀ is A or K; X ₃₄ is R or K; X ₃₆ is R or K; and X ₃₇ is G or K; with the proviso that only one of X ₁₉ , X ₂₃ , X ₂₇ , X ₃₀ , X ₃₄ , X ₃₆ or X ₃₇ is a K moiety, and the derivative contains an extension linked to the K residue of the GLP-1(7-37) analog via a linker, where the extension is

where x is an integer from 4 to 38, where the linker is

,

or

, where m is 1 or 2; n is 1 or 2; and p is any integer from 1 to 8. 2. A derivative or pharmaceutically acceptable salt thereof according to claim 1, where the extension part is selected from: HOOC(CH ₂ ) ₁₄ CO-, HOOC(CH ₂ ) ₁₅ CO-, HOOC(CH ₂ ) ₁₆ CO-, HOOC(CH ₂ ) ₁₇ CO-, HOOC(CH ₂ ) ₁₈ CO-, HOOC(CH ₂ ) ₁₉ CO-, HOOC(CH ₂ ) ₂₀ CO-, HOOC(CH ₂ ) ₂₁ CO- and HOOC(CH ₂ ) ₂₂ CO-. 3. A derivative or pharmaceutically acceptable salt thereof according to claim 1, where the linker is:

, where p is any integer between 1 and 5. 4. A derivative or pharmaceutically acceptable salt thereof according to claim 1, where the linker is:

, and where m is 1 and n is 1 or 2. 5. A derivative or pharmaceutically acceptable salt thereof according to claim 1, which is any derivative selected from the group consisting of: peptide N-ε ²³ -[2-(2-[2-(2-[2-(2-[ 4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val ⁸ Glu ²² Lys ²³ Arg ^26.34 -GLP-1(7-37)) (M2 ), peptide N-ε ³⁰ -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy] ethoxy)acetyl](Val ⁸ Glu ²² Lys ³⁰ Arg ^26.34 -GLP-1(7-37)) (M4), peptide N-ε ³⁴ -[2-(2-[2-(2-[2- (2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val ⁸ Glu ²² Arg ²⁶ Lys ³⁴ -GLP-1(7-37)) (M5), peptide N-ε ³⁷ -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl])(Val ⁸ Glu ²² Arg ^26.34 Lys ³⁷ -GLP-1(7-37)) (M7), or a pharmaceutically acceptable salt thereof. 6. A method for producing a derivative or a pharmaceutically acceptable salt thereof according to claim 1, including: (1) mixing the solution in which the GLP-1 analog is dissolved with the solution in which the extension is dissolved; (2) adjusting the pH to 4-5 to stop the reaction, holding until a precipitate forms, and then collecting the precipitate; and (3) adding TFA (trifluoroacetic acid) to the precipitate and adjusting the pH to 7.5-8.5 to stop the reaction. 7. The method of claim 6, further comprising: adding triethylamine to the solution in which the GLP-1 analog is dissolved, followed by mixing with the solution in which the extension is dissolved. 8. The method of claim 6 wherein the solution of the extension is in acetonitrile. 9. Pharmaceutical composition for the prevention and/or treatment of diabetes or complications of diabetes, containing a therapeutically effective amount of a derivative or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient. 10. A method for preventing and/or treating diabetes or complications of diabetes, comprising administering a prophylactically or therapeutically effective amount of a derivative or a pharmaceutically acceptable salt thereof according to claim 1 to a subject. 11. The method of claim 10 wherein the complication of diabetes is diabetic nephropathy. 12. A method for lowering blood glucose levels, increasing glucose tolerance, reducing islet β-cell apoptosis, enhancing islet β-cell function, increasing the number of islet β-cells, and/or restoring glucose sensitivity of islet β-cells, comprising administering a therapeutically effective the amount of a derivative or a pharmaceutically acceptable salt thereof according to claim 1 subject. 13. The method of claim 12, wherein said blood glucose lowering comprises lowering fasting blood glucose and/or postprandial blood glucose. 14. GLP-1(7-37) analogue containing a polypeptide consisting of the following amino acid sequence: HX ₈ EGTFTSDVSSX ₁₉ LEEX ₂₃ AARX ₂₇ FIX ₃₀ WLVX ₃₄ GX ₃₆ X ₃₇ (SEQ ID NO: 39), where X ₈ is selected from V; X ₁₉ is Y or K; X ₂₃ is Q or K; X ₂₇ is E or K; X ₃₀ is A or K; X ₃₄ is R or K; X ₃₆ is R or K; X ₃₇ is G or K; and only one of X ₁₉ , X ₂₃ , X ₂₆ , X ₂₇ , X ₃₀ , X ₃₄ , X ₃₆ or X ₃₇ is K. 15. Pharmaceutical composition for the prevention and/or treatment of diabetes or complications of diabetes, containing a therapeutically effective amount of the analogue according to claim 14 and a pharmaceutically acceptable excipient. 16. A product for the prevention and/or treatment of diabetes or complications of diabetes, containing: a container containing a pharmaceutical composition according to claim 9, and a package insert containing instructions for using the pharmaceutical composition. 17. The product of claim 16, further comprising a container containing one or more other drugs. 18. The product of claim 17 wherein the one or more other drugs are other drugs for the treatment of diabetes or complications of diabetes. 19. A product for the prevention and/or treatment of diabetes or complications of diabetes, containing: a container containing a pharmaceutical composition according to claim 15, and a package insert containing instructions for using the pharmaceutical composition.