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A kind of sodium-dependent glucose transporter inhibitor and preparation method and use thereof

A technology for use and diabetes, applied in the field of medicine, to achieve the effect of long half-life, better absorption, and improved half-life

Active Publication Date: 2015-07-29
BEIJING PRELUDE PHARM SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Therefore, one object of the present invention is to provide a kind of novel compound or pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof of sodium-dependent glucose transporter (SGLT2) inhibitory activity , to address the deficiencies of existing antidiabetic and related disease treatments

Method used

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  • A kind of sodium-dependent glucose transporter inhibitor and preparation method and use thereof
  • A kind of sodium-dependent glucose transporter inhibitor and preparation method and use thereof
  • A kind of sodium-dependent glucose transporter inhibitor and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Embodiment 1: the preparation of compound 2 of the present invention

[0122]

[0123] step 1):

[0124]

[0125] At -7°C, (3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (14.2g) and N - To a solution of methylmorpholine (80 mL) in dry THF (120 mL) was added TMSCl (71 mL), then the mixture was slowly warmed to room temperature and stirred overnight. At 10 ° C, toluene (160 mL) and H 2 O (300 mL) was poured into the mixture, then washed with H 2 The organic phase was washed with O (120 mL), 1M HCl (150 mL x 4) and brine (120 mL). Na 2 SO 4 It was dried and then concentrated to give crude product which was purified by silica gel column chromatography (PE / EA=10 / 1). 30 g of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran were obtained -2-one.

[0126] Step (2):

[0127]

[0128] To a solution of 5-bromo-2-chlorobenzoic acid (40 g) in DCM (300 mL) was added dropwise (COCl) at room t...

Embodiment 2

[0153] Embodiment 2: the preparation of compound 3 of the present invention

[0154]

[0155] step 1):

[0156]

[0157] With embodiment 1 step (1).

[0158] Step (2):

[0159]

[0160] With embodiment 1 step (2).

[0161] Step (3):

[0162]

[0163] With embodiment 1 step (3).

[0164] Step (4)-1:

[0165]

[0166] To a solution of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone in dry DCM was slowly added BBr at -78 °C 3 (4.4g, 3eq), then the mixture was stirred at 0°C for 1 h and 24g at room temperature. TLC (PE / EA=1 / 1) showed the starting material was completely reacted. Slowly add saturated NaHCO to the mixture 3 , to adjust the pH to 8-9. The mixture was then extracted with DCM, the combined organic phases were washed with Na 2 SO 4 Dry and concentrate. The crude product (2.5 g) was used directly in the next step.

[0167] Step (4)-2:

[0168]

[0169] To a solution of (5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone (6.2 g) in dry DMF...

Embodiment 3

[0184] Embodiment 3: in vitro stability test

[0185] In this example, the in vitro metabolic stability of compound 2 and compound 3 of the present invention was tested, and compared with known compound 1.

[0186] Test compounds: compound 1, compound 2 and compound 3;

[0187] Control compound: verapamil.

[0188] Microsomes: Human liver microsomes (HMMC; PL050B) and male rat liver microsomes (RTMC; RT046) were purchased from CellzDirect (Invitrogen); stored at -80°C until use.

[0189] method:

[0190] 1) Prepare the mother solution as shown in Table 1, and then add the test compound or control compound, so that the final concentration of these compounds in the reaction system is 2 μM. The mixed solution was then preheated at 37°C for 2 minutes.

[0191] Table 1. Preparation of mother liquors

[0192]

[0193] 2) NADPH was added to the mixed solution to make the final concentration 1 mM, and then the reaction system was placed at 37°C. In the blank control, the sa...

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Abstract

Disclosed is a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R1 and R2 are each independently hydrogen, -OH, alkyl, -CF 3 , -OCHF 2 , -OCF 3 or halogen; R3 is cycloalkyl, -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 F or -OCH 2 CH 3 ; R4 is hydrogen, -OH, -O aryl, -OCH 2 aryl, alkyl, cycloalkyl, -CF 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 F or halogen; A is -CX 1 X 2 , wherein X 1 and X 2 are each independently H, F and Cl, and when both X 1 and X 2 are H, R3 is not -OCH 2 CH 3 . The compound has an activity of inhibitors of sodium-dependent glucose transport protein. Also disclosed is a method for preparing the compound, a pharmaceutical composition comprising the compound, use of the compound and pharmaceutical composition thereof in preparing medicaments of SGLT2 inhibitors and treating related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to a novel compound having sodium-dependent glucose transporter (SGLT2) inhibitor activity, a preparation method of the compound, a pharmaceutical composition comprising the compound, and the compound And the application of the pharmaceutical composition in the preparation of SGLT2 inhibitor drugs. Background technique [0002] Research data show that the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million, and it is estimated that nearly 500 million people worldwide will suffer from diabetes by 2030. Diabetes can lead to infection, heart disease, cerebrovascular disease, renal failure, blindness, gangrene of lower extremities, etc., which will have a huge impact and harm on patients' physical and mental health and normal life. [0003] Pathologically, diabetes is a series of clinical syndromes caused by absolute or relative ins...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/10A61K31/351A61P3/04A61P3/06A61P3/10A61P5/48A61P9/10A61P9/12
CPCA61K9/1623C07H7/04C07D309/10A61K9/1635A61K45/06A61K9/2018A61K31/351A61K9/2027A61K9/2059A61K9/0019A61K31/70A61K9/1652A61P13/12A61P25/00A61P27/02A61P3/04A61P3/06A61P5/48A61P9/00A61P9/10A61P9/12A61P3/10A61K2300/00
Inventor 王志岩
Owner BEIJING PRELUDE PHARM SCI & TECH
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