Application of chemokine receptor 2 antagonist in preparation of medicine for treating diabetes complicated with anxiety disorder

Abstract

The invention relates to application of a compound shown in a formula I, in particular to application of the compound shown in the formula I or pharmaceutically acceptable salt of the compound to preparation of medicine for treating diabetes complicated with anxiety disorder # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to the application of the compound of formula I in the preparation of a method for treating diabetes-related anxiety.

[0002] Background Art

[0003] Diabetes is a major challenge to global health, and its complications have become 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 diabetic patients worldwide. Anxiety associated with diabetes not only affects the patient's mental health, but may also increase the difficulty of controlling diabetes and the risk of other complications. In addition, anxiety-like behaviors have also been observed in diabetic mice (such as db / db mice). Although diabetic mice and diabetic patients have been found to increase the risk of anxiety, in clinical practice, it is difficult for most patients with diabetes to obtain effective treatment for anxiety. Drugs generally 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, there is a need to explore potential drugs without the risk of metabolic deterioration to treat diabetic anxiety. Summary of the invention

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

[0006]

[0007] Specifically, the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or alleviating or treating diabetes-related anxiety.

[0008] In the first aspect of the present invention, there is provided a use of a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a drug or a pharmaceutical composition for treating diabetes-related anxiety disorder.

[0009]

[0010] In another preferred embodiment, the treatment of anxiety disorder 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 greater than or equal to 7.0mmol / L;

[0014] (c2) Blood glucose level is greater than or equal to 11.1 mmol / L two hours after a meal.

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

[0016] (a) a first active ingredient, a compound of formula I of the present invention, 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 drug or pharmaceutical composition is an oral preparation or an injectable preparation.

[0020] In another preferred embodiment, the oral preparation is selected from the following group: capsules, tablets, powders, sprays, sustained-release preparations, oral liquids, pills, and nano preparations.

[0021] The second aspect of the present invention provides a method for treating anxiety, comprising the steps of administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof, thereby improving anxiety.

[0022] In another preferred embodiment, the anxiety disorder is diabetes-related anxiety disorder.

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

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

[0025] In another preferred embodiment, the concentration of the compound of the present invention 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 greater than or equal to 7.0mmol / L;

[0028] (c2) Blood glucose level is greater than or equal to 11.1 mmol / L two hours after a meal.

[0029] The third aspect of the present invention provides a medicine kit, comprising:

[0030] (a) a first pharmaceutical composition, 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 invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof

[0032]

[0033] In another preferred embodiment, the medicine kit is used to treat diabetes-related anxiety.

[0034] In another preferred embodiment, the medicine kit comprises instructions.

[0035] In another preferred embodiment, the instructions state 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 sulfonylurea drugs, biguanide hypoglycemic drugs, α-glucosidase inhibitors, insulin sensitizers, glinide insulin secretagogues, insulin preparations, or a combination thereof.

[0037] In another preferred embodiment, the sulfonylurea drug is selected from the following group: tolbutamide, glibenclamide, gliclazide, glipizide, gliquidone, glimepiride, or a combination thereof.

[0038] In another preferred embodiment, the biguanide hypoglycemic drug is selected from the following group: phenformin, metformin, buformin, or a combination thereof.

[0039] In another preferred embodiment, the α-glucosidase inhibitor is selected from the following group: acarbose, voglibose, or a combination thereof.

[0040] In another preferred embodiment, the meglitinide insulin secretagogue is selected from the following group: repaglinide, nateglinide, or a combination thereof.

[0041] In another preferred embodiment, the insulin preparation is selected from the following group: animal insulin, human insulin, insulin analogs, or a combination thereof.

[0042] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE 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 invention are shown.

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

[0045] Figure 3 The elevated plus maze test was used to evaluate the anxiety-like behavior of diabetic model mice after treatment with the compounds of the present invention. Figure 3 A shows the arm movement distance of mice in different groups. Figure 3 B shows the duration of entry into the open arms for mice in different groups. DETAILED DESCRIPTION

[0046] The inventors have conducted extensive and in-depth research and unexpectedly discovered for the first time through a large number of screenings a class of compounds that improve anxiety associated with diabetes, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof. The inventors have found that the compounds of the invention can significantly improve anxiety associated with diabetes without increasing fasting blood sugar in diabetes. The invention has been completed on this basis.

[0047] the term

[0048] In order to more easily understand the present invention, some technical and scientific terms are specifically defined below. Unless otherwise clearly defined in this article, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, because such methods and conditions can be changed. It should also be understood that the terms used herein are intended only to describe specific embodiments, and are not intended to be restrictive, and the scope of the present invention will be limited only by the appended claims.

[0049] As used herein, the term “comprise” or variations thereof such as “include” or “comprising”, etc., is understood to include the described elements or components but does not exclude other elements or components.

[0050] Anxiety disorders

[0051] Anxiety disorder, also known as anxiety neurosis, is the most common type of neurosis, with anxious emotional experience as its main feature.

[0052] Diabetes and anxiety disorders

[0053] Diabetes is a lifelong disease with no cure. Diabetic patients can only maintain normal circulation through oral medication or insulin injection.

[0054] Diabetes is also prone to develop complications, up to more than 100 types, making it the disease with the most known complications, such as diabetic anxiety, diabetic nephropathy, diabetic eye complications, diabetic cerebrovascular disease, diabetic neuropathy, etc.

[0055] Diabetes anxiety disorder refers to patients' worries and fears related to their long-term struggle with diabetes, including their blood sugar management, the threat of complications, potential loss of function, and concerns about obtaining responsive care.

[0056] Active compounds and active ingredients of the invention

[0057] In the present invention, an active ingredient that can effectively improve anxiety is provided. The active ingredient is selected from the following group: 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 invention", "active compound of the present invention", "active ingredient of the present invention", "drug or pharmaceutical composition of the present invention", "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 ingredients of the present invention include active compounds of the present invention, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or prodrugs thereof. It should be understood that the active ingredients of the present invention also include crystalline forms, amorphous compounds, and deuterated compounds of the active compounds of the present invention.

[0061] The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of the pharmaceutical composition of the present invention with an inorganic acid or an organic acid. For example, conventional non-toxic salts can be prepared by reacting the active compound of the present invention with an inorganic acid or an organic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic 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-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the active compound of the present invention forms an ester 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, and then forms a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with an inorganic base; or the active compound of the present invention forms an ester with lysine, arginine, or ornithine, and then forms a corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or a corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

[0062] Pharmaceutical compositions and applications

[0063] The present invention also provides the use of the compound of formula I, or its or its pharmaceutically acceptable salt, or its prodrug, or its extract, or a mixture of one or more of its medicinal materials as an effective ingredient in the preparation of a drug for treating anxiety.

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

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

[0066] When necessary, the drug of the present invention may also include a pharmaceutically acceptable carrier, which includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0067] The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

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

[0069] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered by oral, nasal, skin, lung or gastrointestinal tract administration. Oral administration is most preferred. The most preferred daily dose is 0.01-10 mg / kg body weight, taken at one time, or 0.01-5 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, a small dose is started and the dose is gradually increased until the most suitable dose is found.

[0070] The drugs or inhibitors of the present invention can be administered in various ways, for example, by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediated methods such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed or wrapped with other substances to introduce into the body. From the standpoint of easy administration, the preferred pharmaceutical composition is a liquid composition, especially an injection.

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

[0072] (a) The compounds of the present invention can prevent the occurrence of anxiety-like behaviors without obvious metabolic changes or increasing fasting blood sugar levels, and can treat anxiety disorders complicated by diabetes.

[0073] (b) The compound of the present invention can be prepared into a drug for treating diabetes-related anxiety.

[0074] (c) The toxicity and side effects of the drug of the present invention are low and the drugability is good, which indicates that the compound of the present invention has a good medicinal prospect in treating anxiety complicated by diabetes.

[0075] The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. In the following examples, specific experimental conditions and methods are not specified, and are usually carried out according to conventional conditions such as: DL Spector 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 Weitong Lihua Laboratory Animal Technology Co., Ltd.; CCR2 inhibitor INCB3284 was purchased from MCE; behavioral experimental equipment was purchased from Shanghai Xinruan Information Technology Co., Ltd. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

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

[0078] 1.1 Methods

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

[0080] The fasting blood glucose of the three groups of mice was measured by Blood glucose meter measurement.

[0081] 1.2 Results

[0082] The fasting blood glucose of diabetic mice increased by 1 times compared with that of normal mice, and there was no significant difference between the fasting blood glucose of diabetic mice treated with INCB3284 and that of untreated diabetic mice ( Figure 1 ).

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

[0084] Example 2 Evaluation of anxiety-like behavior in diabetic model mice after INCB3284 treatment using light-dark box experiment

[0085] 2.1 Methods

[0086] The light-dark box experiment is a paradigm widely used to measure anxiety-related behaviors. Specifically, the apparatus is divided into two boxes, a light and a dark one, with a shuttle door between the two boxes. The walls of the black box are painted black, and there is a removable black lid on the top. Place mice from different groups in the dark box with the lid closed, and allow the mice to freely enter the light box. Count the number of times the mice enter the light box and the duration of entry into the light box. The test time for each mouse is 5 minutes.

[0087] 2.2 Results

[0088] The number of times the diabetic model mice entered the light box was significantly reduced by about 2 times compared with the normal mouse group, which indicated an increase in anxiety-like behavior in the diabetic model mice and suggested that the construction of the diabetes-related anxiety model was successful.

[0089] Compared with diabetic mice, the number of times diabetic mice treated with INCB3284 entered the light box increased significantly by about 1 times, indicating that anxiety-like behavior was significantly improved ( Figure 2 (A).

[0090] The duration of diabetic model mice entering the light box was significantly reduced by 2 times compared with the normal mouse group. Compared with diabetic mice, the duration of diabetic model mice treated with INCB3284 entering the light box increased significantly by 1.5 times, indicating that anxiety-like behavior was significantly improved ( Figure 2 (middle B).

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

[0092] 3.1 Methods

[0093] The elevated plus maze test is another widely used anxiety measurement method. The experimental apparatus is a cross-shaped maze consisting of two open arms and two closed arms. The entire apparatus is about 400 mm above the ground. The mouse is placed at the central junction of the maze and faces the open arm. The test time for each mouse is 5 minutes. The movement distance of the mouse in the open arm and the duration of entering the open arm were recorded by a camera placed above the maze and analyzed using SuperMaze software.

[0094] 3.2 Results

[0095] The distance of movement in the open arms of diabetic model mice was significantly reduced by about 2.5 times compared with the normal mouse group, indicating an increase in anxiety-like behavior in diabetic model mice and the successful construction of a diabetes-related anxiety model. Compared with diabetic model mice, the distance of movement in the open arms of diabetic model mice treated with INCB3284 increased significantly by 2 times, indicating that anxiety-like behavior was significantly improved ( Figure 3 (A).

[0096] The duration of diabetic model mice entering the open arms was significantly reduced by about 2.5 times compared with the normal mouse group. Compared with diabetic model mice, the duration of diabetic model mice treated with INCB3284 entering the open arms was significantly increased by 2 times, indicating that anxiety-like behavior was significantly improved ( Figure 3 (middle B).

[0097] in conclusion:

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

[0099] CCR2 can be used as a new target for the treatment of diabetes-related anxiety.

[0100] discuss:

[0101] Diabetes is a lifelong disease that cannot be cured and brings other complications. Diabetic patients can only maintain normal circulation of the body through oral medication or insulin injection. Long-term use of diabetes medications has drug resistance and safety issues. During the long-term medication process, diabetic patients are under great psychological pressure and are very likely to develop diabetes-related anxiety, which affects their condition.

[0102] The above experiments show that the compounds of the present invention and their pharmaceutically acceptable salts can effectively improve anxiety behavior while maintaining the blood sugar level unchanged. The compounds of the present invention have low toxicity and side effects, good drugability, and are suitable for patients with diabetes complicated with anxiety who need long-term medication.

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

Claims

1. A use of a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that: Drug or drug composition for treating diabetes-related anxiety 2. The use according to claim 1, characterized in that The diabetes mellitus includes type 1 diabetes mellitus and / or type 2 diabetes mellitus.

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

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

5. The use according to claim 1, characterized in that The medicine or pharmaceutical composition is an oral preparation or an injection.

6. The use according to claim 5, characterized in that The oral preparation is selected from the following group: capsules, tablets, powders, sprays, sustained-release preparations, oral liquids, pills, and nano preparations.

7. A medicine box, characterized in that: include: (a) a first pharmaceutical composition, a first active ingredient for treating diabetes or a pharmaceutically acceptable carrier thereof; (b) a second pharmaceutical composition, a compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof 8. The medicine box according to claim 7, characterized in that The first pharmaceutical composition and the second pharmaceutical composition may be taken simultaneously or sequentially.

9. The medicine box according to claim 7, characterized in that The first pharmaceutical composition comprises sulfonylurea drugs, biguanide hypoglycemic drugs, α-glucosidase inhibitors, insulin sensitizers, glinides, insulin secretagogues, insulin preparations, or a combination thereof.

10. The medicine box according to claim 7, characterized in that The medicine kit is used for preparing medicine for treating diabetes-related anxiety.

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