dpp-4 inhibitor compound

Abstract

The invention provides a novel dipeptidyl peptidase IV (DPP-4) inhibitor compound as shown in Formula (I) as shown in the specification. The compound, optical isomers, pharmaceutically acceptable inorganic or organic salt, crystal forms, hydrates or solvates of the compound can be used for treating diabetes, particularly non-insulin dependent diabetes, and other diseases related to DPP-4. Definitions of substituents in the general formula (I) are the same as those in the specification.

Description

technical field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a novel dipeptidyl peptidase IV (DPP-4) inhibitor compound and its application for treating and preventing diabetes and other diseases related to DPP-4. Background technique

[0002] Diabetes is a chronic metabolic disease caused by various pathogenic factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, it is characterized by hyperglycemia. It can be divided into type 1 diabetes (insulin-dependent), type 2 diabetes (non-insulin-dependent), gestational diabetes and other special types of diabetes. Type 2 diabetes accounts for approximately 95% of diabetic patients.

[0003] At present, the main oral hypoglycemic drugs are: sulfonylureas (SU), biguanides, α-glucosidase inhibitors, non-sulfonylurea insulin secretory drugs and insulin sensitizers: thiazolidinediones. These drugs are ...

Examples

Embodiment 1

[0073]

[0074] experiment procedure:

[0075] first step:

[0076] Method A

[0077] Weigh Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (1.0g, 3.0mmol), anhydrous piperazine (0.26g, 3.0mmol), HBTU ( 2.27g, 6.0mmol) was added into a 100ml round bottom flask, dissolved in 20ml of DMF, then DIEA (0.78g, 6.0mmol) was added to the reaction solution, and stirred at room temperature for 1.5 hours. TLC detection (petroleum ether: ethyl acetate = 4:1), the reaction was completed, the reaction solution was added to 10 times the amount of water, a white solid was precipitated, filtered, the filter cake was washed with water, and the obtained solid was dried.

[0078] Method B

[0079] Weigh Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (1.0g, 3.0mmol), anhydrous piperazine (0.26g, 3.0mmol), DCC ( 6.0mmol) and HoBt (6.0mmol) were added to a 100ml round bottom flask, dissolved with 20ml DMF, then DIEA (12.0mmol) was added to the reaction solution, and stirred at ...

Embodiment 2

[0085] Chemical reaction formula:

[0086]

[0087] Experimental process: The specific experimental process of compound 2 is similar to that of Example 1, refer to Example 1.

[0088] MSm / z (ESI):613.5[M+Na]

[0089] 1 H-NMR (500MHz, deuterated DMSO): δ7.31~7.38(m, 2H), 7.13~7.22(m, 2H), 4.01~4.15(m, 2H), 4.42(m,1H), 3.67(s ,3H), 2.80~2.91(m.4H), 2.59~2.72(m,4H).

Embodiment 3

[0091] Chemical reaction formula:

[0092]

[0093] Experimental process: The specific experimental process of compound 3 is similar to that of Example 1, refer to Example 1.

[0094] MSm / z(ESI):539.3[M+H]

[0095] 1 H-NMR (500MHz, deuterated DMSO): δ7.60~7.65(m, 4H), 7.31~7.38(m, 2H), 7.13~7.22(m, 2H), 4.42(m, 1H), 4.01~4.15 (m, 2H), , 3.67 (s, 3H), 2.80~2.91 (m.4H), 2.59~2.72 (m, 4H).

technical field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a novel dipeptidyl peptidase IV (DPP-4) inhibitor compound and its application for treating and preventing diabetes and other diseases related to DPP-4. Background technique

[0002] Diabetes is a chronic metabolic disease caused by various pathogenic factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, it is characterized by hyperglycemia. It can be divided into type 1 diabetes (insulin-dependent), type 2 diabetes (non-insulin-dependent), gestational diabetes and other special types of diabetes. Type 2 diabetes accounts for approximately 95% of diabetic patients.

[0003] At present, the main oral hypoglycemic drugs are: sulfonylureas (SU), biguanides, α-glucosidase inhibitors, non-sulfonylurea insulin secretory drugs and insulin sensitizers: thiazolidinediones. These drugs are ...

Examples

Embodiment 1

[0073]

[0074] experiment procedure:

[0075] first step:

[0076] Method A

[0077] Weigh Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (1.0g, 3.0mmol), anhydrous piperazine (0.26g, 3.0mmol), HBTU ( 2.27g, 6.0mmol) was added into a 100ml round bottom flask, dissolved in 20ml of DMF, then DIEA (0.78g, 6.0mmol) was added to the reaction solution, and stirred at room temperature for 1.5 hours. TLC detection (petroleum ether: ethyl acetate = 4:1), the reaction was completed, the reaction solution was added to 10 times the amount of water, a white solid was precipitated, filtered, the filter cake was washed with water, and the obtained solid was dried.

[0078] Method B

[0079] Weigh Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (1.0g, 3.0mmol), anhydrous piperazine (0.26g, 3.0mmol), DCC ( 6.0mmol) and HoBt (6.0mmol) were added to a 100ml round bottom flask, dissolved with 20ml DMF, then DIEA (12.0mmol) was added to the reaction solution, and stirred at ...

Embodiment 2

[0085] Chemical reaction formula:

[0086]

[0087] Experimental process: The specific experimental process of compound 2 is similar to that of Example 1, refer to Example 1.

[0088] MSm / z (ESI):613.5[M+Na]

[0089] 1 H-NMR (500MHz, deuterated DMSO): δ7.31~7.38(m, 2H), 7.13~7.22(m, 2H), 4.01~4.15(m, 2H), 4.42(m,1H), 3.67(s ,3H), 2.80~2.91(m.4H), 2.59~2.72(m,4H).

Embodiment 3

[0091] Chemical reaction formula:

[0092]

[0093] Experimental process: The specific experimental process of compound 3 is similar to that of Example 1, refer to Example 1.

[0094] MSm / z(ESI):539.3[M+H]

[0095] 1 H-NMR (500MHz, deuterated DMSO): δ7.60~7.65(m, 4H), 7.31~7.38(m, 2H), 7.13~7.22(m, 2H), 4.42(m, 1H), 4.01~4.15 (m, 2H), , 3.67 (s, 3H), 2.80~2.91 (m.4H), 2.59~2.72 (m, 4H).

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