How to treat diseases with treprostinil prodrugs

Abstract

This provides a novel prodrug of treprostinil. [Solution] A pharmaceutical composition for treating a disease or condition in a subject requiring the treatment, comprising an effective amount of treprostinil prodrug, wherein the prodrug is stable in the plasma of the subject for at least about 120 minutes, and the prodrug is of formula: TIFF2026102630000086.tif4369 A pharmaceutical composition is provided, wherein the disease or condition is one or more selected from the group consisting of pulmonary hypertension, congestive heart failure, peripheral vascular disease, Raynaud's phenomenon, scleroderma, renal insufficiency, peripheral neuropathy, finger ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma.

Claims

1. This includes administering an effective dose of treprostinil prodrug to the target person who needs it. a method for treating a disease or condition, wherein the prodrug is present in the target plasma at a concentration of 120 A method for maintaining stability for a certain period of time.

2. This includes administering an effective dose of treprostinil prodrug to the target person who needs it. a method for treating a disease or condition, wherein the prodrug has a hepatic half-life of 15 minutes or less. A method that takes time.

3. This includes administering an effective dose of treprostinil prodrug to the target person who needs it. a method for treating a disease or condition, wherein the prodrug is gastric juice and / or A method for maintaining stability in intestinal fluid for more than 120 minutes.

4. A solution containing an effective dose of treprostinil prodrug is administered to the subject who needs it. A method for treating a disease or condition, comprising the action of the solution having a range of 5 to 9 Having a pH, the solution is stored at a temperature of 30°C to 45°C for at least one week, A method comprising leprostinil itself at a concentration of less than 0.5%.

5. The prodrug has a liver half-life of 15 minutes or less, as described in claim 1, 3, or 4. Method of loading.

6. The prodrug has a half-life of more than 120 minutes in gastric juice and / or intestinal juice. The method described in item 1, 2, or 4.

7. The prodrug has a hepatic half-life of 15 minutes or less, and is in gastric and / or intestinal fluid. The method according to claim 1, wherein the half-life is more than 120 minutes.

8. The prodrug is administered as a solution, and the solution has a pH in the range of 5 to 9. After the aforementioned solution is stored at a temperature of 30°C to 45°C for at least one week, treprostini The following is a description of any one of claims 1 to 3 and 7, which contains the substance itself at a concentration of less than 0.5% Method of loading.

9. The method according to any one of claims 1 to 8, wherein the prodrug is administered orally. 。

10. The method according to any one of claims 1 to 9, wherein the prodrug is administered parenterally. Law.

11. The method according to claim 10, wherein the prodrug is administered by injection.

12. The method according to claim 11, wherein the prodrug is administered subcutaneously.

13. The method according to claim 12, wherein the administration is continuous subcutaneous administration.

14. At least 95% of the aforementioned prodrug remained unchanged after 120 minutes of exposure to skin homogenate. The method according to any one of claims 1 to 13, which remains unchanged.

15. The aforementioned prodrug is EC of treprostinil. ５０ At least 100 times larger than the value Regarding at least one of the IP receptor, EP1 receptor, EP2 receptor, and DP1 receptor EC ５０ The method according to any one of claims 1 to 14, having a value.

16. The prodrug has an EC50 value at least 100 times greater than that of treprostinil. The method according to claim 15, wherein the IP receptor has an EC50 value.

17. The prodrug has an EC50 value at least 100 times greater than that of treprostinil. EC5 for each of the IP receptor, EP1 receptor, EP2 receptor, and DP1 receptor. The method according to claim 15, wherein the value is 0.

18. In the aforementioned administration, the prodrug is converted from treprostinil to an essential conversion product. The method according to any one of claims 1 to 17, wherein the method is replaced.

19. The person according to any one of claims 1 to 18, wherein the disease or condition is pulmonary hypertension. Law.

20. The method according to any one of claims 1 to 19, wherein the subject is a human.

21. The aforementioned prodrug is given by formula: 【Chemistry 1】 (In the formula, X is OH; R ２ and R ３ C(O)R is a phosphorus-containing group. ６ , or -A - Selected from the B-C substituents, where: A may be replaced by C. １ ~C ６ Alkylene, -NR ６ -, -C(O)-, -C (O) O−, or −C(O)NR ６ is; B may be joined to or substituted with C. １ ~C ６ Alkylene, -C(O)-, -O-, - S- is a heterocyclyl that may be substituted; C is an optionally substituted heterocyclyl, optionally substituted heteroaryl, Optionally substituted aryl, optionally substituted cycloalkyl, -(OCH ２ C H ２ ) ｑ -OR ６ 、-C(O)N(R ６ ) ２ 、-C(O)N(R １８ ) ２、 -C(O)R ６ , -CO ２ H, -OR ６ , -N(R １８ ) ２ , -N(R ６ ) ２ ,or 【Chemistry 2】 And; Here: Both R １８ These molecules form a unified 3- to 8-membered heterocycline, which may be substituted. death; Each R ６ These are H and C, which may be substituted, independently. １ ~C ６ Alkyl, substituted A heteroaryl that may be substituted, an aryl that may be substituted, or both R ６ teeth , a heterocycline that may be substituted with 4 to 8 members or a 5-member substitution as a whole. It may form a heteroaryl; R １０ H, and C which may be substituted. １ ~C ６ Alkyl, optionally substituted C １ ~ C ６ Alkenyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl A reel, or an aryl which may be replaced; (q is 0, 1, 2, 3, 4, 5, or 6) The method according to any one of claims 1 to 20, comprising:

22. R ２ and R ３ However, phosphorus-containing groups; and C(O)R ６ A claim independently selected from The method described in 21.

23. R ２ and R ３ However, as described in claim 21 or 22, which is independently selected from phosphorus-containing groups. The method.

24. The aforementioned prodrug is given by formula: 【Transformation 3】 The method according to claim 23, having the following characteristics.

25. R ２ and R ３ One of them is a phosphorus-containing group, R ２ and R ３ The other is C(O)R ６ dea The method according to claim 22.

26. R ２ and R ３ The method according to claims 21 and 22, wherein the group is the same.

27. R ２ However, R ３ The method according to claims 21 and 22, wherein the group is different from the group described above.

28. R ２ and R ３ However, C(O)R ６ The method according to claim 22, which is independently selected from the above.

29. R ６ However, independently, H and C may be substituted. １ ~C ６ Claim 28, which is alkyl. Methods used.

30. The aforementioned prodrug is, 【Chemistry 4】 The method according to claim 21, having the following characteristics.

31. The aforementioned prodrug is, 【Transformation 5】 The method according to claim 21, having the following characteristics.

32. The aforementioned prodrug is, 【Transformation 6】 The method according to claim 21, having the following characteristics.

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