Pharmaceutical composition for controlling weight of women in menopausal period and application of pharmaceutical composition

Abstract

The invention belongs to the technical field of biological medicine, and particularly provides a medicine for controlling female menopausal body weight, which comprises a fatty acid binding protein 4 inhibitor or pharmaceutically acceptable salt thereof. The medicine for controlling the weight of women in the menopausal period has the effect of controlling the weight of women in the menopausal period and can relieve the obesity of women in the menopausal period. The medicine is a non-hormone medicine, does not have the risk of inducing hormone tumors by regulating the effects of hormones and related pathways, can be orally taken, does not need to be injected, and has the characteristic of convenience in administration.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and specifically relates to a medicine composition for controlling weight during menopause of women and application thereof. BACKGROUND

[0002] As women age, they may find it increasingly difficult to maintain a normal weight, especially in the years leading up to menopause, known as the perimenopausal period. Between the ages of 50 and 60, women tend to gain weight at a rate of about 0.7 kilograms per year. The reasons for weight gain during menopause are multifaceted. Hormonal changes during menopause can cause women to accumulate fat more easily in their abdomen relative to their hips and thighs. But hormonal changes are not the only factor contributing to weight gain, and lifestyle and genetic factors are also associated with it.

[0003] Menopausal weight gain can increase a variety of health risks, including but not limited to: (1) Cardiovascular disease: Abdominal fat accumulation is associated with an increased risk of cardiovascular disease. Menopausal weight gain can lead to cardiovascular problems such as high blood pressure, high cholesterol, and arteriosclerosis. (2) Type 2 diabetes: Menopausal weight gain is associated with an increased risk of developing type 2 diabetes. Abdominal obesity can affect insulin sensitivity, increasing the likelihood of developing diabetes. (3) Osteoporosis: Decalcification and weight gain can lead to osteoporosis, increasing the risk of bone fractures, especially in the later stages of menopause in women. (4) Certain cancers: Abdominal fat is associated with an increased risk of various cancers, including breast cancer, endometrial cancer, and colon cancer. (5) Respiratory problems: Increased abdominal fat can lead to respiratory problems such as sleep apnea syndrome (SDB). (6) Joint problems: Overweight and obesity can increase the burden on the joints, potentially leading to joint problems such as osteoarthritis. (7) Heart health: Menopausal weight gain can lead to heart health problems, including heart disease and stroke.

[0004] In summary, menopausal weight gain is associated with an increased risk of various chronic diseases and health problems. Therefore, adopting a healthy lifestyle, maintaining an appropriate weight, and undergoing regular health checks are crucial for maintaining physical health and reducing the risk of chronic diseases.

[0005] There is no specific medication currently available for the treatment of menopausal obesity in women. For the management of obesity in menopausal women, doctors may consider using some general obesity treatment methods, which include: (1) lifestyle intervention: achieving weight control through dietary changes and increasing physical activity. This may include dietary adjustments, moderate aerobic exercise and strength training. (2) Behavior therapy: with the help of psychological and behavioral principles, help individuals change their unhealthy eating and exercise habits. (3) Drug therapy: some drugs may be used to assist weight management, but need to be used under the supervision of a doctor. These drugs may include hormone therapy, weight management drug semaglutide, etc. (4) Surgical intervention: for patients with extreme obesity, surgical procedures such as gastric bypass surgery (Bariatric surgery) may be considered, but this is usually recommended when other methods are ineffective.

[0006] Hormone replacement therapy (HRT) is used in certain cases to alleviate menopausal symptoms such as hot flashes, mood swings and osteoporosis. However, it also has some drawbacks and potential risks that need to be weighed when using it, including: increased risk of breast cancer, increased risk of endometrial cancer, cardiovascular risk, risk of thrombosis, etc.

[0007] Semaglutide is a drug used to treat diabetes, which belongs to the class of glucagon-like peptide-1 (GLP-1) receptor agonists. Semaglutide exerts its effects by activating the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is a hormone produced in the gut that promotes insulin release and lowers blood glucose levels. Semaglutide also controls food intake by slowing down the rate of gastric emptying, delaying the passage of food through the gastrointestinal tract, thereby regulating body weight. However, semaglutide is usually administered by injection, which may be inconvenient for some patients. SUMMARY

[0008] The purpose of the present invention is to overcome the safety hazards or inconvenience of existing menopausal obesity treatment methods for women, and the lack of special drugs.

[0009] Fatty acid binding protein 4 (fatty acid binding protein 4, hereinafter referred to as FABP4 unless otherwise specified) in ovariectomized mice, the content of FABP4 in serum is increased, and inhibition of FABP4 activity can inhibit weight gain in ovariectomized mice. Therefore, FABP4 is a new target for controlling the weight of menopausal women.

[0010] To this end, the present application provides a medicine for controlling weight of women in menopause, comprising a fatty acid binding protein 4 (FABP4) inhibitor or a pharmaceutically acceptable salt thereof.

[0011] Specifically, the FABP4 inhibitor is any one of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (I), formula (II), or a pharmaceutically acceptable salt thereof,

[0012]

[0013] wherein R1R2 is any one of -H, -F; R is any one of -CH3, -CH2CH3 or -OCH2CH3; X is any one of -OCH2-, -OCH(CH2CH3)-, -CH(OH)CH2-, -CH2CH2-, / , -NHCH2-, -OCH(CH3)-;

[0014]

[0015] wherein X is any one of -O(CH2)4-, -m-Ph-O-CH2-;

[0016]

[0017] wherein X is any one of -OCH2-, -NHCH2-; R is any one of -H, -CH2CH3, -CH(CH3)2, -CH3, -CH2F, -CH2COOH;

[0018]

[0019] wherein R1 is any one of -Cl, -CF3; R2R4 is any one of -H, -F; R3 is any one of -H, -Cl;

[0020]

[0021] wherein X is any one of -O-, -NH-; R1R3 is any one of -H, -Cl; R2 is any one of -OCH3, -CH3, cyclopropyl-;

[0022]

[0023] wherein R1 is any one of -Ph, ; R2 is any one of ; and R3 is -H.

[0024]

[0025] wherein X is any one of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-;

[0026]

[0027] wherein R1 is any one of -H, -CH3, -CH3CONH-; R2, R4 is any one of -H, -CH3, -CH3O-, -F; R3 is any one of -H, -CH3, -CH3O-, -F, -Br; R5 is any one of -H, -CH3O-, -F;

[0028]

[0029] wherein R1 is any one of -F, -OCH3, -CF3, -CH3, -CONH2; n is any one of 0, 1, 2;

[0030]

[0031] wherein n is any one of 0, 1, 2;

[0032]

[0033] wherein R2 is any one of -H, -Ph, ; R3 is any one of -Ph, ;

[0034]

[0035] wherein R1 is any one of -H, -CH3, -CH2OH, -CH2OCH3; R2 is any one of -H, -CF3, -CH3, -C5H 11 ; R3 is any one of -H, -CH3; X is any one of -N=, -CH=; m is any one of 1, 2; n is any one of 0, 1;

[0036]

[0037] wherein X is any one of -CH3, -COOH, -N(CH3)CH2CH3, -N(CH2CH3)2, cyclopropy-, -CH(CH2CH3)2, ; Y is -COOH, -CH(CH3)2, any one of -H, -CH3, -Cl; R2is any one of -H, -F; R3is any one of -H, -CF3, -Cl; R4is any one of -H, -CH(CH3)2;

[0038]

[0039] wherein X is any one of -H, -Cl.

[0040] Specifically, the FABP4 inhibitor described above includes BMS309403 (A1) and its derivatives, which are specifically shown in the following table. Unless otherwise specified, the compounds in the present application are represented by the numbers in the following table; A1 is BMS309403.

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Specifically, the FABP4 inhibitor described above includes BMS309403 (A1) and its derivatives, which are specifically shown in the following table. Unless otherwise specified, the compounds in the present application are represented by the numbers in the following table; A1 is BMS309403.

[0054]

[0055] Specifically, the drug described above further includes a pharmaceutically acceptable carrier.

[0056] Specifically, the drug described above is an oral agent.

[0057] The drug provided by the present application can be used to relieve obesity in women during menopause.

[0058] The fatty acid binding protein 4 inhibitor provided by this invention can be used to prepare drugs for weight control in women during menopause.

[0059] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0060] The drug provided by this invention for controlling weight gain in postmenopausal women has the effect of controlling weight gain during menopause and can alleviate postmenopausal obesity. This drug is a non-hormonal drug that does not act by regulating hormones or related pathways, and does not pose a risk of inducing hormone-related tumors. It can be taken orally without injection, making it convenient to administer.

[0061] The present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0062] Figure 1 This is an animal experiment design diagram in an embodiment of the present invention.

[0063] Figure 2 This is the weight measurement result of the mice in the prevention group in this embodiment of the invention.

[0064] Figure 3 These are the weight measurement results of the mice in the treatment group in this embodiment of the invention. Detailed Implementation

[0065] The technical solutions of the present invention will be clearly and completely described below with reference to embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Although representative embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the scope of the present invention. Therefore, the scope of the present invention should not be limited to the embodiments, but should be defined by the appended claims and their equivalents.

[0066] The following specific embodiments illustrate the efficacy of the pharmaceutical composition for controlling postmenopausal weight in women according to the present invention and its application.

[0067] Example 1:

[0068] This embodiment uses an ovariectomized mouse model to verify the role of fatty acid-binding protein 4 (FABP4) inhibitors in controlling postmenopausal weight.

[0069] The ovariectomy mouse model is an experimental animal model in which the ovaries of mice are surgically removed, either completely or partially, to create ovariectomy mice. This surgery is commonly referred to as ovariectomy (OVX). After ovariectomy, the estrogen levels in mice drop significantly, similar to the menopausal state in female animals. This model can be used to study menopausal-related physiological and behavioral changes. Estrogen affects metabolism, and ovariectomy may lead to weight gain and changes in fat distribution; therefore, this model can be used to examine the effects of drugs on weight changes in ovariectomy mice.

[0070] The FABP4 inhibitors used in this embodiment were A1 (i.e., BMS309403, MCE, catalog number HY-101903) and K19 (i.e., RO6806051, AOBIOUS, catalog number AOB33866). The use of the OVX-induced mouse model and all subsequent experimental protocols were approved by the Ethics Committee of the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences.

[0071] like Figure 1 As shown, in the prevention group experiment, 32 female C57BL / 6J mice (11 weeks old) were randomly divided into four groups (n=8 mice per group): sham operation group, OVX group, OVX + 10 mg / kg A1 administration group, and OVX + 10 mg / kg K19 administration group. Under tribromoethanol anesthesia, each group underwent sham surgery, with ovariectomy or bilateral ovariectomy to induce obesity. Seven days post-surgery, the OVX + 10 mg / kg A1 administration group and the OVX + 10 mg / kg K19 administration group received oral administration of A1 or K19 daily for 28 days. Mouse weight was recorded daily, and the results are shown below. Figure 2 As shown.

[0072] In the treatment group experiment, 32 female C57BL / 6J mice (11 weeks old) were randomly divided into three groups (n=8 mice per group): sham surgery group, OVX group, OVX + 10 mg / kg A1 administration group, and OVX + 10 mg / kg K19 administration group. Under tribromoethanol anesthesia, each group underwent sham surgery, with ovariectomy or bilateral ovariectomy to induce obesity. For 28 days post-surgery, the OVX + 10 mg / kg A1 administration group and the OVX + 10 mg / kg K19 administration group received oral administration of A1 or K19 daily for 28 days. Mouse weight was recorded daily, and the results are as follows: Figure 3 As shown.

[0073] In vitro experiments revealed that in the prevention group ( Figure 2 ) and treatment group ( Figure 3In experiments, compared with the surgical group, FABP4 inhibitors A1 and K19 significantly reduced the body weight of ovariectomized mice. Therefore, FABP4 inhibitors A1 and K19 have the effect of controlling weight gain in postmenopausal women and can be administered orally, making them convenient to take.

[0074] The above examples are merely illustrative of the present invention and do not constitute a limitation on the scope of protection of the present invention. All designs that are the same as or similar to the present invention are within the scope of protection of the present invention.

Claims

1. The use of fatty acid-binding protein 4 inhibitors or pharmaceutically acceptable salts thereof in the preparation of drugs for controlling postmenopausal weight in women.

2. The application as described in claim 1, characterized in that: The fatty acid binding protein 4 inhibitor is selected from any one of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (I), and formula (II), or a pharmaceutically acceptable salt thereof; Wherein, R1R2 is any one of -H and -F; R is any one of -CH3, -CH2CH3 or -OCH2CH3; X is any one of -OCH2-, -OCH(CH2CH3)-, -CH(OH)CH2-, -CH2CH2-, / , -NHCH2-, -OCH(CH3-); Wherein, X is either -O(CH2)4- or -m-Ph-O-CH2-; Where X is any one of -OCH2- and -NHCH2-; R is any one of -H, -CH2CH3, -CH(CH3)2, -CH3, -CH2F, and -CH2COOH; Where R1 is any one of -Cl and -CF3; R2R4 is any one of -H and -F; and R3 is any one of -H and -Cl. Where X is any one of -O- and -NH-; R1R3 is any one of -H and -Cl; R2 is any one of -OCH3, -CH3, and cyclopropyl-. Where R1 is -Ph, Any one of them; R2 is Any one of them; Wherein, X is any one of -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-; Wherein, R1 is any one of -H, -CH3, and -CH3CONH-; R2 and R4 are any one of -H, -CH3, -CH3O-, and -F; R3 is any one of -H, -CH3, -CH3O-, -F, and -Br; and R5 is any one of -H, -CH3O-, and -F. Where R1 is any one of -F, -OCH3, -CF3, -CH3, and -CONH2; n is any one of 0, 1, and 2; Where n can be any of 0, 1, or 2; Where R2 is -H, -Ph, Any one of them; R3 is -Ph, Any one of them; Wherein, R1 is any one of -H, -CH3, -CH2OH, and -CH2OCH3; R2 is -H, -CF3, -CH3, or -C5H. 11 Any one of the following; R3 is any one of -H and -CH3; X is any one of -N= and -CH=; m is any one of 1 and 2; n is any one of 0 and 1; Where X is -CH3, -COOH, -N(CH3)CH2CH3, -N(CH2CH3)2, cyclopropy-, -CH(CH2CH3)2, Any one of them; Y is -COOH, -CH(CH3)2, R1 is any one of -H, -CH3, and -Cl; R2 is any one of -H and -F; R3 is any one of -H, -CF3, and -Cl; R4 is any one of -H and -CH(CH3)2. Where X is Any one of -H and -Cl; R is any one of -H and -Cl.

3. The application as described in claim 2, characterized in that, The fatty acid-binding protein 4 inhibitor is selected from:

4. The application as described in claim 3, characterized in that, The fatty acid-binding protein 4 inhibitors include:

5. The application as described in any one of claims 1-4, characterized in that, The aforementioned medication for controlling postmenopausal weight is suitable for patients at high risk of hormone-related tumors.

6. The application as described in any one of claims 1-4, characterized in that, The aforementioned weight-controlling medication for postmenopausal women is intended for patients who are intolerant to injectable medications.

7. A pharmaceutical composition for controlling weight gain in postmenopausal women, characterized in that... This includes fatty acid-binding protein 4 inhibitors or their pharmaceutically acceptable salts.

8. The pharmaceutical composition for controlling postmenopausal weight in women as described in claim 7, characterized in that, It also includes pharmaceutically acceptable carriers.

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