CN102532009B - A compound for inhibiting dipeptide kininase and its preparation method and use - Google Patents

Abstract

The invention provides a compound for inhibiting dipeptide kininase and pharmaceutically acceptable salts thereof, which are obtained by Vilsmeier reaction, Williamson reaction and reductive amination reaction. Preliminary pharmacological experiments show that the compound has stronger inhibition effect on DPP-IV, has obvious hypoglycemic effect on normal rats, has no hepatotoxicity and can be applied to the preparation of medicaments for treating type II diabetes. The invention has reasonable design, short synthetic route of the preparation method, cheap and easily obtained raw materials and is suitable for practical use. The general structural formula is as follows:

Description

A compound for inhibiting dipeptide kininase and its preparation method and use

technical field

The invention belongs to the technical field of medicine, and relates to a compound and a pharmaceutically acceptable salt thereof for inhibiting dipeptide kininase (DPP-IV), a preparation method of this type of compound, and the use of this type of compound in preparing and treating Type II Application in diabetes medicine.

Background technique

Diabetes mellitus is a metabolic disease with multiple etiologies. It is a metabolic disorder in the body caused by an absolute or relative insufficiency of insulin, resulting in elevated blood sugar. Diabetes seriously affects human health and is accompanied by various complications. Diabetes can be divided into two main types: insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes). Among them, type II diabetes is the most common, accounting for more than 90% of diabetic patients. Complications of diabetes include hyperlipidemia, hypertension, retinal disease and renal insufficiency. At present, most of the research on diabetes treatment drugs is launched for type II diabetes. There are many kinds of traditional hypoglycemic drugs, and there are three main categories: insulin sensitizers, including biguanides (such as metformin) and thiazolidinediones (such as pioglitazone); insulin secretagogues, including sulfonylureas ( such as bipagliflozin); and α-glucosidase inhibitors (such as acarbose). However, these drugs are accompanied by side effects such as lowering of blood sugar and weight gain. Therefore, there is an urgent need to develop new hypoglycemic drugs clinically.

Deficiency of dipeptide kininase-IV (DPP-IV) maintains glucagon-like peptide 1 (GLP-1) activity and high insulin levels, resulting in lower blood glucose levels, so this may be a new treatment for diabetes target. DPP-IV is a glycoprotein widely distributed in the body. Its function is similar to that of serine protease. It inactivates the peptide by cutting it, so as to regulate physiological functions. GLP-1 plays an important role in glucose metabolism, for example, (1) GLP-1 strengthens the secretion of insulin; (2), expresses genes necessary for insulin secretion; (3) stimulates the differentiation of pancreatic β-cells; ( 4) Inhibit the secretion of glucagon; (5) Inhibit the secretion and motility of digestive organs; (6) Suppress appetite. Therefore, GLP-1 restricts food intake, delays the digestion and absorption of food, and improves blood sugar utilization. Therefore, the treatment based on GLP-1 can effectively control blood sugar, but as the substrate of DPP-IV, GLP-1 has a short half-life and is quickly cut off and inactivated by DPP-IV within 1-2 minutes after secretion. Therefore, the use of DPP-IV inhibitors can maintain the activity of GLP-1 by blocking the inactivation mechanism of GLP-1, so that various diseases related to glucose metabolism can be treated and prevented, especially non-insulin-dependent diabetes mellitus (type II diabetes mellitus). ) (E. Matteucci, O. Giampietro, Curr. Med. Chem., 2009, 16, 2943).

Currently marketed DPP-IV inhibitors for the treatment of type II diabetes include Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, and Vildagliptin. These compounds have good safety and tolerance, and no patients have been found to have symptoms such as weight gain or potential weight loss and edema (G. R. Lankas, et al., Diabetes, 2005, 54, 2988 ). However, although there are many highly active DPP-IV inhibitors, the selectivity and specificity of DPP-IV are still difficult to solve. Therefore, there is an urgent need to develop more, better and newer DPP-IV inhibitory drugs to meet the needs of clinical medication (S. H. Havale, M. Pal, Bioorg. Med. Chem., 2009, 17, 1783).

Contents of the invention

The first object of the present invention is to provide a compound that inhibits dipeptide kininase and a pharmaceutically acceptable salt thereof, the general structural formula of which is as follows (V):

in:

X stands for carbon or nitrogen atom; Y stands for oxygen or nitrogen atom

A represents a hydrogen atom, or a benzene ring or an aromatic heterocycle substituted or unsubstituted by 1-4 R;

R represents a hydrogen atom, a halogen atom, a carboxyl group, an amino group, a cyano group, a lower alkyl or lower alkoxy group substituted or unsubstituted by one or more halogen atoms, a straight-chain or branched chain alkane with 1 to 3 carbon atoms group or alkoxy group;

R ₁ represents an unsubstituted, monosubstituted, disubstituted or trisubstituted aromatic ring, and the substituents on the ring can be hydrogen atoms, halogen atoms, amino groups, linear or branched alkyl groups containing 1 to 3 carbon atoms or alkoxy;

R ₂ represents 4 to 7 carbon cycloalkane, aromatic ring, aromatic heterocyclic ring or condensed ring of 4-10 carbons, wherein the aromatic ring, aromatic heterocyclic ring and condensed ring can be unsubstituted, monosubstituted or disubstituted aromatic Ring, heteroaromatic ring, the substituents on the ring can be hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, straight chain or branched chain alkyl or alkoxy group containing 1 to 3 carbon atoms.

Another object of the present invention is to provide a preparation method of a dipeptide kininase-inhibiting compound and a pharmaceutically acceptable salt thereof, which is achieved through the following specific steps:

(1) compound of formula I and compound of formula II to synthesize the compound of formula III;

The compound of formula I can undergo Williamson reaction with the compound of formula II under basic conditions to obtain the compound of formula III. The reaction step is generally in a polar solvent such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl In sulfoxide, the commonly used alkaline substances are potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc., and the commonly used catalysts are copper salts such as cuprous iodide, cuprous bromide, and cuprous chloride , the reaction temperature is generally 80-120°C, and the obtained product can be purified by column chromatography.

(2) compound of formula III and compound of formula IV to synthesize the compound of formula V;

The compound of formula III can carry out reductive amination reaction with the compound of formula IV under neutral or alkaline conditions to obtain the compound of formula V. The reaction step is generally carried out in a protic solvent such as methanol, ethanol, methanol-water, ethanol-water, and the reduction Reagents include various sodium borohydride salts, such as sodium borohydride, sodium cyanoborohydride, etc., the reaction temperature is room temperature, and the obtained product is purified by column chromatography.

(3) The compound of formula V is dissolved in methanol, and an appropriate amount of acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalic acid, etc. is added, and the solvent is spin-dried to obtain a pharmaceutically acceptable salt of the compound of formula V.

Wherein A, X, R, R ₁ , R ₂ have the same definition as before; Hal is selected from chlorine or bromine.

The compound of formula I can refer to the literature method (Gangadasu, B. Tetrahedron , 2002, 62, 8398-8403; Bhuyan, P. J. Synlett , 2006, 2593-2596.) to obtain or purchase commercially available compounds through Vilsmeier reaction, formula II and formula IV A commercially available compound.

Another object of the present invention is to provide the application of the dipeptide kininase-inhibiting compound and its pharmaceutically acceptable salt in the preparation of drugs for treating type II diabetes. Pharmacological experiments found that the compound and its pharmaceutically acceptable salts have a good inhibitory effect on DPP-IV, with an IC ₅₀ value between 0.014 and 10.019 μM, and have an obvious hypoglycemic effect on diabetic model rats. These data indicate that this type of compound has good research and development value.

The characteristics of the present invention: take the active DPP-IV inhibitor as the research object, use various drug design and synthesis methods to obtain a new class of compounds with DPP-IV inhibitory activity, the synthetic route is short, and the raw materials are cheap and easy to obtain , suitable for practical use. Preliminary pharmacological activity screening tests show that these compounds have strong DPP-IV inhibitory activity, and have obvious hypoglycemic effect on normal rats, and have good development prospects.

Detailed ways

The present invention will be further described in conjunction with examples, but not limit the present invention in any way.

Example 1, 5-bromo-2-chloro-3-formaldehyde pyridine 2a

Dissolve 5-bromo-2-chloro-3-carboxylic acid pyridine (32.9g, 0.151mol) in 167ml of phosphorus trichloride, add 10.5ml of DMF, heat and reflux for 4h, the reaction is completed, cool to room temperature, and depressurize Recover excess thionyl chloride, add sodium cyanoborohydride aqueous solution (31.42 g, 0.5 mol) dropwise under ice-water bath, stir overnight at room temperature, after the reaction, extract with ethyl acetate, wash with saturated sodium chloride, anhydrous sulfuric acid The sodium was dried, the solvent was recovered under reduced pressure, and the obtained intermediate was put into the next reaction without further purification. The obtained intermediate 1a (2.01g, 9.02mmol) was dissolved in 20ml of anhydrous dichloromethane, PCC (2.35g, 10.8mmol) was added, stirred at room temperature for 24h, the solvent was recovered under reduced pressure after the reaction was completed, washed with water, and extracted with ethyl acetate , washed with saturated sodium chloride, dried over anhydrous sodium sulfate, recovered solvent under reduced pressure and carried out column chromatography with eluent (petroleum ether: dichloromethane = 20:1) to obtain 1.65 g of white solid 2a, yield: 83% ;Melting point: 112-113℃

¹ H NMR (δ, CDCl ₃ ): 9.73(s, 1H), 7.84(d, 1H, J = 2.5 Hz), 8.04(d, 1H, J = 2.5 Hz).

Example 2, 5-methyl-2-chloro-3-formaldehyde pyridine 4a

Add benzylamine as raw material (5g, 46mmol) into a 50ml flask, slowly add propionaldehyde (2.71g, 46mmol) dropwise at 0°C, and keep the dropping process for 1h. After the dropwise addition, add LiOH (960mg, 23mmol ), continue to stir until there is obvious stratification, and take the organic layer for later use. Take the above organic layer (6g, 40mmol) into a reaction flask, add acetic anhydride (4.08g, 40mmol) and triethylamine (4.12g, 40mmol) at 0-5°C, stir overnight at room temperature to obtain intermediate 3a, product The rate is 88%. Add DMF (13.5g, 185mmol) to triphosgene (54.7g, 185mmol) at 0°C, stir for 30min, add the intermediate 3a (5g, 26mmol) obtained above, after the addition, remove the ice-water bath, and Stir for 2 hours, heat to 70°C and react for 4 hours. After the reaction, pour the mixture into ice water, extract with dichloromethane, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and recover the solvent under reduced pressure with eluent (petroleum ether :dichloromethane=20:1) to conduct column chromatography to obtain white solid 4a, yield: 64%; melting point: 42-45°C.

¹ H NMR (δ, CDCl ₃ ): 9.73(s, 1H), 8.04(d, 1H, J = 2.5 Hz), 8.24(d, 1H, J = 2.5 Hz), 2.31(s, 1H).

Example 3, 2-chloro-6-methyl-3-quinoline formaldehyde 5a

Add phosphorus trichloride (13ml, 98.28mmol) dropwise to a reaction flask containing DMF (2.7ml, 34.65mmol) at 0-5°C, stir for 30min, add p-methylacetanilide (1.54g, 10.37mmol), and heat up Stir at 85°C for 8 hours. After the reaction, pour the mixture into ice water to precipitate a light yellow solid, filter, wash with water, and dry in vacuo to obtain 1.62 g of light yellow solid 5a, yield: 80%; melting point: 124-125°C.

Embodiment 4, 3-chloroquinoxaline-2-formaldehyde 6a

The operation process is the same as in Example 1, except that p-3-chloroquinoxaline-2-carboxylic acid is used instead of 5-bromo-2-chloro-3-carboxylic acid pyridine to obtain light yellow solid compound 6a, yield: 38%; melting point: 63-65 ℃.

Example 5, 2-chloro-1,8-naphthyridine-3-carbaldehyde 7a

The operation process is the same as in Example 1, except that 2-chloro-1,8-naphthalene-3-carboxylic acid is used instead of 5-bromo-2-chloro-3-carboxylic acid pyridine to obtain light yellow solid compound 7a, yield: 24 %; Melting point: 143-144°C.

Embodiment 6, 2,6-dichloroquinoline-3-formaldehyde 8a

The operation process is the same as in Example 1, except that 5-bromo-2-chloro-3-carboxylic acid pyridine is replaced with 2,6-dichloroquinoline-3-carboxylic acid to obtain light yellow solid compound 8a, yield: 65%; melting point: 146 -148°C.

Example 7, 2-chloro-6,7-dimethoxyquinoline-3-carbaldehyde 9a

The operation process is the same as that of Example 1, except that 2-chloro-6,7-dimethoxyquinoline-3-carboxylic acid is used instead of 5-bromo-2-chloro-3-carboxylic acid pyridine to obtain light yellow solid compound 9a. The yield : 76%; Melting point: 175-176°C.

Example 8, 6-chlorothieno[2,3-b]pyridine-5-carbaldehyde 10a

The operation process is the same as Example 1, except that 5-bromo-2-chloro-3-carboxylic acid pyridine is replaced by 6-chlorothieno[2,3-b]pyridine-5-carboxylic acid to obtain light yellow solid compound 10a, yield: 77%; melting point: 157-158°C.

Example 9, 3-chloro-6-methylpyrazine-2-formaldehyde 11a

The operation process was the same as in Example 1, except that 5-bromo-2-chloro-3-carboxylic acid pyridine was replaced with 3-chloro-6-methylpyrazine-2-carboxylic acid to obtain light yellow solid compound 11a, yield: 45%; Melting point: 123-124°C.

Example 10, 3-chloro-7-(trifluoromethyl)quinoxaline-2-carbaldehyde 12a

The operation process is the same as in Example 1, except that 3-chloro-7-(trifluoromethyl)quinoxaline-2-carboxylic acid is used instead of 5-bromo-2-chloro-3-carboxylic acid pyridine to obtain pale yellow solid compound 12a, which is obtained as Efficiency: 51%; Melting point: 156-157°C.

Example 11, 2-(4-chlorophenoxy)pyridine-3-aldehyde 1b

Dissolve the compound 2-chloro-3 pyridinecarbaldehyde (141mg, 1mmol) in 5ml DMF, add

Potassium phosphate (424mg, 4mmol), cuprous iodide (19mg, 0.1mmol), p-chlorophenol (121mg, 1mmol), put them in an ultrasonic reactor with an ultrasonic power of 600W, and react for 8min. After the reaction, wash with water and wash with acetic acid Extracted with ethyl ester, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and recovered the solvent under reduced pressure to obtain a yellow crude product 1b, yield: 84%; melting point: 93-94°C.

Example 12, 2-(2,4-dichlorophenoxy)pyridine-3-aldehyde 2b

The operation process is the same as in Example 11, except that p-chlorophenol is replaced by 2,4-dichlorophenol to obtain compound 2b as a yellow solid with a yield of 79% and a melting point of 114-115°C.

Example 13, 2-(4-methylphenoxy)pyridine-3-aldehyde 3b

The operation process was the same as in Example 11, except that p-chlorophenol was replaced by 4-methylphenol to obtain compound 3b as a yellow solid, yield: 86%; melting point: 126-127°C.

Example 14, 2-(2-cyanophenoxy)pyridine-3-aldehyde 4b

The operation process was the same as in Example 11, except that p-chlorophenol was replaced by 2-cyanophenol to obtain compound 4b as a yellow solid, yield: 76%; melting point: 154-156°C.

Example 15, 2-(4-methoxyphenoxy)pyridine-3-aldehyde 5b

The operation process was the same as in Example 11, except that p-chlorophenol was replaced by 4-methoxyphenol to obtain compound 5b as a yellow solid, yield: 84%; melting point: 136-137°C.

Example 16, 5-bromo-2-(4-methoxyphenoxy)-3-formaldehyde pyridine 6b

The operation process was the same as in Example 11, except that compound 2a was used instead of 2-chloro-3-pyridinecarbaldehyde, and 4-methoxyphenol was used instead of p-chlorophenol to obtain compound 6b as a yellow solid, yield: 67%; melting point: 123-124°C.

Example 17, 5-methyl-2-(4-chlorophenoxy)-3-formaldehyde pyridine 7b

The operation process was the same as in Example 11, except that compound 4a was used instead of 2-chloro-3-pyridinecarbaldehyde to obtain compound 7b as a yellow solid, yield: 73%; melting point: 154-155°C.

Example 18, 3-(4-chlorophenoxy)-6-methylpyrazine-2-carbaldehyde 8b

The operation process was the same as in Example 11, except that 2-chloro-3-pyridinecarbaldehyde was replaced by compound 11a to obtain compound 8b as a yellow solid, yield: 66%; melting point: 210-211°C.

Example 19, 2-(4-chlorophenylamino)nicotinaldehyde 9b

The operation process was the same as in Example 11, but 4-chloroaniline was used instead of p-chlorophenol to obtain compound 9b as a yellow solid, yield: 66%; melting point: 154-155°C.

Example 20, 3-(3,4-dichlorophenylamino)pyrazine-2-carbaldehyde 10b

The operation process is the same as in Example 11, and the compound 3-chloropyrazine-2-carbaldehyde is used instead of 2-chloro-3-pyridinecarbaldehyde, and 3,4-dichloroaniline is used instead of p-chlorophenol to obtain yellow solid compound 10b, yield: 33% ; Melting point: 171-172°C.

Example 21, 6-methyl-2-(4-chlorophenoxy)-3-formaldehyde quinoline 11b

The operation process was the same as in Example 11, except that 2-chloro-3-pyridinecarbaldehyde was replaced by compound 5a to obtain compound 11b as a yellow solid, yield: 78%; melting point: 134-135°C.

Example 22, 2-(4-methoxyphenoxy)-6-(trifluoromethyl)quinoline-3-carbaldehyde 12b

The operation process was the same as in Example 11, except that compound 12a was used instead of 2-chloro-3-pyridinecarbaldehyde, and 4-methoxyphenol was used instead of p-chlorophenol to obtain compound 12b as a yellow solid, yield: 43%; melting point: 123-124°C.

Example 23, 2-(p-methylphenoxy)-1,8-naphthyridine-3-carbaldehyde 13b

The operation process was the same as in Example 11, except that compound 7a was used instead of 2-chloro-3-pyridinecarbaldehyde, and 4-methylphenol was used instead of p-chlorophenol to obtain compound 13b as a yellow solid, yield: 36%; melting point: 144-145°C.

Example 24, 2-(3,4-dimethylphenoxy)-6,7-dimethoxyquinoline-3-carbaldehyde 14b

The operation process is the same as in Example 11, except that compound 9a is used instead of 2-chloro-3 pyridinecarbaldehyde, and 3,4-dimethylphenol is used instead of p-chlorophenol to obtain yellow solid compound 14b, yield: 77%; melting point: 146-147 ℃.

Example 25, 6-(3,4-dichlorophenylamino)thieno[2,3-b]pyridine-5-carbaldehyde 15b

The operation process is the same as in Example 11, except that compound 10a is used instead of 2-chloro-3-pyridinecarbaldehyde, and 3,4-dichloroaniline is used instead of p-chlorophenol to obtain yellow solid compound 15b, yield: 41%; melting point: 165-166°C .

Example 26, 1-(2-(4-chlorophenoxy)pyridin-3-yl)-N-(pyridin-3-ylmethyl)methanamine 1c

Compound 1b (23mg, 0.1mmol) was dissolved in 5ml methanol, 3-aminomethylpyridine (45ul, 0.4mmol) was added, stirred at 70°C for 2h, cooled to room temperature, sodium borohydride (15mg, 0.4mmol) was added, Stir at room temperature for 2 hours. After the reaction, recover the solvent under reduced pressure, wash with water, extract with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and use eluent (petroleum ether: ethyl acetate: Triethylamine=5:1:0.1) was subjected to column chromatography to obtain colorless transparent liquid 1c, yield: 72%.

¹ H NMR(δ, CDCl ₃ ): 8.59(s, 1H), 8.50(d, 1H, J = 4.5Hz), 8.04(d, 1H, J = 4.5Hz), 7.70(m, 2H), 7.33( d, 2H, J = 8.5Hz), 7.24(m, 1H), 7.04(d, 2H, J = 8.5Hz), 6.99(m, 1H), 3.91(s, 2H), 3.86(s, 2H).

Example 27, N-((2-(4-chlorophenoxy)pyridin-3-yl)methyl)cyclopentylamine 2c

The operation process was the same as in Example 26, except that cyclopentylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 2c, yield: 82%.

¹ H NMR(δ, CDCl ₃ ): 8.02(d, 1H, J = 5Hz), 7.70(d, 1H, J = 7Hz), 7.34(d, 2H, J = 8.5Hz), 7.05 (d, 2H, J = 8.5Hz), 6.98(m, 1H), 3.88 (s, 2H), 3.10(m, 1H), 1.83(m, 2H), 1.67(m, 2H), 1.50(m, 2H), 1.36( m, 2H).

Example 28, 1-(benzo[d][1,3]dioxazol-5-yl)-N-((2-(4-chlorophenoxy)pyridin-3-yl)methyl)methanol Amine 3c

The operation process was the same as in Example 26, except that piperonylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 3c, yield: 64%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 5Hz), 7.73(d, 1H, J = 7Hz), 7.34(d, 2H, J = 9.0Hz), 7.05(d, 2H, J = 8.5Hz), 6.99(m, 1H), 6.88(s, 1H), 6.75(m, 2H), 5.94(d, 2H), 3.90(s, 2H), 3.76(s, 2H).

Example 29, 1-(2-(2,4-dichlorophenoxy)pyridin-3-yl)-N-(4-fluorobenzyl)methanamine 4c

The operation process was the same as in Example 26, except that compound 2b was used instead of 1b, and 4-fluorobenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 4c, yield: 58%.

¹ H NMR(δ, CDCl ₃ ): 7.99(d, 1H, J = 5Hz), 7.70(d, 1H, J = 7.5Hz), 7.46(d, 1H, J = 2.5Hz), 7.28(m, 3H ), 7.17(d, 1H, J = 8.5Hz), 7.00(m, 3H), 3.95(s, 2H), 3.81(s, 2H).

Example 30, 1-(furan-2-yl)-N-((2-(p-methylphenoxy)pyridin-3-yl)methyl)methanamine 5c

The operation process was the same as in Example 26, except that compound 3b was used instead of 1b, and furfurylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 5c, yield: 87%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 5Hz), 7.68(d, 1H, J = 7.5Hz), 7.36(s, 1H), 7.19(d, 2H, J = 8Hz) , 7.00(d, 2H, J = 8.5Hz), 6.94(m, 1H), 6.31(m, 1H), 6.20(d, 1H, J = 3Hz), 3.93(s, 2H), 3.84(s, 2H ), 2.36(s, 3H).

Example 31, 2-(3-((4-hydroxybenzylamino)methyl)pyridine-2-oxyl)benzonitrile 6c

The operation process was the same as in Example 26, except that compound 4b was used instead of 1b, and 4-hydroxybenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 6c, yield: 58%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 5Hz), 7.73(d, 1H, J = 7.5Hz), 7.65(d, 1H, J = 8.0Hz), 7.58(d, 1H , J = 8H), 7.25(m, 2H), 7.11(d, 2H, J = 8.5Hz), 7.01(m, 1H), 6.62(d, 2H, J = 8.5Hz), 3.98(s, 2H) , 3.76(s, 2H).

Example 32, N-(3,4-dimethylbenzyl)-1-(2-(4-methoxyphenoxy)pyridin-3-yl)methanamine 7c

The operation process was the same as in Example 26, except that compound 5b was used instead of 1b, and 3,4-dimethylbenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 7c, yield: 74%.

¹ H NMR(δ, CDCl ₃ ): 8.01(d, 1H, J = 5Hz), 7.68(d, 1H, J = 7Hz), 7.23(d, 2H, J = 8Hz), 7.34(d, 1H, J = 7.5Hz), 7.12(d, 1H, J = 8.5Hz), 7.02(s, 1H), 6.93(m, 1H), 6.90(d, 2H, J = 8Hz), 3.92(s, 2H), 3.81 (s, 2H), 3.803 (s, 3H), 2.33 (s, 6H).

Example 33, 4-(((5-bromo-2-(4-methoxyphenoxy)pyridin-3-yl)methylamino)methyl)benzoic acid 8c

The operation process was the same as in Example 26, except that compound 6b was used instead of 1b, and 4-carboxybenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 8c, yield: 61%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 2.5Hz), 7.77(d, 1H, J = 2.5Hz), 7.13(d, 2H, J = 8.5Hz), 7.00(d, 2H, J = 8.5Hz), 6.90 (d, 2H, J = 8.5Hz), 6.67(d, 2H, J = 8.5Hz), 3.90(s, 2H), 3.79(s, 3H), 3.76(s, 2H).

Example 34, 4-(((2-(4-chlorophenoxy)-5-methylpyridin-3-yl)methylamino)methyl)aniline 9c

The operation process was the same as in Example 26, except that compound 7b was used instead of 1b, and 4-aminobenzylamine was used instead of 3-aminomethylpyridine to obtain light yellow transparent liquid 9c, yield: 57%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 2.5Hz), 7.81(d, 1H, J = 2.5Hz), 7.16(t, 4H, J = 7.5Hz, 8Hz), 6.96( d, 2H, J = 9Hz), 6.72(d, 2H, J = 9Hz), 3.90(s, 2H), 3.77(s, 2H), 2.35(s, 3H).

Example 35, 1-(3-(4-chlorophenoxy)-6-methylpyrazin-2-yl)-N-(4-methylbenzyl)methanamine 10c

The operation process was the same as in Example 26, except that compound 8b was used instead of 1b, and 4-methylbenzylamine was used instead of 3-aminomethylpyridine to obtain a colorless transparent liquid 10c, yield: 72%.

¹ H NMR(δ, CDCl ₃ ): 8.04(s, 1H), 7.24(d, 2H, J = 7.5Hz), 7.16(d, 2H, J = 7.5Hz), 6.96(d, 2H, J = 9Hz ), 6.72(d, 2H, J = 9Hz), 3.90(s, 2H), 3.77(s, 2H), 2.35(s, 6H).

Example 36, N-(4-chlorophenyl)-3-((4-methylbenzylamino)methyl)pyridin-2-amine 11c

The operation process was the same as in Example 26, except that compound 9b was used instead of 1b, and 4-methylbenzylamine was used instead of 3-aminomethylpyridine to obtain a colorless transparent liquid 11c, yield: 43%.

¹ H NMR(δ, CDCl ₃ ): 8.04(d, 1H, J = 5Hz), 7.69(d, 1H, J = 7Hz), 7.32(d, 2H, J = 9Hz), 7.10(d, 2H, J = 9Hz), 7.02(d, 2H, J = 9H), 6.97(m, 1H), 6.62(d, 2H, J = 9Hz), 3.93(s, 2H), 3.75(s, 2H), 2.36(s , 3H).

Example 37, N-(3,4-dichlorophenyl)-3-((4-fluorobenzylamino)methyl)pyrazin-2-amine 12c

The operation process was the same as in Example 26, except that compound 10b was used instead of 1b, and 4-fluorobenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 12c, yield: 54%.

¹ H NMR(δ, CDCl ₃ ): 8.06(d, 1H, J = 2.5Hz), 7.83(d, 1H, J = 2.5Hz), 7.46(d, 2H, J = 8.5Hz), 7.31(d, 1H, J = 8Hz), 7.26 (s, 1H), 7.19(d, 1H, J = 8Hz), 7.00(d, 2H, J = 8.5Hz), 3.91(s, 2H), 3.87(s, 2H) .

Example 38, 1-(2-(4-chlorophenoxy)quinolin-3-yl)-N-(4-methylbenzyl)methanamine 13c

The operation process was the same as in Example 26, except that compound 11b was used instead of 1b, and 4-methylbenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 13c, yield: 67%.

¹ H NMR(δ, CDCl ₃ ): 8.03(s, 1H, J = 2.5Hz), 7.60(d, 1H, J = 8.5Hz), 7.51(s, 1H), 7.38(d, 1H, J = 8.5 Hz), 7.35(d, 2H, J =9Hz), 7.25(d, 2H, J =7.5Hz), 7.16(d, 2H, J = 7.5Hz), 7.13(d, 2H, J = 7.5Hz), 4.02(s, 2H), 3.84(s, 2H), 2.35(s, 6H).

Example 39, N-(4-fluorobenzyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl)quinoxalin-2-yl)methanamine 14c

The operation process was the same as in Example 26, except that compound 12b was used instead of 1b, and 4-fluorobenzylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 14c, yield: 42%.

¹ H NMR(δ, CDCl ₃ ): 7.62(d, 1H, J = 8.5Hz), 7.33(m, 4H), 7.23(d, 1H, J = 8.5Hz), 7.16(d, 1H, J = 8.5 Hz), 7.06(d, 2H, J = 9Hz), 7.01 (d, 2H, J = 9Hz), 4.03(s, 2H), 3.90(s, 2H), 3.86(s, 3H).

Example 40, N-((2-(p-methylphenoxy)-1,8-phthalazin-3-yl)methyl)cyclopentylamine 15c

The operation process was the same as Example 26, except that compound 13b was used instead of 1b, and cyclopentylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 15c, yield: 55%.

¹ H NMR(δ, CDCl ₃ ): 8.32(s, 1H), 8.02(d, 1H, J = 5Hz), 7.70(d, 1H, J = 5Hz), 7.34(d, 2H, J = 8.5Hz) , 7.05 (d, 2H, J = 8.5Hz), 6.98(m, 1H), 3.88 (s, 2H), 3.10(m, 1H), 2.33(s, 3H), 1.83(m, 2H), 1.67( m, 2H), 1.50(m, 2H), 1.36(m, 2H).

Example 41, N-((6-(3,4-dichlorophenoxy)thieno[2,3-b]pyridin-5-yl)methyl)cyclopentylamine 16c

The operation process was the same as in Example 26, except that compound 15b was used instead of 1b, and cyclopentylamine was used instead of 3-aminomethylpyridine to obtain colorless transparent liquid 16c, yield: 76%.

¹ H NMR(δ, CDCl ₃ ): 8.32(s, 1H), 8.02(d, 1H, J = 7.5Hz), 7.70(d, 1H, J = 7.5Hz), 7.34(s, 1H), 7.05 ( d, 1H, J = 5Hz), 6.98(d, 1H, J = 5Hz), 3.88 (s, 2H), 3.10(m, 1H), 1.83(m, 2H), 1.67(m, 2H), 1.50( m, 2H), 1.36(m, 2H).

Example 42, 1-(2-(3,4-dimethylphenoxy)-6,7-dimethoxyquinolin-3-yl)-N-(pyridin-3-ylmethyl)methyl Amine 17c

The operation process is the same as in Example 26, except that compound 14b is used instead of 1b to obtain yellow transparent liquid 17c, yield: 39%.

¹ H NMR(δ, CDCl ₃ ): 8.61(s, 1H), 8.51(d, 1H, J = 4.5Hz), 8.02(s, 1H), 7.79(d, 1H, J = 7.5Hz), 7.36 ( d, 1H, J = 7.5Hz), 7.27 (m, 1H), 7.15(d, 1H, J = 7.5Hz), 7.06 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 4.05(s, 2H), 3.97(s, 3H), 3.94(s, 3H), 3.92(s, 2H), 2.37(s, 6H).

Example 43, N-(4-methylbenzyl)-1-(2-(pyridine-4-oxyl)pyridin-3-yl)methanamine 18c

The operation process is the same as in Example 26, except that the compound 2-(pyridine-4-oxyl)nicotinaldehyde is used instead of 1b, and 4-methylbenzylamine is used instead of 3-aminomethylpyridine to obtain a colorless transparent liquid 18c, yield: 51 %.

¹ H NMR(δ, CDCl ₃ ): 8.51(d, 2H, J = 9Hz), 7.69(d, 1H, J = 7.5Hz), 7.36 (d, 1H, J = 7.5Hz), 7.15(d, 2H , J = 7.5Hz), 6.98 (m, 1H), 7.06 (d, 2H, J = 9Hz), 7.03 (d, 2H, J = 9Hz), 3.97(s, 2H), 3.92(s, 2H), 2.37 (s, 3H).

Example 44, 1-(2-(4-chlorophenoxy)pyridin-3-yl)-N-(pyridin-3-ylmethyl)methanamine hydrochloride 1d

Compound 1c (650 mg, 2 mmol) was dissolved in 5 ml of methanol, 25 ml of dilute hydrochloric acid was added dropwise in an ice-water bath, stirred for 30 min, and the solvent was spin-dried under reduced pressure to obtain a white solid 1d with a yield of 78%; melting point: >200°C.

Example 45, N-((2-(4-chlorophenoxy)pyridin-3-yl)methyl)cyclopentylamine hydrochloride 2d

The operation process was the same as Example 44, except that compound 2c was replaced by 1c to obtain white solid 2d with a yield of 89%; melting point: >200°C.

Example 46, 1-(Benzo[d][1,3]dioxazol-5-yl)-N-((2-(4-chlorophenoxy)pyridin-3-yl)methyl)methanol Amine Sulfate 3d

The operation process was the same as in Example 44, except that compound 3c was replaced by 1c, and dilute sulfuric acid was used instead of dilute hydrochloric acid to obtain white solid 3d with a yield of 77%; melting point: >200°C.

Example 47, 1-(2-(2,4-dichlorophenoxy)pyridin-3-yl)-N-(4-fluorobenzyl)methanamine hydrochloride 4d

The operation process was the same as that of Example 44, except that compound 4c was replaced by 1c to obtain white solid 4d with a yield of 87%; melting point: >200°C.

Example 48, 1-(furan-2-yl)-N-((2-(p-methylphenoxy)pyridin-3-yl)methyl)methanamine hydrochloride 5d

The operation process is the same as in Example 44, except that compound 5c is replaced by 1c to obtain white solid 5d with a yield of 89%; melting point: >200°C.

Example 49, 2-(3-((4-hydroxybenzylamino)methyl)pyridine-2-oxyl)benzonitrile hydrochloride 6d

The operation process is the same as in Example 44, except that compound 6c is replaced by 1c to obtain white solid 6d with a yield of 72%; melting point: >200°C.

Example 50, N-(3,4-dimethylbenzyl)-1-(2-(4-methoxyphenoxy)pyridin-3-yl)methanamine phosphate 7d

The operation process was the same as that of Example 44, except that compound 7c was replaced by 1c, and dilute hydrochloric acid was replaced by phosphoric acid to obtain white solid 7d with a yield of 88%; melting point: >200°C.

Example 51, 4-(((5-bromo-2-(4-methoxyphenoxy)pyridin-3-yl)methylamino)methyl)benzoic acid hydrochloride 8d

The operation process is the same as in Example 44, except that compound 8c is replaced by 1c to obtain white solid 8d with a yield of 75%; melting point: >200°C.

Example 52, 4-(((2-(4-chlorophenoxy)-5-methylpyridin-3-yl)methylamino)methyl)aniline hydrochloride 9d

The operation process is the same as in Example 44, except that compound 9c is replaced by 1c to obtain white solid 9d with a yield of 86%; melting point: >200°C.

Example 53, 1-(3-(4-chlorophenoxy)-6-methylpyrazin-2-yl)-N-(4-methylbenzyl)methanamine hydrochloride 10d

The operation process was the same as Example 44, except that compound 10c was replaced by 1c to obtain white solid 10d with a yield of 70%; melting point: >200°C.

Example 54, N-(4-chlorophenyl)-3-((4-methylbenzylamino)methyl)pyridin-2-amine hydrochloride 11d

The operation process is the same as in Example 44, except that compound 11c is replaced by 1c to obtain white solid 11d with a yield of 78%; melting point: >200°C.

Example 55, N-(3,4-dichlorophenyl)-3-((4-fluorobenzylamino)methyl)pyrazin-2-amine hydrochloride 12d

The operation process was the same as that of Example 44, except that compound 12c was replaced by 1c to obtain white solid 12d with a yield of 69%; melting point: >200°C.

Example 56, 1-(2-(4-chlorophenoxy)quinolin-3-yl)-N-(4-methylbenzyl)methanamine hydrochloride 13d

The operation process was the same as Example 44, except that compound 13c was replaced by 1c to obtain white solid 13d with a yield of 86%; melting point: >200°C.

Example 57, N-(4-fluorobenzyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl)quinoxalin-2-yl)methanamine salt salt 14d

The operation process was the same as Example 44, except that compound 14c was replaced by 1c to obtain white solid 14d with a yield of 75%; melting point: >200°C.

Example 58, N-((2-(p-methylphenoxy)-1,8-phthalazin-3-yl)methyl)cyclopentylamine hydrochloride 15d

The operation process is the same as in Example 44, except that compound 15c is replaced by 1c to obtain white solid 15d with a yield of 67%; melting point: >200°C.

Example 59, N-((6-(3,4-dichlorophenoxy)thieno[2,3-b]pyridin-5-yl)methyl)cyclopentylamine hydrochloride 16d

The operation process is the same as in Example 44, except that compound 16c is replaced by 1c to obtain white solid 16d with a yield of 88%; melting point: >200°C.

Example 60, 1-(2-(3,4-dimethylphenoxy)-6,7-dimethoxyquinolin-3-yl)-N-(pyridin-3-ylmethyl)methyl Amine hydrochloride 17d

The operation process was the same as Example 44, except that compound 17c was replaced by 1c to obtain white solid 17d with a yield of 90%; melting point: >200°C.

Example 61, N-(4-methylbenzyl)-1-(2-(pyridin-4-oxyl)pyridin-3-yl)methanamine hydrochloride 18d

The operation process is the same as Example 44, except that compound 18c is replaced by 1c to obtain white solid 18d with a yield of 74%; melting point: >200°C.

Embodiment 62, DPP-IV inhibitory activity assay:

The inhibitory rate of the compound provided by the present invention to DPP-IV can be measured by DPP-IV-Glo ^TM protease homogeneous luminescence detection system (DPP-IV-Glo ^TM Protease Assay, Promega cat#G8350). The system contains the DPP-IV substrate Gly-Pro-aminoluciferin and a buffer system for the detection of luciferase activity. After DPP-IV-Glo ^TM is cut by DPP-IV, the luciferase reaction will be activated to produce ""glow-type" type luminescent signal, and then detect the luminescent signal with a Turner Veritas ^TM microplate luminescence photometer to characterize the activity of DPP-IV.

Experimental method: Release GP-PNA in their respective buffers at a concentration of 100 μmol/L, 25 μmol per well; enzyme gradient dilution, the initial concentration is DPP-IV: 0.01mU/μl, diluted 5 times, 25 μl per well , mix well; 37°C, 360/460nm, measure the dynamic change of the fluorescence value for 30 minutes; the concentration of the enzyme whose absorbance rises linearly and S/N≥5 is used as the concentration.

Determination of inhibitor activity: All enzymes and inhibitors are prepared with assay buffer, and no compound control and no enzyme solution control are set. Prepare enzyme solution according to the concentration of enzyme used, 25 μl per well; serially dilute inhibitor (10-fold or 5-fold dilution), 25 μl per well, mix well; add 50 μl of diluted GP-AMC solution, mix well; react at 37°C for 20 Minutes, 360/460nM to measure the fluorescence value. See Table 1 for the inhibitory rate of the compound in vitro to inhibit DPP-IV activity and the IC ₅₀ (μM) value of the compound's pharmaceutically acceptable salt for inhibiting DPP-IV activity in vitro.

It can be seen from the above table that 1) all 18 compounds have certain inhibitory activity on DPP-IV. 2) The DPP-IV inhibitory activity of the compound whose core is 5-substituted pyridine or 6-substituted quinoline is higher than that of the compound whose core is unsubstituted pyridine. 3) Compounds with clogP values between 4-5 have higher DPP-IV inhibitory activity than compounds with clogP values greater than 5, such as compound 11d and compound 12d, wherein the IC ₅₀ value of compound 11d reaches 0.014 μM.

Example 63. Effect test of some compounds on oral glucose tolerance in diabetic rats

Normal animals, abnormal glucose tolerance or diabetic model animals were used to give the test compound, and the solvent was used as a negative control, and sitagliptin was used as a positive control to conduct an oral glucose tolerance test, and the area under the glucose tolerance curve was calculated by the trapezoidal method.

In the preliminary experiment, animals with abnormal glucose tolerance whose fasting blood glucose was less than 7 mmol/L were used (feeding high-fat feed for 4 weeks, adding small doses of streptozotocin and then high-fat feed for 3 weeks, resulting in the animal's glucose tolerance curve being significantly higher than that of the normal control) , intragastric administration of the corresponding doses of test compounds 11c and 12c, 0.5h later, intragastric administration of glucose 1g/kg, and rapid blood glucose meter to measure before administration, after administration, and after administration of glucose 20, 40, 60, 120 The blood glucose values at each time point were calculated, and the area under the glucose tolerance curve (AUC) was calculated. The results showed that the AUC value of the model rat control group was significantly higher than that of the normal rat control group ( p <0.001). Both test substances can significantly reduce the AUC value of model animals ( p <0.05), and the positive control drug sitagliptin can also significantly reduce the AUC value of model animals ( p <0.01). There was no significant difference between the AUC value of the test compound and sitagliptin ( p >0.05). There was no significant difference between each administration group and the normal rat control group ( p >0.05). It can be seen that the test compound, like the positive drug sitagliptin, can improve the oral glucose tolerance of model rats, and has obvious hypoglycemic effect in vivo. See Table 3.

t test, compared with the model rat control group, * p <0.05, ** p <0.01, *** p <0.001.

In summary, it can be seen from the above biological activity data that this type of compound has good application prospects for lowering blood sugar, and thus has good commercial value.

Claims (2)

1. suppress compound and the pharmacy acceptable salt thereof of dipeptides kininase, described compound is specially:

(1) 1-(2-(4-chlorophenoxy) pyridin-3-yl)-N-(pyridin-3-yl methyl) methylamine;

(2) N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) cyclopentamine;

(3) 1-(benzo [d] [1,3] bis-oxazole-5-yl)-N-((2-(4-chlorophenoxy) pyridin-3-yl) methyl) methylamine;

(4) 1-(2-(2,4 dichloro benzene oxygen base) pyridin-3-yl)-N-(4-fluorobenzene methyl) methylamine;

(5) 1-(furans-2-yl)-N-((2-(p-tolyloxy) pyridin-3-yl) methyl) methylamine;

(6) 2-(3-((4-hydroxybenzene methylamino) methyl) pyridine-2-oxygen base) cyanobenzene;

(7) N-(3,4-dimethyl benzene methyl)-1-(2-(4-methoxyphenoxy) pyridin-3-yl) methylamine;

(8) 4-(((the bromo-2-of 5-(4-methoxyphenoxy) pyridin-3-yl) methylamino) methyl) phenylformic acid;

(9) 4-(((2-(4-chlorophenoxy)-5-picoline-3-yl) methylamino) methyl) aniline;

(10) 1-(3-(4-chlorophenoxy)-6-methylpyrazine-2-yl)-N-(4-methylbenzene methyl) methylamine;

(11) N-(4-chloro-phenyl-)-3-((4-methylbenzene methylamino) methyl) pyridine-2-amine;

(12) N-(3,4-dichlorophenyl)-3-((4-fluorobenzene methylamino) methyl) pyrazine-2-amine;

(13) 1-(2-(4-chlorophenoxy) quinoline-3-yl)-N-(4-methylbenzene methyl) methylamine;

(14) N-(4-fluorobenzene methyl)-1-(3-(4-methoxyphenoxy)-7-(trifluoromethyl) quinoxaline-2-yl) methylamine;

(15) N-((2-(p-tolyloxy)-1,8-naphthyridine-3-yl) methyl) cyclopentamine;

(16) N-((6-(3,4-dichlorophenoxy) thieno-[2,3-b] pyridine-5-yl) methyl) cyclopentamine;

(17) 1-(2-(3,4-dimethyl phenoxy)-6,7-dimethoxy-quinoline-3-yl)-N-(pyridin-3-yl methyl) methylamine;

(18) N-(4-methylbenzene methyl)-1-(2-(pyridine-4-oxygen base) pyridin-3-yl) methylamine.

2. the compound of inhibition dipeptides kininase according to claim 1 and pharmacy acceptable salt thereof the application in preparation treatment type ii diabetes medicine.