# US 11,028,111 B2 · Compound for treating metabolic diseases and preparation method and use thereof

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- Number: US 11,028,111 B2
- Document ID: US11028111B2
- Status: Granted
- Kind: B2
- Application number: 16/626,934
- Filed: 2018-08-15
- Published: 2020-04-30
- Granted: 2021-06-08
- Earliest claimed: 2017-12-19
- Assignees: Xi' An Biocare Pharma Ltd.
- Applicants: Xi' An Biocare Pharma Ltd.
- Inventors: Guoqin Fu; Wei Ding; Bo Yin; Chao Yang; Cuiqin Wang; Yong Dou; Ruiling Wang
- Web page: https://patentgrep.com/patent/US11028111B2

## CPC

- C07F 9/65742: {non-condensed with carbocyclic rings or heterocyclic rings or ring systems}
- A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/664: Amides of phosphorus acids
- A61K 31/685: one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 9/12: Antihypertensives
- C07F 9/222: {Amides of phosphoric acids}
- C07F 9/242: {of hydroxyaryl compounds}
- C07F 9/657181: {the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative}
- 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
- C07J 9/005: {containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton}
- C07J 41/0094: {containing nitrile radicals, including thiocyanide radicals}
- C07J 51/00: Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07J: STEROIDS (seco-steroids C07C)

## 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

### Claim 1

A compound as shown in Formula (I), or
a racemate, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein,
R1 is hydrogen, substituted or unsubstituted alkyl or halogen;
each of the R2 is independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, hydroxyl, nitro, cyano, sulphonic acid group and carboxyl;
m is 0, 1, 2, 3 or 4;
each of the R3 is independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, hydroxyl and aryl; and
n is 0, 1, 2, 3 or 4.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is hydrogen, substituted or unsubstituted C1-5 alkyl or halogen.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
each of the R2 is independently selected from the group consisting of fluorine, chlorine, bromine, nitro, 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.

### Claim 5 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

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),
wherein,
R1 is hydrogen, substituted or unsubstituted alkyl, and halogen;
each of the R2 is independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, hydroxyl, nitro, sulfonyl hydroxide and carboxyl;
m is 0, 1, 2, 3 or 4;
each of the R3 is independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, hydroxyl and aryl; and
n is 0, 1, 2, 3 or 4.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the reaction is performed under the catalysis of tert-butylmagnesium chloride and with 1,4-dioxane as the solvent.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

A method for 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.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the receptor FXR and/or TGR5 mediated disease is selected from chronic liver disease, metabolic disease and portal hypertension.

### Claim 11 (depends on 10)

The method according to claim 10, 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.

### Claim 12

A compound as shown in Formula (II), or
a racemate, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein,
R4 is hydrogen, substituted or unsubstituted alkyl or halogen;
each of the R5 is independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, hydroxyl, cyano, nitro, sulphonic acid group, and carboxyl;
R6 is selected from the group consisting of substituted or unsubstituted C1-5 alkyl, aryl, heteroaryl, and cyclohexyl;
x is 0, 1, 2, 3 or 4; and
y is 0 or 1.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein R4 is hydrogen, substituted or unsubstituted C1-6 alkyl or halogen.

### Claim 14 (depends on 12)

The compound according to claim 12, 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.

### Claim 15 (depends on 12)

The compound according to claim 12, which is selected from the group consisting of:
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein
each of the R2 is independently cyano;
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.