Combined products, salt and its use

Abstract

The present invention relates to novel combination products, pharmaceutical compositions, salt formulations, and their use in the treatment and / or prevention of diseases.

Claims

1. It is a combination product, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, 【Chemistry 1】 (I) Here, R １ 、R ２ 、R ３ 、R ４ 、R ５ and R ６ are the same or different and each independently is hydrogen, halogen, a hydroxy group, C １ -C ６ alkyl group, C １ -C ６ haloalkyl group, C １ -C ６ alkoxy group and C １ -C ６ haloalkoxy group, and the hydroxy group, C １ -C ６ alkyl group, C １ -C ６ haloalkyl group, C １ -C ６ alkoxy group and C １ -C ６ haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C １ -C ６ alkyl group and phenyl group, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) containing bile acids or their derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, Combination product.

2. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The combination product according to claim 1.

3. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The combination product according to claim 1 or 2.

4. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The combination product according to any one of the above claims.

5. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The combination product according to any one of the above claims.

6. A pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, methanesulfonate, phosphate, acetate, mandelate, or sulfate, preferably maleate or hydrochloride, and more preferably hydrochloride. The combination product according to any one of the above claims.

7. The compound of formula (I) is 【Chemistry 2】 Selected from, The combination product according to any one of the above claims.

8. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. The combination product according to any one of the above claims.

9. The molar ratio of component (a) to component (b) is 1:1000 to 1000:1, preferably 1:5 to 5:1, more preferably 1:2 to 2:1, even more preferably 1:1 to 2:1, and most preferably 1:1 or 2:

1. The combination product according to any one of the above claims.

10. Used to treat and / or prevent liver disease, preferably chronic cholestatic liver disease, The combination product according to any one of the above claims.

11. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. The combination product according to any one of the above claims.

12. The aforementioned components (a) and (b) have a synergistic effect in mitigating deoxycholic acid-induced hepatocyte injury. The combination product according to any one of the above claims.

13. A pharmaceutical composition, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, 【Transformation 3】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Bile acids or their derivatives or analogs or their pharmaceutically acceptable salts, solvates, hydrates or stereoisomers, (c) comprising a pharmaceutically acceptable carrier, excipient and / or diluent, Pharmaceutical composition.

14. R １ , R ２ and R ３ are each independently selected from hydrogen, a hydroxy group, a methoxy group, and a benzyloxy group, or any two adjacent ones of １ R ２ and R ３ form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are attached. The pharmaceutical composition according to claim 13.

15. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The pharmaceutical composition according to claim 13 or 14.

16. R １ 、R ２ and R ３ One or two of which in R １ 、R ２ and R ３ Any two adjacent ones in R form a 5-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are attached. A pharmaceutical composition according to any one of claims 13 to 15.

17. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. A pharmaceutical composition according to any one of claims 13 to 16.

18. A pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, methanesulfonate, phosphate, acetate, mandelate, or sulfate, preferably maleate or hydrochloride, and more preferably hydrochloride. A pharmaceutical composition according to any one of claims 13 to 17.

19. The compound of formula (I) is 【Chemistry 4】 Selected from, A pharmaceutical composition according to any one of claims 13 to 18.

20. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. A pharmaceutical composition according to any one of claims 13 to 19.

21. The molar ratio of component (a) to component (b) is 1:1000 to 1000:1, preferably 1:5 to 5:1, more preferably 1:2 to 2:1, even more preferably 1:1 to 2:1, and most preferably 1:1 or 2:

1. A pharmaceutical composition according to any one of claims 13 to 20.

22. Used to treat and / or prevent liver disease or inflammatory bowel disease, preferably chronic cholestatic liver disease, A pharmaceutical composition according to any one of claims 13 to 21.

23. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. A pharmaceutical composition according to any one of claims 13 to 22.

24. The aforementioned components (a) and (b) have a synergistic effect in mitigating deoxycholic acid-induced hepatocyte injury. A pharmaceutical composition according to any one of claims 13 to 23.

25. The acid-base addition salt of formula (II), (A ＋ ) ｍ (B － ) ｎ (C － ) ｐ (II) Here, (a) A ＋ This is the cation moiety of the compound of formula (I), 【Transformation 5】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) B － is an anionic moiety which is a bile acid or a derivative or analog thereof, and (c) C － It is a rhizal anion, Here, m, n, and p are integers independently selected from 1 to 6 such that the salt composition reaches charge equilibrium, and when m = n, p is 0. Acid-base addition salt.

26. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The acid-base addition salt according to claim 25.

27. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The acid-base addition salt according to claim 25 or 26.

28. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The acid-base addition salt according to any one of claims 25 to 27.

29. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The acid-base addition salt according to any one of claims 25 to 28.

30. The compound of formula (I) is 【Transformation 6】 A cation moiety selected from the group consisting of, The acid-base addition salt according to any one of claims 25 to 29.

31. The aforementioned component (b) is an anionic portion selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. The acid-base addition salt according to any one of claims 25 to 30.

32. m is 1, n is 1, and p is 0, or m is 2, n is 1, and p is 1. The acid-base addition salt according to any one of claims 25 to 31.

33. Used to treat and / or prevent liver disease or inflammatory bowel disease, preferably chronic cholestatic liver disease, The acid-base addition salt according to any one of claims 25 to 32.

34. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. The acid-base addition salt according to any one of claims 25 to 33.

35. A combination product according to any one of claims 1 to 12 or an acid-base addition salt according to any one of claims 25 to 34, Pharmaceutical composition.

36. A method for treating and / or preventing liver disease or inflammatory bowel disease, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, according to any one of claims 1 to 35. method.

37. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. The method according to embodiment 36.

37. A method for treating and / or preventing liver disease or inflammatory bowel disease, comprising Method 1 and Method 2, In Method 1, for patients who require it, (a) Administer a therapeutic and / or prophylactic effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, 【Transformation 7】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. In Method 2, for patients who require it, (a) A therapeutic and / or prophylactic effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, 【Transformation 8】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Administer therapeutic and / or prophylactic effective amounts of bile acids or their derivatives or analogs or their pharmaceutically acceptable salts, solvates, hydrates or stereoisomers simultaneously, together, individually or sequentially. method.

38. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The method according to claim 37.

39. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The method according to claim 37 or 38.

40. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The method according to any one of claims 37 to 39.

41. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The method according to any one of claims 37 to 40.

42. A pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, methanesulfonate, phosphate, acetate, mandelate, or sulfate, preferably maleate or hydrochloride, and more preferably hydrochloride. The method according to any one of claims 37 to 41.

43. The compound of formula (I) is 【Chemistry 9】 Selected from, The method according to any one of claims 37 to 42.

44. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. The method according to any one of claims 37 to 43.

45. The molar ratio of component (a) to component (b) is 1:1000 to 1000:1, preferably 1:5 to 5:1, more preferably 1:2 to 2:1, even more preferably 1:1 to 2:1, and most preferably 1:1 or 2:

1. The method according to any one of claims 37 to 44.

46. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. The method according to any one of claims 37 to 45.

47. A combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, as described in any one of claims 1 to 35, used for treating, alleviating and / or preventing liver disease or inflammatory bowel disease.

48. The aforementioned liver diseases include cholestatic liver disease (chronic cholestatic liver disease), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic fatty liver disease, The liver disease is selected from autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma) and cholangiocarcinoma, and preferably the liver disease is primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), and more preferably the primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC) is accompanied by inflammatory bowel disease as a complication. The combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof according to claim 47.

49. The aforementioned inflammatory bowel disease is a complication caused by primary sclerosing cholangitis (PSC) and / or primary biliary cirrhosis (PBC). The combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof according to claim 47.

50. A reagent kit comprising a combination product, acid-base addition salt, pharmaceutical composition, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and instructions for use, wherein the reagent kit is used to treat and / or prevent liver disease or inflammatory bowel disease. Reagent kit.

51. The aforementioned liver diseases are selected from cholestatic liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestatic disease (especially progressive familial intrahepatic cholestatic disease types 1, 2, and 3), cystic fibrosis, drug-induced cholestasis or non-cholstatic liver disease, chronic viral hepatitis (B, C, D), alcoholic or non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease or α-1-antitrypsin deficiency, liver cancer (especially hepatocellular carcinoma), and cholangiocarcinoma. The reagent kit according to claim 50.

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