Pharmaceutical composition comprising FXR agonist and GLP-1 receptor small molecule agonist

Abstract

A pharmaceutical composition comprising an FXR agonist and a GLP-1 receptor small molecule agonist, wherein the FXR agonist is a compound represented by formula (I), or a tautomer, solvate, or pharmaceutically acceptable salt thereof, and the GLP-1 receptor small molecule agonist is selected from danuglipron, orforglipron, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition exhibits a synergistic effect in reducing body weight, and thus can be used for treating and / or preventing metabolic disorders or conditions.

Description

Pharmaceutical compositions comprising an FXR agonist and a small molecule GLP-1 receptor agonist

[0001] Citation of relevant applications

[0002] This disclosure claims priority to Chinese Patent Application No. 202510046669.2, filed on January 10, 2025, entitled "Pharmaceutical Composition Containing an FXR Agonist and a GLP-1 Receptor Small Molecule Agonist", and Chinese Patent Application No. 202510052597.2, filed on January 13, 2025, entitled "Pharmaceutical Composition Containing an FXR Agonist and a GLP-1 Receptor Small Molecule Agonist", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the pharmaceutical field and specifically relates to a pharmaceutical composition comprising a specific FXR agonist and a GLP-1 receptor small molecule agonist; it also relates to the use of the pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of metabolic disorders. Background Technology

[0004] Metabolic disorders (including diabetes and insulin resistance syndrome) are characterized by abnormalities in multiple metabolic risk markers, such as hyperinsulinemia, impaired glucose metabolism, elevated plasma triglyceride levels, decreased high-density lipoprotein cholesterol levels, elevated blood pressure, and obesity. Elevated blood glucose levels, decreased insulin secretion, and / or increased insulin resistance can be associated with a variety of conditions, including primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), various chronic hepatitis states (hepatitis B and hepatitis C), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). These diseases are often associated with abnormal expression of multiple nuclear receptors involved in metabolic regulation.

[0005] The farnesoid X receptor (FXR) is mainly distributed in the liver. It reduces liver fat content by inhibiting de novo lipogenesis (DNL) of fatty acids through the inhibition of cholesterol regulatory element-binding protein-1c (SREBP-1c). Since cytochrome 7A1 (CYP7A1) is the rate-limiting enzyme in bile acid biosynthesis, FXR agonists indirectly inhibit CYP7A1 gene expression by activating FXR, thereby inhibiting hepatic bile acid synthesis and mitigating the toxicity of excessive bile acids to hepatocytes. Bile acids participate in the regulation of various metabolic processes, regulating not only their own synthesis and enterohepatic circulation, but also triglycerides, cholesterol, glucose, and energy homeostasis. Bile acids also play an additional role in regulating intestinal glucagon release and metabolic regulation by modulating energy expenditure. FXR agonists can regulate fatty acid synthesis and oxidation, promote fat metabolism and regulate bile acid synthesis and metabolism, promote bile acid excretion, and reduce fat accumulation in the liver. At the same time, they can reduce liver inflammation and the occurrence and development of liver fibrosis by inhibiting inflammatory response and hepatic stellate cell activation, inhibiting inflammatory factors and reducing collagen synthesis.

[0006] CN 114315830 A discloses an FXR agonist with the structure shown below. These compounds possess advantages such as high FXR agonist activity, simple synthesis, and readily available starting materials.

[0007] Glucagon-like peptide-1 (GLP-1) is a 30-amino acid polypeptide hormone secreted by enteroendocrine cells in response to diet. GLP-1 is believed to play a role in postprandial blood glucose regulation by directly increasing diet-induced insulin secretion from pancreatic β-cells in a glucose concentration-dependent manner, reducing glucagon secretion from pancreatic α-cells, and promoting satiety by delaying food transit through the intestines. GLP-1 mediates intracellular signaling via the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor family located on the cell membrane, which, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Small molecule agonists of the GLP-1 receptor can promote insulin secretion, lower blood glucose, reduce insulin resistance, delay gastric emptying, reduce appetite, decrease food intake, and aid in weight loss; they also reduce glucose production and fat synthesis, helping to reduce fat accumulation.

[0008] Currently marketed GLP-1 drugs are mainly single-target peptide injectable drugs, such as Novo Nordisk's semaglutide and liraglutide, Eli Lilly's dulaglutide, and Renhui's benaglutide.

[0009] Compared to traditional injectable peptide drugs, small molecule GLP-1 drugs have significant advantages in terms of administration methods, delivery devices, storage methods, preparation methods, preparation difficulty, and preparation costs. Representative drugs in this area include Eli Lilly's Orforglipron and Pfizer's Danuglipron.

[0010] Orforglipron (LY3502970) is a novel oral GLP-1R agonist acquired and marketed by Eli Lilly and Company. With a half-life of 29-49 hours, it supports once-daily dosing and can be taken without restrictions on food, water, or other medications, either before or after meals, offering great convenience to patients. The structure of Orforglipron is shown below. The main adverse reactions of Orforglipron are gastrointestinal reactions (such as nausea, constipation, vomiting, and diarrhea) in the early stages of drug use.

[0011] Danuglipron (PF-06882961) is an oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist developed by Pfizer for the treatment of type 2 diabetes and obesity. The structure of Danuglipron is shown below. Although the Phase IIb clinical trial of this drug met its pre-specified primary endpoint, it was accompanied by serious side effects. In patients receiving twice-daily dosing, 75% experienced nausea, nearly half experienced vomiting, and one-quarter experienced diarrhea, leading to a discontinuation rate exceeding 50%. Therefore, the researchers decided to terminate the clinical trial and consider changing the dosing frequency to once-daily in future studies to minimize adverse reactions in patients.

[0012] Currently, several domestic companies have entered the GLP-1 small molecule field, and many products have entered the clinical development stage, as shown in CN116390926A, CN202210505406, CN115698003, CN116003403A, and CN113801136A. Among them, foreign companies such as Eli Lilly's Orforglipron capsules are in Phase III clinical trials, Hengrui Medicine's HRS-7535 tablets and Huadong Medicine's HDM1002 tablets have entered Phase II clinical trials, while companies such as Derui Pharmaceutical, Hansoh Pharmaceutical, and Sinopharm are still in Phase I clinical trials. Summary of the Invention

[0013] The problem the invention aims to solve

[0014] While current clinical studies have found that FXR agonists or GLP-1 receptor small molecule agonists alone have some efficacy in treating metabolic disorders, the desired therapeutic effect is still not achieved. Furthermore, FXR agonists commonly cause adverse reactions such as increased low-density lipoprotein cholesterol (LDL-c) and severe itching. Therefore, developing highly effective drugs or drug compositions for the treatment and / or prevention of metabolic disorders is a pressing issue in this field. To address these issues, this disclosure provides a drug composition comprising a specific FXR agonist and a GLP-1 receptor small molecule agonist.

[0015] Solution for solving the problem

[0016] [Pharmaceutical Composition]

[0017] This disclosure provides a pharmaceutical composition comprising an FXR agonist and a GLP-1 receptor small molecule agonist, wherein the FXR agonist is selected from compounds of formula (I), their tautomers, solvates, or pharmaceutically acceptable salts, and the GLP-1 receptor small molecule agonist is selected from orforglipron, Danuglipron, or pharmaceutically acceptable salts thereof.

[0018] Among them, R 1 R 2 R 3 and R 4 Each of the following is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl or C3-C6 cycloalkyl-O-, wherein the alkyl group is optionally substituted with one or more halogens;

[0019] R 11 R 12 R 13 R 14 and R 15 Each of the following is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, -CN or -NO2, wherein the alkyl group is optionally substituted with one or more halogens.

[0020] In some implementations, R in equation (I) 1 R 2 R 3 and R 4 Each is independently hydrogen, halogen, or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more halogens.

[0021] In some implementations, R in equation (I) 1 R 2R 3 and R 4 Each can be either hydrogen or halogen.

[0022] In some implementations, R in equation (I) 1 R 2 R 3 and R 4 Each can be independently hydrogen, F, Cl, Br, or I.

[0023] In some implementations, R in equation (I) 1 R 2 R 3 and R 4 Each can be either hydrogen or F.

[0024] In some implementations, R in equation (I) 11 R 12 R 13 R 14 and R 15 Each of the following is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl-O-, -CN or -NO2, wherein the alkyl group is optionally substituted with one or more halogens.

[0025] In some implementations, R in equation (I) 11 R 12 R 13 R 14 and R 15 Each can be independently hydrogen, halogen, CF3, -OCF3, -OCF2H, CH3, -CN, or -NO2.

[0026] In some implementations, R in equation (I) 11 R 12 R 13 R 14 and R 15 Each can be independently hydrogen, F, Cl, CF3, -OCF3, -OCF2H or CH3.

[0027] In some embodiments, the FXR agonist is a compound, its tautomer, solvate, or a pharmaceutically acceptable salt, as shown below:

[0028] In some embodiments, the FXR agonist is a compound, its tautomer, solvate, or a pharmaceutically acceptable salt, as shown below:

[0029] In some embodiments, the pharmaceutical composition comprises an FXR agonist and a small molecule GLP-1 receptor agonist, wherein the FXR agonist is a compound as shown below, its tautomer, solvate or pharmaceutically acceptable salt, and the small molecule GLP-1 receptor agonist is Orforglipron or its pharmaceutically acceptable salt.

[0030] In some embodiments, the pharmaceutical composition comprises an FXR agonist and a small molecule GLP-1 receptor agonist, wherein the FXR agonist is a compound as shown below, its tautomer, solvate or pharmaceutically acceptable salt, and the small molecule GLP-1 receptor agonist is Danuglipron or its pharmaceutically acceptable salt.

[0031] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients and / or absorption enhancers.

[0032] In some embodiments, the excipient is a pharmaceutically acceptable carrier or adjuvant, including but not limited to one or more of fillers, diluents, binders, disintegrants, lubricants and glidants.

[0033] In some embodiments, the absorption enhancer is octanoate or a composition of octanoate and N-(8-(2-hydroxybenzoyl)amino)octanoate (NAC).

[0034] In some embodiments, the octanoate is sodium octanoate; and / or, the N-(8-(2-hydroxybenzoyl)amino)octanoate is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC).

[0035] [Use and treatment method]

[0036] The present disclosure provides the use of the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing metabolic disorders.

[0037] The present disclosure also provides a method for treating and / or preventing metabolic disorders, the method comprising administering an effective amount of the above pharmaceutical composition to a subject in need thereof.

[0038] The present disclosure provides the above pharmaceutical composition for treating and / or preventing metabolic disorders.

[0039] In some embodiments, the metabolic disorders include, but are not limited to: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), different chronic hepatitis conditions (hepatitis B and hepatitis C), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.

[0040] [Dosage and Administration]

[0041] In some embodiments, a certain dose of an FXR agonist and a small molecule GLP-1 receptor agonist are administered over a certain time period. The time period can be within one dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours.

[0042] In some embodiments, the FXR agonist and the small molecule GLP-1 receptor agonist can be administered simultaneously or sequentially.

[0043] In some embodiments, the FXR agonist and the small molecule GLP-1 receptor agonist are administered simultaneously, formulated independently and co-administered, or formulated independently and administered相继给药.

[0044] In some embodiments, the FXR agonist is administered once a day or twice a day, preferably once a day.

[0045] In some embodiments, the small molecule GLP-1 receptor agonist is administered twice a day, once a day, once every two days, once every three days, or once a week, preferably twice a day or once a day.

[0046] In some embodiments, the FXR agonist is administered once a day and the small molecule GLP-1 receptor agonist is administered twice a day.

[0047] In some embodiments, the FXR agonist is administered once a day and the small molecule GLP-1 receptor agonist is administered once a day.

[0048] In some embodiments, the FXR agonist is administered once a day for a treatment period of one week or more.

[0049] In some embodiments, the small molecule GLP-1 receptor agonist is administered twice a day for a treatment period of one week or more.

[0050] In some embodiments, the small molecule GLP-1 receptor agonist is administered once a day for a treatment period of one week or more.

[0051] In some embodiments, for the administration of the FXR agonist, the treatment period is one week, four weeks, twelve weeks, twenty-four weeks, thirty-six weeks, forty-eight weeks, sixty weeks, seventy-two weeks, eighty-four weeks, or ninety-six weeks.

[0052] In some embodiments, for the administration of the GLP-1 receptor small molecule agonist, the treatment period is one week, four weeks, twelve weeks, twenty-four weeks, thirty-six weeks, forty-eight weeks, sixty weeks, seventy-two weeks, eighty-four weeks, or ninety-six weeks.

[0053] In some embodiments, the mass ratio of the FXR agonist to the GLP-1 receptor small molecule agonist is from 10:1 to 1:100, preferably from 1:1 to 3:100, and most preferably 1:1, 3:10, or 3:100.

[0054] In some embodiments, the mass ratio of the FXR agonist to the GLP-1 receptor small molecule agonist at the time of single administration is from 10:1 to 1:100, preferably from 1:1 to 3:100, and most preferably 1:1, 3:10, or 3:100.

[0055] In some embodiments, the dosage of the FXR agonist for each administration is 0.001 to 10 mg, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.015 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.2 mg, 0.4 mg, 0.6 mg, 1 mg, 1.4 mg, 2 mg, 2.8 mg, 4 mg, 6 mg, or 8 mg.

[0056] In some embodiments, the dosage of the FXR agonist for each administration is 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg.

[0057] In some embodiments, the dosage of the small molecule agonist of the GLP-1 receptor is 0.001 to 50 mg per administration, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.045 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.7 mg, 1 mg, 1.4 mg, 1.7 mg, 2.0 mg, 2.4 mg, 2.5 mg, 2.8 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg.

[0058] In some embodiments, the dosage of the small molecule agonist of the GLP-1 receptor is 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg per administration.

[0059] In some embodiments, Orforglipron or a pharmaceutically acceptable salt thereof is administered twice a day, once a day, once every two days, once every three days or once a week, preferably twice a day or once a day.

[0060] In some embodiments, the FXR agonist is administered once a day, and Orforglipron or a pharmaceutically acceptable salt thereof is administered twice a day.

[0061] In some embodiments, the FXR agonist is administered once a day, and Orforglipron or a pharmaceutically acceptable salt thereof is administered once a day.

[0062] In some embodiments, Orforglipron or a pharmaceutically acceptable salt thereof is administered twice a day for a treatment period of one week or more.

[0063] In some embodiments, the Orforglipron or a pharmaceutically acceptable salt thereof is administered once daily for a treatment period of one week or more weeks.

[0064] In some embodiments, the dosage of the Orforglipron or a pharmaceutically acceptable salt thereof is 0.001 to 50 mg per administration, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.045 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.7 mg, 1 mg, 1.4 mg, 1.7 mg, 2.0 mg, 2.4 mg, 2.5 mg, 2.8 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg.

[0065] In some embodiments, the dosage of the Orforglipron or a pharmaceutically acceptable salt thereof is 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg per administration.

[0066] In some embodiments, the Danuglipron or a pharmaceutically acceptable salt thereof is administered twice daily, once daily, once every two days, once every three days or once weekly, preferably twice daily or once daily.

[0067] In some embodiments, the FXR agonist is administered once daily and the Danuglipron or a pharmaceutically acceptable salt thereof is administered twice daily.

[0068] In some embodiments, the FXR agonist is administered once daily, and the Danuglipron or a pharmaceutically acceptable salt thereof is administered once daily.

[0069] In some embodiments, the Danuglipron or a pharmaceutically acceptable salt thereof is administered twice daily for a treatment period of one week or more.

[0070] In some embodiments, the Danuglipron or a pharmaceutically acceptable salt thereof is administered once daily for a treatment period of one week or more.

[0071] In some embodiments, the dosage of the Danuglipron or a pharmaceutically acceptable salt thereof is 0.001 to 50 mg per administration, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.045 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.7 mg, 1 mg, 1.4 mg, 1.7 mg, 2.0 mg, 2.4 mg, 2.5 mg, 2.8 mg, 3.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg.

[0072] In some embodiments, the dosage of the Danuglipron or a pharmaceutically acceptable salt thereof is 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg per administration.

[0073] In some embodiments, the pharmaceutical composition can be administered to the FXR agonist and the GLP-1 receptor small molecule agonist by the same administration route or different administration routes.

[0074] In some embodiments, the pharmaceutical composition can be administered via any suitable route of administration. For example, it can be administered orally, subcutaneously, sublingually, transmucosally, parenterally, intravenously, intraarterially, intraperitoneally, sublingually, locally, vaginally, rectically, ocularly, ocularly, nasally, by inhalation, or transdermally, or combinations thereof, to a patient or subject requiring this treatment. When intended for oral administration, the pharmaceutical composition can be formulated into oral dosage forms, such as oral solid dosage forms like tablets, capsules, pills, granules, etc.; or oral liquid dosage forms like oral solutions, oral suspensions, syrups, etc. The oral dosage forms may also contain suitable fillers, binders, disintegrants, lubricants, etc.

[0075] In some embodiments, the FXR agonist is administered orally, and the GLP-1 receptor small molecule agonist is also administered orally.

[0076] In some embodiments, the pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form. For example, the pharmaceutical composition can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays.

[0077] The effects of the invention

[0078] The pharmaceutical composition disclosed herein has a synergistic effect on weight loss and is expected to have a positive effect on multiple aspects, including comprehensive regulation of insulin sensitivity, lipid and bile acid metabolism, as well as on improving the body's metabolic state and reducing serum total cholesterol, low-density lipoprotein cholesterol, total liver triglycerides and hydroxyproline. It also shows potential application value in the prevention and / or treatment of metabolic disorder-related diseases or conditions. Attached Figure Description

[0079] Figure 1: Weight change curves in hGLP1R obese mice when FXR agonist 1 (represented as "1" in the figure) was combined with Orforglipron.

[0080] Figure 2: Weight changes in obese hGLP1R mice after four weeks of combined administration of FXR agonist 1 and Orforglipron. ****p<0.0001, relative to the model animal group, one-way ANOVA was used; #p<0.05, ###p<0.001, ####p<0.0001, t-test was used.

[0081] Figure 3: Weight change curves in hGLP1R obese mice when FXR agonist 1 was combined with Danuglipron.

[0082] Figure 4: Weight changes in obese hGLP1R mice after four weeks of combined administration of FXR agonist 1 and Danuglipron. **p<0.01, ****p<0.0001, relative to the model animal group, one-way ANOVA was used; ##p<0.01, ###p<0.001, t-test was used. Detailed Implementation

[0083] I. Definition

[0084] In this disclosure, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are those widely used and standard practices in their respective fields. To better understand this disclosure, definitions and explanations of related terms are provided below.

[0085] As used in the claims and specification, the words “comprising,” “having,” “including,” or “containing” mean inclusive or open-ended and do not exclude additional, uncited elements or method steps. At the same time, “comprising,” “having,” “including,” or “containing” can also mean closed-ended, excluding additional, uncited elements or method steps.

[0086] In this disclosure, the term "agonist" refers to a substance (ligand) that activates signal transduction by means of a target receptor type.

[0087] In this disclosure, the term "solvent" refers to an association formed by one or more solvent molecules with a compound of this disclosure. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0088] In this disclosure, the term "pharmaceutically acceptable salt" refers to a salt of a compound of this disclosure, prepared by reacting a compound having specific substituents, as discovered in this disclosure, with a relatively non-toxic acid or base. When the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this disclosure contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0089] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0090] In this disclosure, the term "treatment" means: after a person has contracted a disease, exposing (e.g., administering medication) a pharmaceutical composition of this disclosure to reduce the symptoms of the disease compared to when the person is not exposed, without implying that the symptoms of the disease must be completely suppressed.

[0091] In this disclosure, the term "prevention" means: to reduce the symptoms of a disease by exposing a subject to (e.g., administering medication) the pharmaceutical composition of this disclosure before the onset of the disease, compared to the absence of exposure, and does not imply complete suppression of the disease.

[0092] In this disclosure, the term "metabolic disorder" can refer to disorders of glucose metabolism, disorders of lipid metabolism, etc. Metabolic disorders or conditions include primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), various chronic hepatitis states (hepatitis B and hepatitis C), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, and diabetes.

[0093] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0094] When the lower and upper limits of a numerical range are disclosed, any value or subrange falling within that range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b", or equivalently "above a and below b", or equivalently "about ab") should be understood to encompass every value and subrange therein. For example, "C..." 1-4 "This should be understood as encompassing any subrange and every point value, such as C." 2-4 C 3-4 C 1-2 C 1-3 C 1-4 And so on, as well as C1, C2, C3, C4, etc.

[0095] The term “substituted” or “substituted” refers to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the particular atom or group is normal and the substituted compound is stable.

[0096] The term "independently" means that at least two groups (or ring systems) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0097] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0098] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" refers alone or in combination to a saturated straight-chain or branched alkyl group containing 1 to 6 carbon atoms, including (but not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. Alkyl groups can be optionally substituted or unsubstituted.

[0099] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic hydrocarbon group. For example, the term "C3-C6 cycloalkyl" as used in this disclosure refers to a cycloalkyl group having 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups can be optionally substituted or unsubstituted.

[0100] The term "pharmaceutical composition" refers to a formulation or combination of formulations containing one, two or more active ingredients, wherein the active ingredients contained therein are present in a biologically effective form and do not contain any additional ingredients that would have unacceptable toxicity to a subject administering the formulation.

[0101] In this document, "excipient" refers to any component in a pharmaceutical composition other than the active ingredient and absorption enhancer. Excipients may be inert, inactive, and / or pharmaceutically inactive substances. Those skilled in the art can select any one or more excipients through routine testing without any undue burden, based on the specific desired performance of the dosage form. The amount of each excipient used can vary within the range conventionally practiced in the art. The excipients described herein include one or more of fillers, diluents, binders, disintegrants, lubricants, and flow aids. Fillers include, but are not limited to, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, dicalcium phosphate, sorbitol, or any mixture thereof. Binders include, but are not limited to, povidone and its homologues, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and its homologues, or any mixture thereof. Disintegrants include, but are not limited to, microcrystalline cellulose, alginate, alginate, potassium polymethyl cellulose, dicalcium phosphate, corn starch, pregelatinized starch, sodium carboxymethyl starch, sodium glycolate starch, crospovidone, cellulose powder, and cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and crospovidone carboxymethyl cellulose. Lubricants include, but are not limited to, magnesium stearate, glyceryl behenate, sodium stearoyl fumarate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, or any mixture thereof. Flow aids are selected from colloidal silica or talc.

[0102] The term "absorption enhancer" as used in this article refers to special excipients that can improve the absorption of drugs through the intestinal mucosa.

[0103] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the disease being treated or preventing the occurrence of the disease or its symptoms.

[0104] As used herein, the term "subject" refers to any animal, such as a mammal or marsupial. Subjects of this disclosure include, but are not limited to, humans, non-human primates (such as cynomolgus monkeys or rhesus monkeys or other types of macaques), mice, pigs, dogs, horses, donkeys, cattle, sheep, rats, and any kind of poultry.

[0105] II. Specific Implementation Examples

[0106] The following provides exemplary test protocols for the treatment of obesity using the pharmaceutical compositions of this disclosure, to demonstrate the beneficial activity or technical effects of the compositions of this disclosure. However, it should be understood that the following test protocols are merely examples of the content of this disclosure and not limitations on the scope of this disclosure. Those skilled in the art, guided by this specification, can make appropriate modifications or changes to the technical solutions of this disclosure without departing from the spirit and scope of this disclosure.

[0107] The reagents or instruments used in the examples are all commercially available conventional products. Unless otherwise specified, all conditions were performed under conventional conditions or conditions recommended by the manufacturer. When used to modify a numerical value or range, the term "about" as used in this disclosure means including the numerical value or range and a range of errors acceptable to those skilled in the art, such as ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0108] Experimental materials

[0109] Test sample:

[0110] Orforglipron (CAS No.: 2212020-52-3, Brand: Bidepharm, Catalog No.: BD01124628) and Danuglipron (CAS No.: 2230198-02-2, Brand: Bidepharm, Catalog No.: BD01093777) are available for direct purchase; FXR agonist 1 (structure shown below) can be prepared according to the method disclosed in patent CN114315830A.

[0111] Laboratory animals:

[0112] The model animal group and the drug-treated group were obtained from male human hGLP1R transgenic mice with a C57BL / 6 background, induced by a high-fat diet, and purchased from Cyagen (Suzhou) Biotechnology Co., Ltd. The animals in Examples 1 and 2 were induced with a high-fat diet for 16 weeks from 7-8 weeks of age, and the weight of the animals in the model group and the drug-treated group was approximately 40-45g at the time of grouping.

[0113] Feed used to build the model:

[0114] High-fat feed, brand: Research Diet Inc, item number: D12492

[0115] FXR agonist 1, Orforglipron and Danuglipron formulation:

[0116] Solutol becomes liquid at 60°C. Add an appropriate volume of the weighed FXR agonist 1, Orforglipron, or Danuglipron, and magnetically stir until uniformly dispersed. Repeat stirring and sonication until completely dissolved. Add a certain amount of ultrapure water, magnetically stir until homogeneous, and sonicate until completely dissolved. Then, bring the volume to the required level, i.e., 15% soutol. The prepared solution (the concentration of FXR agonist 1 in Examples 1 and 2 is 0.06 mg / mL; the concentration of Orforglipron in Example 1 is 0.06 and 0.2 mg / mL; the concentration of Danuglipron in Example 2 is 2 mg / mL) is stored at 4°C and prepared every 7 days.

[0117] Example 1: The efficacy of the disclosed pharmaceutical composition (FXR agonist 1 + Orforglipron) in a high-fat-induced human hGLP1R obese mouse model.

[0118] Animals were introduced into the experiment after one week of acclimatization within the barrier. The model animal group and the drug-treated group were randomly assigned based on animal body weight. Mice in both groups were fed a high-fat diet, and all animals were housed for 16 weeks before the experiment began. Animal weight was measured and recorded every three days.

[0119] Experimental grouping and drug administration:

[0120] The experiment was divided into 6 groups (n=6): model animal group (group 1); FXR agonist 1, 0.3 mpk (mg / kg) group (group 2); Orforglipron, 0.3 mpk group (group 3); Orforglipron, 1 mpk group (group 4); FXR agonist 1, 0.3 mpk + Orforglipron, 0.3 mpk group (group 5); and FXR agonist 1, 0.3 mpk + Orforglipron, 1 mpk group (group 6). The model animal group was given a solvent (15% solubilitol + 85% ultrapure water). FXR agonist 1 and Orforglipron were administered orally at a volume of 5 mL / kg, once daily for 4 weeks.

[0121] Experimental data analysis:

[0122] Weight change curve (Figure 1)

[0123] During the experiment, the animals in the Orforglipron, 0.3 mpk and 1 mpk dose groups (groups 3 and 4) experienced a continuous decrease in body weight, reaching a plateau after 2–3 weeks of administration. The FXR agonist 1, 0.3 mpk + Orforglipron, 0.3 mpk group (group 5), and the FXR agonist 1, 0.3 mpk + Orforglipron, 1 mpk group (group 6) showed a continuous decrease in body weight during the 4-week administration period. Orforglipron exhibited a dose-dependent effect; the combined Orforglipron, 1 mpk dose group (group 6) showed a better effect on body weight reduction than the combined Orforglipron, 0.3 mpk group (group 5), and the combined groups (groups 5 and 6) showed significantly better body weight reduction than the single-drug groups (groups 2, 3, and 4).

[0124] Weight changes over four weeks of drug administration (Figure 2)

[0125] Compared with the model animal groups, the weight loss in animals treated with Orforglipron at 0.3 mpk and 1 mpk (groups 3 and 4), Orforglipron at 0.3 mpk in combination with FXR agonist 1 (group 5), and Orforglipron at 1 mpk in combination with FXR agonist 1 (group 6) was significantly different and statistically significant. The weight loss in animals treated with Orforglipron at 0.3 mpk or 1 mpk in combination with FXR agonist 1 (groups 5 and 6) was more significant and statistically significant compared with either drug alone. Among them, the animal body weight of the combination group of Orforglipron, 0.3mpk and FXR agonist 1 (Group 5) decreased by 18.61%, which was greater than the sum of the percentage changes in body weight of Orforglipron, 0.3mpk (Group 3) and FXR agonist 1 (Group 2) alone (11.61% + 5.85% = 17.46%); the animal body weight of the combination group of Orforglipron, 1mpk and FXR agonist 1 (Group 6) decreased by 30.72%, which was greater than the sum of the percentage changes in body weight of Orforglipron, 1mpk (Group 4) and FXR agonist 1 (Group 2) alone (13.56% + 5.85% = 19.41%), demonstrating the synergistic effect of the combination therapy.

[0126] Experimental conclusions: The results of weight change (Figures 1 and 2) showed that in high-fat-induced human hGLP1R obese mice, administration of Orforglipron or FXR agonist 1 could reduce the weight of the mice. Among them, the combined administration of Orforglipron and FXR agonist 1 had a more significant effect on reducing the weight of the mice than the single administration, demonstrating the synergistic effect of the combined administration.

[0127] Example 2: The efficacy of the disclosed pharmaceutical composition (FXR agonist 1 + Danuglipron) in a high-fat-induced human hGLP1R obese mouse model.

[0128] Experimental grouping and drug administration:

[0129] The experiment was divided into 4 groups (n=6): model animal group (group 1), FXR agonist 1, 0.3 mpk group (group 2), Danuglipron, 10 mpk group (group 3), and FXR agonist 1, 0.3 mpk + Danuglipron, 10 mpk group (group 4). The model animal group was given a solvent (15% solubilol + 85% ultrapure water). FXR agonist 1 and Danuglipron were administered orally at a dose of 5 mL / kg. FXR agonist 1 was administered once daily, and Danuglipron twice daily. Both drugs were administered continuously for 4 weeks.

[0130] Weight change curve (Figure 3)

[0131] During the experiment, in the Danuglipron, 10mpk dose group (group 3), the animals reached a plateau in weight loss after 2-3 weeks of administration; in the Danuglipron, 10mpk combined with FXR agonist 1 group (group 4), the animals' weight loss was more significant with the extension of administration time, and the weight loss effect of the combined group was significantly better than that of the single drug group.

[0132] Weight changes over four weeks of drug administration (Figure 4)

[0133] Compared with the model animal groups, the Danuglipron-treated groups (group 3) and the Danuglipron + FXR agonist 1 combination group (group 4) showed significant and statistically significant weight loss. Furthermore, the weight loss in the Danuglipron + FXR agonist 1 combination group (group 4) was more pronounced than in either of the single-drug groups (groups 2 and 3), showing a statistically significant difference. Specifically, the Danuglipron + FXR agonist 1 combination group (group 4) showed a weight loss of 18.34%, which was greater than the combined percentage change in weight for Danuglipron (group 3) and FXR agonist 1 (group 2) alone (8.36% + 4.84% = 13.20%), demonstrating the synergistic effect of the combination therapy.

[0134] Experimental conclusions: The results of weight change showed (Figures 3 and 4) that in high-fat-induced human hGLP1R obese mice, administration of Danuglipron or FXR agonist 1 could reduce the weight of the mice. The combined administration of Danuglipron and FXR agonist 1 had a more significant effect on reducing the weight of the mice than the administration of either drug alone, demonstrating the synergistic effect of the combined administration.

Claims

1. A pharmaceutical composition comprising an FXR agonist and a GLP-1 receptor small molecule agonist, wherein the FXR agonist is selected from a compound as shown in Formula (I), a tautomer, a solvate, or a pharmaceutically acceptable salt thereof, and the GLP-1 receptor small molecule agonist is selected from Danuglipron, Orforglipron, or a pharmaceutically acceptable salt thereof: In formula (I), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6alkyl-O-, C3-C6cycloalkyl or C3-C6cycloalkyl-O-, said alkyl being optionally substituted by one or more halogens; R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, halogen, C1-C6alkyl, C1-C6alkyl-O-, C3-C6cycloalkyl, C3-C6cycloalkyl-O-, -CN, or -NO2, said alkyl optionally substituted with one or more halogen.

2. The pharmaceutical composition of claim 1, wherein R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, or Ci-C6alkyl optionally substituted with one or more halogen; or, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or F.

3. The pharmaceutical composition of claim 1 or 2, wherein R 11 , R 12 , R 13 , R 14 , and R 15 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl-O-, -CN, or -NO2, said alkyl optionally substituted with one or more halogen; or, R 11 , R 12 , R 13 , R 14 , and R 15 are each independently hydrogen, F, Cl, CF3, -OCF3, -OCF2H, or CH3.

4. The pharmaceutical composition of any one of claims 1-3, wherein the FXR agonist is a compound shown below, a tautomer, solvate, or pharmaceutically acceptable salt thereof:

5. The pharmaceutical composition of any one of claims 1-4, wherein the FXR agonist is a compound shown below, a tautomer, solvate, or pharmaceutically acceptable salt thereof, and the GLP-1 receptor small molecule agonist is Danuglipron or a pharmaceutically acceptable salt thereof, 6. The pharmaceutical composition of any one of claims 1-4, wherein the FXR agonist is a compound shown below, a tautomer, solvate, or pharmaceutically acceptable salt thereof, and the GLP-1 receptor small molecule agonist is Orforglipron or a pharmaceutically acceptable salt thereof, 7. The pharmaceutical composition according to any one of claims 1-6, further comprising one or more pharmaceutically acceptable excipients and / or absorption enhancers; preferably, the absorption enhancer is octanoate or a combination of octanoate and N-(8-(2-hydroxybenzoyl)amino)octanoate; preferably, the octanoate is sodium octanoate, and the N-(8-(2-hydroxybenzoyl)amino)octanoate is sodium N-(8-(2-hydroxybenzoyl)amino)octanoate.

8. Use of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a medicament for treating and / or preventing metabolic disorders; preferably, the metabolic disorder is selected from primary biliary cirrhosis, primary sclerosing cholangitis, hepatitis B, hepatitis C, non-alcoholic fatty liver disease, or obesity.

9. The use according to claim 8, wherein the dosage of the FXR agonist is 0.001 to 10 mg per dose, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.015 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.12 mg, 0.15 mg, 0.2 mg, 0.4 mg, 0.6 mg, 1 mg, 1.4 mg, 2 mg, 2.8 mg, 4 mg, 6 mg, or 8 mg; The dosage of GLP-1 receptor small molecule agonists is 0.001 to 50 mg per dose, preferably 0.0012 mg, 0.00135 mg, 0.004 mg, 0.0045 mg, 0.008 mg, 0.009 mg, 0.012 mg, 0.0135 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.045 mg, 0.05 mg, 0.06 mg, 0.07 mg, etc. 0.08mg, 0.09mg, 0.1mg, 0.25mg, 0.4mg, 0.45mg, 0.5mg, 0.7mg, 1mg, 1.4mg, 1.7mg, 2.0mg, 2.4mg, 2.5mg, 2.8mg, 3.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg or 45mg.

10. The use according to claim 8 or 9, wherein the FXR agonist is administered once daily or twice daily, and the GLP-1 receptor small molecule agonist is administered twice daily, once daily, once every two days, once every three days, once weekly, or once every two weeks; Alternatively, FXR agonists can be administered once daily, and GLP-1 receptor small molecule agonists can be administered twice daily. Alternatively, the FXR agonist is administered once per day and the GLP-1 receptor small molecule agonist is administered once per day.

11. The use according to any one of claims 8-10, wherein the FXR agonist is administered once per day for a treatment period of one or more weeks and the GLP-1 receptor small molecule agonist is administered twice per day for a treatment period of one or more weeks; or, the GLP-1 receptor small molecule agonist is administered once per day for a treatment period of one or more weeks.

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