COMPOUND FOR TREATING METABOLIC DISEASES AND PREPARATION METHOD AND USE THEREOF

• US 20200131212A1
• Filed: 08/15/2018
• Published: 04/30/2020
• Est. Priority Date: 12/19/2017
• Status: Active Grant

• Current Assignee: Xi'an Biocare Pharma Ltd.
• Original Assignee: XI' An Biocare Pharma Limited
• Inventors: Fu, Guoqin, Ding, Wei, Yin, Bo, Yang, Chao, Wang, Cuiqin, Dou, Yong, Wang, Ruiling
• Granted Patent: US 11,028,111 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 9/222 Amides of phosphoric acids
• CPC Class Codes: C07F 9/242 of hydroxyaryl compounds
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/65742 non-condensed with carbocyclic rings or heterocyclic rings or ring systems
• CPC Class Codes: C07J 41/0094 containing nitrile radicals, including thiocyanide radicals
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
• CPC Class Codes: C07J 9/005 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Abstract

Provided are a compound for treating metabolic diseases having the structure as shown in formula (I) or formula (II), or a racemate, stereoisomer, geometric isomer, tautomer, solvate, hydrate, metabolite, pharmaceutically acceptable salt or prodrug thereof. The compound is an activator of FXR and/or a TGR5 receptor, and thus has the activity of activating FXR and/or a TGR5 receptor, and can be used in the preparation of drugs for treating chronic liver diseases, metabolic diseases or portal hypertension.

Claims

1. A compound as shown in Formula (I), or

a racemate, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

2. The compound according to claim 1, wherein R₁ is hydrogen, substituted or unsubstituted C_1-5 alkyl or halogen.

3. The compound according to claim 1, wherein R₁ is hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, or substituted or unsubstituted isopropyl.

4. The compound according to claim 1, wherein

each of the R₂ is independently selected from the group consisting of fluorine, chlorine, bromine, nitro, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, and substituted or unsubstituted isopropyl;

m is 0 or 1;

each of the R₃ is independently selected from the group consisting of fluorine, chlorine, bromine, substituted or unsubstituted methyl, and substituted or unsubstituted ethyl; and

n is 0 or 1.

5. The compound according to claim 1, which is selected from the group consisting of:

10. A method of producing the compound according to claim 1, comprising:

reacting Compound (10) with Compound (16) to obtain a compound as shown in Formula (I),

11. The method according to claim 10, wherein the reaction is performed under the catalysis of tert-butylmagnesium chloride and with 1,4-dioxane as the solvent.

16. A method for activating receptor FXR and/or TGR5 comprising administering to a subject or sample in need thereof a therapeutically effective amount of the compound according to claim 1.

17. A method for preventing, treating or ameliorating receptor FXR and/or TGR5 mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 1.

18. The method according to claim 17, wherein the receptor FXR and/or TGR5 mediated disease is selected from chronic liver disease, metabolic disease and portal hypertension.

19. The method according to claim 18, wherein the chronic liver disease is selected from primary biliary cholestatic cirrhosis, primary sclerosing cholangitis, liver fibrosis-related disease, drug-induced cholestasis, progressive familial intrahepatic cholestasis, cholestasis of pregnancy, alcoholic liver disease and non-alcoholic fatty liver disease;

the portal hypertension is a portal hypertension with increased portal pressure caused by liver fibrosis, cirrhosis, splenomegaly or another reason; and

the metabolic disease is selected from hypercholesterolemia, dyslipidemia, cholesterol gallstones and hypertriglyceridemia.

6-9. -9. (canceled)

12-15. -15. (canceled)

20. A compound as shown in Formula (II), or

a racemate, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

21. The compound according to claim 20, wherein R₄ is hydrogen, substituted or unsubstituted C_1-6 alkyl or halogen.

22. The compound according to claim 20, wherein

R₄ is hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl or substituted or unsubstituted isopropyl;

each of the R₅ is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, and substituted or unsubstituted isopropyl; and

R₆ is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, phenyl, pyridyl and cyclohexyl.

23. The compound according to claim 20, which is selected from the group consisting of: