DRUG COMBINATION FOR TREATING DIABETES MELLITUS AND COMPLICATIONS THEREOF AND PHARMACEUTICAL COMPOSITION OF DRUG COMBINATION

Abstract

Use of a component (i) represented by a general formula (I) or a pharmaceutically acceptable salt or isomer of the compound, in combination with a component (ii) of a SGLT2 inhibitor in the manufacture of a medicament for the prevention and/or treatment of diabetes mellitus and/or a diabetic complication, as well as a pharmaceutical composition comprising the component (i) and the component (ii).

Claims

1-6. (canceled)

7. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a component (i) and a component (ii), wherein, the component (i) is a compound having the formula shown in general Formula (I), or a pharmaceutically acceptable salt or isomer thereof; the component (ii) is a sodium-dependent glucose transporter 2 (SGLT2) inhibitor: ##STR00005## wherein rings A and B are respectively benzene rings, with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; X is a covalent bond, O or S; R.sup.1 is H or alkyl; R.sup.2 is H or alkyl; R.sup.3 is H or alkyl; R.sup.4 and R.sup.5 are H or alkyl, respectively, or R.sup.4 and R.sup.5 together form a benzene ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; Alk.sup.1 is C.sub.1-6 alkylidene; Alk.sup.2 is C.sub.1-2 alkylidene; Ar.sup.1 is a benzene ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; Ar.sup.2 is a benzene ring or pyridine ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy.

8. The pharmaceutical composition according to claim 7, wherein the component (i) is a compound having the structure shown in Formula (II), or a pharmaceutically acceptable salt or isomer thereof; ##STR00006## .

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt, an ammonium salt and a salt of N.sup.+(C.sub.1-4 alkyl).sub.4, the alkali metal salt comprises a potassium salt and a sodium salt, and the alkaline earth metal salt comprises a calcium salt and a magnesium salt; and the isomer comprises S-configuration and R-configuration isomers.

10. The pharmaceutical composition according to claim 7, wherein the component (ii), sodium-dependent glucose transporter 2 (SGLT2) inhibitor, comprises Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin or Ipragliflozin L-Proline (a complex of Ipragliflozin and L-Proline), Luseogliflozin, Tofogliflozin, and Ertuglifolzin.

11. The pharmaceutical composition according to claim 7, wherein the component (i) and the component (ii) have a dosage in therapeutically effective amount, the dosage of component (i) is 1-100 mg, and the dosage of component (ii) is 1-500 mg.

12. A compound medicament, characterized in that, the compound medicament comprises the pharmaceutical composition according to claim 7, and one or more pharmaceutically acceptable excipients or carriers.

13. The compound medicament according to claim 12, which is in a dosage form including tablets, capsules, granules, pills, powders and suppositories.

14. A kit, characterized in that, the kit comprises the pharmaceutical composition according to claim 7.

15. The kit according to claim 14, characterized in that, the component (i) and the component (ii) are unit preparations having the same or different specifications, respectively, and may be provided in separate containers.

16. A method of preventing and/or treating diabetes mellitus and/or a diabetic complication, comprising a step of administering a therapeutically effective amount of the pharmaceutical composition according to claim 7; preferably, the diabetes mellitus is type II diabetes mellitus, and the diabetic complication comprises cardiovascular disease, kidney disease and liver disease.

17. A method of preventing and/or treating diabetes mellitus and/or a diabetic complication, comprising a step of administering a therapeutically effective amount of the compound medicament according to claim 12; preferably, the diabetes mellitus is type II diabetes mellitus, and the diabetic complication comprises cardiovascular disease, kidney disease and liver disease.

18. A method of preventing and/or treating diabetes mellitus and/or a diabetic complication, comprising a step of administering a therapeutically effective amount of the kit according to claim 14; preferably, the diabetes mellitus is type II diabetes mellitus, and the diabetic complication comprises cardiovascular disease, kidney disease and liver disease.

19. A method of preventing and/or treating diabetes mellitus and/or a diabetic complication, comprising a step of administering a therapeutically effective amount of a component (i) in combination with a component (ii), wherein, the component (i) is a compound having the formula shown in general Formula (I), or a pharmaceutically acceptable salt or isomer thereof; the component (ii) is a sodium-dependent glucose transporter 2 (SGLT2) inhibitor: ##STR00007## wherein ring A and ring B are respectively benzene rings, with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; X is a covalent bond, O or S; R.sup.1 is H or alkyl; R.sup.2 is H or alkyl; R.sup.3 is H or alkyl; R.sup.4 and R.sup.5 are H or alkyl, respectively, or R.sup.4 and R.sup.5 together form a benzene ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; Alk.sup.1 is C.sub.1-6 alkylidene; Alk.sup.2 is C.sub.1-2 alkylidene; Ar.sup.1 is a benzene ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy; Ar.sup.2 is a benzene ring or pyridine ring with no substituent or one or more substituents on the ring, and the substituent is fluorine, alkyl or alkoxy.

20. The method according to claim 19, wherein the component (i) is a compound having the structure shown in Formula (II), or a pharmaceutically acceptable salt or isomer thereof: ##STR00008## .

21. The method according to claim 19, wherein the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt, an ammonium salt and a salt of N.sup.+(C.sub.1-.sub.4 alkyl).sub.4, the alkali metal salt comprises a potassium salt and a sodium salt, and the alkaline earth metal salt comprises a calcium salt and a magnesium salt; and the isomer comprises S-configuration and R-configuration isomers.

22. The method according to claim 19, wherein the component (ii), sodium- dependent glucose transporter 2 (SGLT2) inhibitor, comprises Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin or Ipragliflozin L-Proline (a complex of Ipragliflozin and L-Proline), Luseogliflozin, Tofogliflozin, and Ertuglifolzin.

23. The method according to claim 19, wherein the component (i) and the component (ii) have a dosage in therapeutically effective amount, the dosage of component (i) is 1-100 mg, and the dosage of component (ii) is 1-500 mg.

24. The method according to claim 19, wherein the diabetes mellitus is type II diabetes mellitus, and the diabetic complication comprises cardiovascular disease, kidney disease and liver disease.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIG. 1 shows the effect on body weight and blood glucose of chiglitazar sodium in combination with empagliflozin, compared with monotherapy thereof.

[0052] FIG. 2 shows the effect on body weight and blood glucose of chiglitazar sodium in combination with dapagliflozin, compared with monotherapy thereof.

[0053] FIG. 3 shows the effect on blood lipids of chiglitazar sodium in combination with empagliflozin.

[0054] FIG. 4 shows the effect on blood lipids of chiglitazar sodium in combination with dapagliflozin.

SPECIFIC MODELS FOR CARRYING OUT THE DISCLOSURE

[0055] The present disclosure discloses a drug combination and pharmaceutical composition thereof for the treatment of diabetes mellitus and its complications, which can be implemented by those skilled in the art by drawing on the contents disclosed herein with appropriate substitutions or modifications. In particular, it is noted that all similar substitutions and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present disclosure. The applications described herein have been described by way of preferred examples, and it is apparent that interested persons are able to implement and apply the techniques of the present disclosure by making changes or appropriate alterations and combinations to the applications described herein without departing from the content, spirit and scope of the present disclosure.

[0056] The present disclosure is further described below by means of non-limiting examples which are not intended to limit the scope covered by the present disclosure.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skilled in the art.

Example 1: Comparison of Effects on Body Weight and Blood Glucose Between Chiglitazar Sodium in Combination with Empagliflozin and Monotherapy Thereof

[0058] Experimental design: the effects on body weight and blood glucose of single and combined medication were investigated, by oral administration of chiglitazar sodium, empagliflozin, or a combination thereof to mice.

[0059] Experimental procedure: 6-Week-old db/db male mice were orally administered once a day with 100 .Math.L of vehicle (0.1% sodium carboxymethylcellulose), 10 mg/kg chiglitazar sodium, 3 mg/kg empagliflozin, or a combination of chiglitazar sodium and empagliflozin at the same doses simultaneously, respectively, according to body weight. Wild-type C57BLKS/Jnju mice were used as normal control (administered with the vehicle). The period of administration was 14 days, and the animals were treated and dissected on Day 15. Starting from the administration, the mice were subjected to weighing and measurement of fasting blood glucose (4-6 hours of fasting) every 3 days. The results of the experiment were shown in FIG. 1.

[0060] The results showed that chiglitazar sodium and empagliflozin alone could reduce blood glucose to a certain extent, and the combination of the two generated an unexpected synergistic effect, it could alleviate the weight gain caused by chiglitazar sodium on the one hand, and it had better blood glucose lowering effect on the other, even to a level close to that of the normal control group.

Example 2: Comparison of Effects on Body Weight and Blood Glucose Between Chiglitazar Sodium in Combination With Dapagliflozin and Monotherapy Thereof

[0061] Experimental design: the effects on body weight and blood glucose of single and combined medication were investigated, by oral administration of chiglitazar sodium, dapagliflozin, or a combination thereof to mice.

[0062] Experimental procedure: 6-Week-old db/db male mice were orally administered once a day with 100 .Math.L of vehicle (0.1% sodium carboxymethylcellulose), 10 mg/kg chiglitazar sodium, 1.5 mg/kg dapagliflozin, or a combination of chiglitazar sodium and dapagliflozin at the same doses simultaneously, respectively, according to body weight. Wild-type C57BLKS/Jnju mice were used as normal control (administered with vehicle). The period of administration was 14 days, and the animals were treated and dissected on Day 15. Starting from the administration, the mice were subjected to weighing and measurement of fasting blood glucose (4-6 hours of fasting) every 3 days. The results of the experiment were shown in FIG. 2.

[0063] The results showed that chiglitazar sodium and dapagliflozin alone could reduce blood glucose to a certain extent, and the combination of the two generated an unexpected synergistic effect, it could alleviate the weight gain caused by chiglitazar sodium on the one hand, and it had better blood glucose lowering effect on the other, even to a level close to that of the normal control group.

Example 3: Effect on Blood Lipids of Chiglitazar Sodium in Combination With Empagliflozin

[0064] Experimental design: the effects on total cholesterol (TC) and triglyceride (TG) in mouse serum of single and combined medication were investigated, by oral administration of chiglitazar sodium, empagliflozin, or a combination thereof to diabetic mice.

[0065] Experimental procedure: 6-Week-old db/db male mice were orally administered once a day with 100 .Math.L of vehicle (0.1% sodium carboxymethylcellulose), 10 mg/kg chiglitazar sodium, 3 mg/kg empagliflozin, or a combination of chiglitazar sodium and empagliflozin at the same doses simultaneously, respectively, according to body weight. Wild-type C57BLKS/Jnju mice were used as normal control (administered with vehicle). The period of administration was 14 days, and the animals were treated and dissected on Day 15. Whole blood was collected, serum was centrifuged and serum TC and TG were measured by biochemical analyzer. The experimental results were shown in FIG. 3.

[0066] The results showed that chiglitazar sodium and empagliflozin alone could reduce the serum total cholesterol and triglyceride levels to a certain extent, wherein chiglitazar sodium showed relatively better effect; while the combination of the two showed better effect in reducing the serum total cholesterol and triglyceride levels, a synergistic effect was generated.

Example 4: Effect on Blood Lipids of Chiglitazar Sodium in Combination With Dapagliflozin

[0067] Experimental design: the effects on total cholesterol (TC) and triglyceride (TG) in mouse serum of single and combined medication were investigated, by oral administration of chiglitazar sodium, dapagliflozin, or a combination thereof to diabetic mice.

[0068] Experimental procedure: 6-Week-old db/db male mice were orally administered once a day with 100 .Math.L of vehicle (0.1% sodium carboxymethylcellulose), 10 mg/kg chiglitazar sodium, 1.5 mg/kg dapagliflozin, or a combination of chiglitazar sodium and dapagliflozin at the same doses simultaneously, respectively, according to body weight. Wild-type C57BLKS/Jnju mice were used as normal control (administered with vehicle). The period of administration was 14 days, and the animals were treated and dissected on Day 15. Whole blood was collected, serum was centrifuged and serum TC and TG were measured by biochemical analyzer. The experimental results were shown in FIG. 4.

[0069] The results showed that chiglitazar sodium and dapagliflozin alone could reduce the serum total cholesterol and triglyceride levels to a certain extent, wherein chiglitazar sodium showed relatively better effect; while the combination of the two showed better effect in reducing the serum total cholesterol and triglyceride levels, a synergistic effect was generated.

[0070] In the present disclosure, it was verified by Examples 1 to 4 that the combination of chiglitazar sodium with SGLT2 inhibitor, empagliflozin or dapagliflozin, could synergistically reduce blood glucose in db/db diabetic mice and also alleviate the weight gain induced by chiglitazar sodium, showing an unexpected synergistic effect. Also, the combination of chiglitazar sodium with SGLT2 inhibitor improved lipidemia index, particularly serum triglyceride levels. Chiglitazar sodium is a peroxisome proliferator-activated receptor (PPAR) agonist, and peroxisome proliferator-activated receptor (PPAR) agonists have the effects including alleviating insulin resistance, reducing the risk of new-onset diabetes, and protecting cardiovascular system, while sodium-glucose linked transporter-2

[0071] (SGL T2) inhibitors benefit cardiovascular disease and nephropathy. Clinical studies show that chiglitazar sodium has efficacy in reducing blood glucose and improving lipids in diabetic patients, as well as reducing systemic inflammation and having certain hepatic and renal protective effects, but having certain weight gain effect; while SGLT2 inhibitors have efficacy in reducing blood glucose, blood pressure, and body weight in diabetic patients, thereby bringing renal function and cardiovascular protection. Thus, it can be seen that the combination of the two classes of drugs can produce combined effects in controlling weight, lipids, blood pressure, hepatic and renal protection, in addition to more efficient in reducing of blood glucose, thus bringing more benefits to the prevention and/or treatment of diabetes and its complications, including cardiovascular and cerebrovascular diseases, renal and liver diseases.

[0072] The present disclosure has been described in detail above; specifically, the principles and implementation of the present disclosure are illustrated with preferred examples. The description of the above examples is only intended to assist in understanding the method of the present disclosure and its core ideas, including the best mode, and also to enable any person skilled in the art to practice the present disclosure, including manufacture and use of the disclosure, and method to implement any combinations. It should be noted that for a person of ordinary skilled in the art, there are several improvements and modifications that can be made to the present disclosure without departing from the principles of the present disclosure, and these improvements and modifications also fall within the scope of protection of the claims of the present disclosure. The scope of the patent protection of the present disclosure is limited by the claims and may include other embodiments that can be thought of by a person skilled in the art. If these other embodiments have structural elements that are not different from the literal representation of the claims, or if they include equivalent structural elements that are not substantially different from the literal representation of the claims, then these other embodiments shall also be included in the scope of the claims.