Use of a chemokine receptor 2 antagonist for the preparation of a medicament for the treatment of diabetes complicated by anxiety

Abstract

The present invention relates to the use of a compound of formula I, in particular to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diabetes complicated by anxiety

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to the application of a compound of formula I in the field of treating diabetes complicated with anxiety

[0002] BACKGROUND

[0003] Diabetes is a major global health challenge, and its complications are also a problem that cannot be ignored. Epidemiological studies have shown that anxiety is one of the most common complications of diabetes, threatening the quality of life of 110 million diabetes patients worldwide. Diabetes complicated with anxiety not only affects the psychological health of patients, but also may increase the difficulty of diabetes control and the risk of other complications. In addition, anxiety-like behavior has also been observed in diabetic mice (such as db / db mice). Although both diabetic mice and diabetic patients are found to have an increased risk of anxiety, in clinical practice, most patients with diabetes complicated with anxiety are difficult to obtain effective treatment. Generally, the drugs selected for the treatment of anxiety include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and benzodiazepines. However, these traditional anti-anxiety drugs have the risk of weight change and promotion of diabetic complications.

[0004] Therefore, it is necessary to explore potential drugs without the risk of metabolic deterioration to treat diabetes complicated with anxiety. SUMMARY

[0005] The purpose of the present application is to provide the use of a compound of formula I or a pharmaceutically acceptable salt thereof

[0006]

[0007] In particular, the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or alleviating, treating diabetes complicated with anxiety.

[0008] In a first aspect of the present application, the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament or a pharmaceutical composition for treating diabetes complicated with anxiety is provided

[0009]

[0010] In another preferred embodiment, the treatment of anxiety includes anti-anxiety.

[0011] In another preferred embodiment, the diabetes includes type 1 diabetes and / or type 2 diabetes.

[0012] In another preferred embodiment, the diabetes has one or more of the following characteristics:

[0013] (c1) fasting blood glucose is greater than or equal to 7.0 mmol / L;

[0014] (c2) two-hour postprandial blood glucose is greater than or equal to 11.1 mmol / L.

[0015] In another preferred embodiment, the pharmaceutical composition comprises:

[0016] (a) a first active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt thereof;

[0017] (b) a second active ingredient, an active ingredient for treating diabetes; and

[0018] (c) a pharmaceutically acceptable carrier.

[0019] In another preferred embodiment, the pharmaceutical or pharmaceutical composition is an oral preparation, or an injection preparation.

[0020] In another preferred embodiment, the oral preparation is selected from the group consisting of a capsule, a tablet, a powder, a spray, a sustained-release preparation, an oral liquid, a dripping pill, a nano-preparation.

[0021] In a second aspect of the present application, a method for treating anxiety is provided, comprising the step of administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, thereby improving anxiety.

[0022] In another preferred embodiment, the anxiety is diabetes complicated with anxiety.

[0023] In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0024] In another preferred embodiment, the pharmaceutical or pharmaceutical composition is an oral preparation, or an injection preparation, or a tablet.

[0025] In another preferred embodiment, the concentration of the compound of the present application or a pharmaceutically acceptable salt thereof in the method is 0.5-20 μM, preferably 1-10 μM.

[0026] In another preferred embodiment, the subject has one or more of the following characteristics:

[0027] (c1) fasting blood glucose is greater than or equal to 7.0 mmol / L;

[0028] (c2) two-hour postprandial blood glucose is greater than or equal to 11.1 mmol / L.

[0029] In a third aspect of the present application, a kit is provided, comprising:

[0030] (a) a first pharmaceutical composition for a first active ingredient for treating diabetes or a pharmaceutically acceptable carrier thereof;

[0031] (b) a second pharmaceutical composition, a compound of Formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof

[0032]

[0033] In another preferred embodiment, the kit is used for treating diabetes complicated with anxiety.

[0034] In another preferred embodiment, the kit comprises an instruction.

[0035] In another preferred embodiment, the instruction indicates that the first pharmaceutical composition and the second pharmaceutical composition can be taken simultaneously or sequentially.

[0036] In another preferred embodiment, the first pharmaceutical composition comprises a sulfonylurea, a biguanide hypoglycemic agent, an alpha glucosidase inhibitor, an insulin sensitizer, a glinide insulin secretagogue, an insulin preparation, or a combination thereof.

[0037] In another preferred embodiment, the sulfonylurea is selected from the group consisting of tolbutamide, glibenclamide, glicazide, glipizide, glimepiride, or a combination thereof.

[0038] In another preferred embodiment, the biguanide hypoglycemic agent is selected from the group consisting of phenformin, metformin, buformin, or a combination thereof.

[0039] In another preferred embodiment, the alpha glucosidase inhibitor is selected from the group consisting of acarbose, voglibose, or a combination thereof.

[0040] In another preferred embodiment, the glinide insulin secretagogue is selected from the group consisting of repaglinide, nateglinide, or a combination thereof.

[0041] In another preferred embodiment, the insulin preparation is selected from the group consisting of animal insulin, human insulin, insulin analog, or a combination thereof.

[0042] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail hereinafter (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 The blood glucose levels of normal mice, diabetic model mice, and diabetic model mice treated with the compound of the present application are shown.

[0044] Figure 2The light-dark box test was used to evaluate the anxiety-like behavior of the diabetic model mice treated with the compounds of the present application. Figure 2 A shows the number of times the mice of different groups entered the light box, Figure 2 B shows the duration of the mice of different groups entering the light box.

[0045] Figure 3 The elevated plus maze test was used to evaluate the anxiety-like behavior of the diabetic model mice treated with the compounds of the present application. Figure 3 A shows the distance of the mice of different groups moving in the open arms, Figure 3 B shows the duration of the mice of different groups entering the open arms. DETAILED DESCRIPTION

[0046] The present inventors have made extensive and in-depth research and, through a large number of screenings, first discovered a class of compounds for improving diabetes complicated with anxiety, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof. The present inventors have found that the compounds of the present application can significantly improve diabetes complicated with anxiety without increasing the fasting blood glucose of diabetes. On this basis, the present application is completed.

[0047] TERMS

[0048] For the purpose of facilitating the understanding of the present application, certain technical and scientific terms are defined below. Unless otherwise defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present application belongs. Before describing the present application, it should be understood that the present application is not limited to the particular methodology and experimental conditions described, as such methodology and conditions can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present application will be limited only by the appended claims.

[0049] As used herein, the term "comprises" or its variants such as "comprising" or "comprised of" is understood to include the elements or components described, but not to exclude other elements or components.

[0050] Anxiety

[0051] Anxiety, also known as anxiety neurosis, is the most common type of neurosis, which is characterized by anxiety.

[0052] Diabetes complicated with anxiety

[0053] Diabetes is a lifelong disease and cannot be cured. Diabetic patients can only maintain normal circulation of the body by taking oral drugs or injecting insulin.

[0054] Diabetes is also prone to complications, as many as 100, is the most known complications of the disease, for example, diabetes and anxiety, diabetic nephropathy, diabetic eye complications, diabetic cerebrovascular disease, diabetic neuropathy, etc.

[0055] Diabetes and anxiety, refers to the patient in the fight with diabetes and other long-term concerns and fears, including its blood sugar management, the threat of complications, potential loss of function, and concerns about getting responsive care.

[0056] Active compounds and active ingredients of the present application

[0057] In the present application, an active ingredient effective in improving anxiety is provided. The active ingredient is selected from the group consisting of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a combination thereof, or a crystal thereof, or a solvate thereof

[0058]

[0059] As used herein, the terms "compound of the present application", "active compound of the present application", "active ingredient of the present application", "pharmaceutical or pharmaceutical composition of the present application", "compound of Formula I", "CCR2 antagonist INCB3284", "INCB3284" are used interchangeably to refer to a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a combination thereof, or a crystal thereof, or a solvate thereof.

[0060] It should be understood that the active ingredient of the present application includes the active compound of the present application, or its pharmaceutically acceptable salt, enantiomer, diastereoisomer or racemate, or its prodrug. It should be understood that the active ingredient of the present application also includes the crystal form, amorphous compound, and deuterated compound, etc. of the active compound of the present application.

[0061] The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by reacting the active compound of the present application with an inorganic acid or an organic acid. For example, the conventional non-toxic salt can be prepared by reacting the active compound of the present application with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, and phosphoric acid, or an organic acid such as citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, and isethionic acid; or an ester formed by reacting the active compound of the present application with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid, or glutamic acid, followed by reacting with a sodium salt, potassium salt, calcium salt, aluminum salt, or ammonium salt of an inorganic base; or an ester formed by reacting the active compound of the present application with lysine, arginine, ornithine, followed by reacting with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, or phosphoric acid, or with formic acid, acetic acid, picric acid, methanesulfonic acid, or ethanesulfonic acid.

[0062] Pharmaceutical composition and use

[0063] The present application also provides the use of the compound of formula I, or one or more of its or its pharmaceutically acceptable salts, or its prodrugs, or its extracts, or its mixture of medicinal materials as an effective ingredient in the preparation of a medicine for treating anxiety.

[0064] Experiments show that the pharmaceutical composition of the present application can effectively improve the anxiety-like behavior of a diabetic model mouse.

[0065] The pharmaceutical composition provided by the present application preferably contains the compound of the present application in a weight ratio of 0.001-99 wt%, preferably the compound of the present application accounts for 0.01 wt% to 90 wt% or 0.05 wt% to 50 wt% of the total weight, and the rest is a pharmaceutically acceptable carrier, diluent, or solution or salt solution.

[0066] The medicine of the present application can also include a pharmaceutically acceptable carrier as needed. The carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. that are conventional in the pharmaceutical field.

[0067] The compound and the pharmaceutical composition provided by the present application can be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, etc., and can exist in a suitable solid or liquid carrier or diluent and a suitable sterilized instrument for injection or drip.

[0068] The pharmaceutical composition of the present application can be prepared according to the conventional preparation method in the pharmaceutical field. The unit dose of the preparation formula generally contains 0.05-1000 mg of the compound of the present application, preferably, the unit dose of the preparation formula contains 1 mg-500 mg of the compound of the present application.

[0069] The compound and pharmaceutical composition of the present application can be clinically used for mammals, including humans and animals, and can be administered through oral, nasal, dermal, pulmonary or gastrointestinal routes. The most preferred is oral administration. The most preferred daily dose is 0.01-10 mg / kg of body weight, taken at one time or 0.01-5 mg / kg of body weight taken in several times. Regardless of the administration method, the optimal dose for an individual should be determined according to the specific treatment. Generally, the dose is started from a small dose and gradually increased until the optimal dose is found.

[0070] The drug or inhibitor of the present application can be administered in various ways, for example, can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spraying, nose drops, eye drops, penetration, absorption, physical or chemical mediated methods; or mixed or wrapped with other substances and introduced into the body. From the point of view of easy administration, the preferred pharmaceutical composition is a liquid composition, especially an injection.

[0071] The main advantages of the present application include:

[0072] (a) The compound of the present application can prevent the occurrence of anxiety-like behavior without significant metabolic changes, without increasing fasting blood glucose levels, and treating anxiety associated with diabetes.

[0073] (b) The compound of the present application can be made into a drug for treating anxiety associated with diabetes.

[0074] (c) The drug of the present application has low toxicity and good drug properties. This suggests that the compound of the present application has good prospects for the treatment of anxiety associated with diabetes.

[0075] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The specific experimental conditions and methods are not specified in the following examples, which are generally in accordance with the conventional conditions, such as: D.L. Spetor et al., Science Press, 2001, Cell Experiment Guide; Lv Hongsheng, Science Press, 1982, or according to the conditions recommended by the manufacturer.

[0076] C57 mice were purchased from Vantian Lihua Experimental Animal Technology Co., Ltd.; CCR2 inhibitor INCB3284 was purchased from MCE; behavioral experiment equipment was purchased from Shanghai Xinsuo Information Technology Co., Ltd. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0077] Example 1 Blood glucose level of normal mice, diabetic model mice and diabetic model mice treated with INCB3284

[0078] 1.1 Method

[0079] C57 mice of six weeks old were first divided into two groups: normal mice group (11 mice) and diabetic model mice group (17 mice). For the diabetic model mice group, C57 mice were injected intraperitoneally with 60 mg / kg streptozotocin for 5 consecutive days, while the normal mice group was injected with the same dose of phosphate buffer (streptozotocin solvent) as control. One week after streptozotocin injection, the diabetic model mice were divided into two groups, one group was treated with 5 mg / kg INCB3284 by gavage every day, and the other group was gavaged with the same dose of 0.5% carboxymethylcellulose sodium (solvent of INCB3284) as control. At the same time, the normal mice group was also gavaged with the same dose of 0.5% carboxymethylcellulose sodium. One week after INCB3284 administration, the mice in the three groups were fasted for six hours, and their fasting blood glucose was measured.

[0080] The fasting blood glucose of the mice in the three groups was measured using a blood glucose meter. The blood glucose meter was used to measure the fasting blood glucose of the mice in the three groups.

[0081] 1.2 Results

[0082] The fasting blood glucose of the diabetic mice was increased by 1-fold compared with the normal mice group, and there was no significant difference in the fasting blood glucose of the diabetic mice treated with INCB3284 and the untreated diabetic mice. Figure 1

[0083] The above results show that the administration of INCB3284 does not further worsen the fasting blood glucose of the diabetic mice.

[0084] Example 2 Evaluation of anxiety-like behavior of diabetic model mice treated with INCB3284 using the light-dark box test

[0085] 2.1 Method

[0086] The light-dark box test is a paradigm widely used to measure anxiety-like behavior. Specifically, the device is divided into two boxes, light and dark, with a shuttle door between the two boxes. The walls of the dark box are painted black, and there is a removable black cover on the top. Different groups of mice were placed in the dark box with the cover on, and the mice were allowed to freely enter the light box. The number of times and the duration of entering the light box were counted. Each mouse was tested for 5 minutes.

[0087] 2.2 Results

[0088] The number of times of entering the light box by the diabetic model mice was significantly reduced by about 2-fold compared with the normal mice group, indicating an increase in anxiety-like behavior in the diabetic model mice and suggesting the successful construction of a model of diabetes complicated with anxiety.​

[0089] The number of entries into the open field was significantly increased by about 1-fold in the diabetic model mice treated with INCB3284 compared to the diabetic mice, indicating that the anxiety-like behavior was significantly improved (Fig. 2A). Figure 2

[0090] The duration of entries into the open field was significantly decreased by 2-fold in the diabetic model mice compared to the normal mice group. The duration of entries into the open field was significantly increased by 1.5-fold in the diabetic model mice treated with INCB3284 compared to the diabetic model mice, indicating that the anxiety-like behavior was significantly improved (Fig. 2B). Figure 2

[0091] Example 3 Evaluation of anxiety-like behavior of diabetic model mice after treatment with INCB3284 using elevated plus maze test

[0092] 3.1 Methods

[0093] The elevated plus maze test is another widely used anxiety measurement method. The experimental device is a cross-shaped maze, which consists of two open arms and two closed arms. The entire device is about 400 mm above the ground. The mice were placed at the center intersection of the maze and faced the open arms. The test time for each mouse was 5 minutes. The movement distance in the open arms and the duration of entries into the open arms of the mice were recorded by a camera placed above the maze and analyzed using SuperMaze software.

[0094] 3.2 Results

[0095] The movement distance in the open arms was significantly decreased by about 2.5-fold in the diabetic model mice compared to the normal mice group, suggesting an increase in anxiety-like behavior in the diabetic model mice and suggesting the successful construction of the diabetic model with anxiety. The movement distance in the open arms was significantly increased by 2-fold in the diabetic model mice treated with INCB3284 compared to the diabetic model mice, indicating that the anxiety-like behavior was significantly improved (Fig. 3A). Figure 3

[0096] The duration of entries into the open arms was significantly decreased by about 2.5-fold in the diabetic model mice compared to the normal mice group. The duration of entries into the open arms was significantly increased by 2-fold in the diabetic model mice treated with INCB3284 compared to the diabetic model mice, indicating that the anxiety-like behavior was significantly improved (Fig. 3B). Figure 3

[0097] Conclusion:

[0098] The active compound of the present application can significantly improve the anxiety-like behavior of diabetic model mice.

[0099] CCR2 can be used as a new target for treating diabetes complicated with anxiety.​​​​

[0100] Discussion:

[0101] Diabetes is a lifelong disease and cannot be cured, and it also brings other complications. Diabetic patients can only maintain the normal circulation of the body by taking oral drugs or injecting insulin. Long-term use of drugs for treating diabetes has problems of drug resistance and safety. In the long-term medication process, diabetic patients bear a lot of psychological pressure, and are prone to develop diabetes complicated with anxiety, thereby affecting the disease.

[0102] The above experiments show that the compound and the pharmaceutically acceptable salt thereof can effectively improve the anxiety behavior while keeping the blood glucose level unchanged. The compound has low toxic side effects, good drug property, and is suitable for diabetic patients complicated with anxiety who need long-term medication.

[0103] All the documents mentioned in the present application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that, after reading the above teaching of the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that, For the preparation of drugs or pharmaceutical compositions for the treatment of anxiety as a complication of diabetes.

2. The use as described in claim 1, characterized in that, The diabetes includes type 1 diabetes and / or type 2 diabetes.

3. The use as described in claim 1, characterized in that, The diabetes mellitus has one or more of the following characteristics: (c1) Fasting blood glucose is greater than or equal to 7.0 mmol / L; (c2) Blood glucose two hours after a meal is greater than or equal to 11.1 mmol / L.

4. The use as described in claim 1, characterized in that, The pharmaceutical composition also contains a pharmaceutically acceptable carrier.

5. The use as described in claim 1, characterized in that, The drug or drug composition is an oral preparation or an injection.

6. The use as described in claim 5, characterized in that, The oral preparations are selected from the group consisting of: capsules, tablets, powders, sprays, sustained-release preparations, oral liquids, drop pills, and nano-preparations.

7. The use of a medicine box, characterized in that, A pharmaceutical composition for treating diabetic comorbidity and anxiety, the kit comprising: (a) a first pharmaceutical composition, a first active ingredient for the treatment of diabetes or a pharmaceutically acceptable carrier thereof; and (b) A second pharmaceutical composition, a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof.

8. The use as described in claim 7, characterized in that, The first and second drug compositions may be taken simultaneously or sequentially.

9. The use as described in claim 7, characterized in that, The first pharmaceutical composition includes sulfonylureas, biguanides, alpha-glucosidase inhibitors, insulin sensitizers, meglitinides, insulin secretagogues, insulin preparations, or combinations thereof.

10. The use as described in claim 7, characterized in that, The medicine box is used to prepare a treatment for diabetes comorbid anxiety.

11. The use as described in claim 9, characterized in that, The sulfonylurea drugs are selected from the following group: tolbutamide, glibenclamide, gliclazide, glipizide, glimepiride, glimepiride, or combinations thereof.

12. The use as described in claim 9, characterized in that, The biguanide hypoglycemic drugs are selected from the following group: phenformin, metformin, buprofen, or combinations thereof.

13. The use as described in claim 9, characterized in that, The α-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose, or combinations thereof.

14. The use as described in claim 9, characterized in that, The meglitinide insulin secretagogues are selected from the group consisting of repaglinide, nateglinide, or combinations thereof.

15. The use as described in claim 9, characterized in that, The insulin preparation is selected from the group consisting of human insulin, insulin analogs, or combinations thereof.

16. The use as described in claim 9, characterized in that, The insulin preparations include animal insulin.

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