CN-121991027-A - Benzamide compound, preparation method thereof, pharmaceutical composition and application

Abstract

The invention belongs to the technical field of pharmacy, and relates to a benzamide compound, a preparation method, a pharmaceutical composition and application thereof. The benzamide compound is shown as a formula (I), and is an EPHB4 inhibitor. The inhibition of EPHB4 kinase activity by this compound was verified by in vitro phosphorylation reaction. Meanwhile, the cell model system of insulin resistance verifies that the cell model system has the effect of increasing the insulin sensitivity of model cells.

Inventors

• XU HENG
• LI PINGPING
• XING XIAOWEI
• QI HAIXIANG
• LIU XINGFENG
• WANG SHUNING

Assignees

• 中国医学科学院药物研究所

Dates

Publication Date

20260508

Application Date

20241104

Claims (6)

1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R 1 is selected from hydrogen, C 1-3 alkyl.
2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
3. 3. a pharmaceutical composition comprising at least one compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient.
4. 4. The pharmaceutical composition of claim 3, further comprising a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.
5. 5. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 3 or 4, in the manufacture of a medicament for the prevention and/or treatment of a disease associated with EPHB 4.
6. 6. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 3 or 4, in the manufacture of a medicament for the prevention and/or treatment of insulin resistance and related metabolic disorders.

Description

Benzamide compound, preparation method thereof, pharmaceutical composition and application Technical Field The invention belongs to the technical field of pharmacy, and relates to a benzamide compound, and a preparation method, application and a pharmaceutical composition thereof. Background In recent years, the incidence of metabolic diseases such as obesity and diabetes has been rapidly increasing. The related research data show that only 2021 years, the number of people suffering from diabetes mellitus in China is more than 400 ten thousand, and more than 98% of patients are type 2 diabetes patients. The total number of people suffering from diabetes in China exceeds 1.17 hundred million, and the Chinese diabetes mellitus is the most prominent country of diabetes patients in the world today. Obesity and diabetes mellitus can not be effectively treated and controlled in time, and can induce related metabolic syndromes of tissues and organs such as cardiovascular diseases, kidney diseases, eyes and the like, so that serious threat is brought to physical and mental health of people, and meanwhile, heavy economic burden is brought to society. Insulin signaling plays an important role in regulating glucose metabolic homeostasis in the body, and insulin resistance is one of the important pathological features of type 2 diabetes, and is also recognized as an important causative factor for various metabolic diseases. Studies have shown that insulin resistance has occurred in the body 10-20 years before the diagnosis of type 2 diabetes patients, and may be caused by chronic tissue inflammation, endoplasmic reticulum stress, intestinal flora, and the like. In the case of insulin resistance, the body will compensatively increase insulin secretion, thereby leading to hyperinsulinemia. Our studies indicate that high levels of insulin further promote the interaction of the insulin receptor with EphB4 protein, ephB4 promotes endocytosis of the insulin receptor in a Clathrin-dependent manner through binding to the adaptor protein Ap2 and degradation via the lysosomal pathway, thereby inhibiting insulin signaling and exacerbating insulin resistance. There is still a lack of good insulin sensitizers in clinic. Thiazolidinedione (TZD) compounds which have been shown to improve insulin resistance and increase insulin sensitivity have a target PPARgamma, belonging to the mammalian nuclear receptor superfamily. However, TZD-based drugs have been removed from the market or limited in their use because of their side effects such as weight gain and cardiovascular risk. Therefore, no better insulin sensitizer exists in the medicaments practically applied at present. Our research proves that EphB4 can be used as the acting target of insulin sensitization medicine, therefore, the invention takes EphB4 as the target, develops a novel inhibitor thereof and is used as a novel insulin sensitizer to solve the current problems. Disclosure of Invention The object of the present invention is to provide a novel EPHB4 inhibitor which has a potent inhibitory activity on EPHB4 kinase and thus has a preventive and/or therapeutic effect on diseases related to EPHB4, particularly insulin resistance and related metabolic diseases. In order to solve the technical problems of the invention, the invention provides the following technical scheme: according to a first aspect of the present invention, there is provided a compound represented by formula (I): wherein R 1 is selected from hydrogen, C 1-3 alkyl. In particular, preferred compounds according to the invention are as follows: According to a second aspect of the technical scheme, the invention provides a preparation method of the compound, which comprises the following steps: (1) Using the compound A as a starting material, and preparing a compound B by carrying out Suzuki reaction on the compound A and 4-pyridine boric acid; (2) Hydrolyzing the compound B with concentrated sulfuric acid to prepare a compound C; (3) Preparing a compound D from the compound C through bromination reaction; (4) The compound D is subjected to Suzuki reaction to prepare a compound shown in a formula (I) or pharmaceutically acceptable salt thereof; In a third aspect of the present invention there is provided a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient, preferably the pharmaceutical composition further comprises one or more pharmaceutically active ingredients other than the compound or a pharmaceutically acceptable salt thereof, for the prophylaxis and/or treatment of tumours. In a further aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the compounds or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent or excipient, preferably selected from the group consisting of parenteral formulations,