CN104610017B - A class of halogenated phenylpropanediol derivatives, its preparation method and use - Google Patents

Abstract

The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to II type sodium dependent glucose transhipment (SGLT2) inhibitor of a class halogenophenyl propylene glycol structure, its preparation method and the application in preparation treatment diabetes medicament. wherein, R ₁be selected from halogenic substituent; R ₂be selected from C ₁-C ₅alkyl.

Description

A class of halogenated phenylpropanediol derivatives, its preparation method and use

technical field

The present invention relates to the field of medicine related to type II diabetes. Specifically, the present invention relates to a type 2 sodium-dependent glucose transporter (SGLT2) inhibitor of a halogenated phenylpropanediol structure that has a therapeutic effect on type II diabetes, a preparation method, and a medical application.

Background technique

Diabetes patients worldwide are gradually increasing, and the vast majority of them are type 2 diabetes patients. The antidiabetic drugs currently in clinical use mainly include sulfonylureas, metformin, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors and insulin drugs. These drugs have a good therapeutic effect, but there are serious side effects in long-term treatment; and due to the existence of drug resistance, in some cases, it is difficult to control the patient's blood sugar in time with combination drugs.

Sodium-dependent glucose transporter type 2 (SGLT2) is a new target for the treatment of diabetes discovered in recent years. SGLT2 is mainly distributed in the proximal tubule of the kidney, and its function is to absorb glucose in urine and return it to the blood, so inhibiting SGLT2 can reduce the concentration of glucose in the blood. When SGLT2 function is inhibited, more glucose is excreted in the urine, which helps diabetics maintain correct blood sugar levels.

Chinese patent CN200610093189.9 discloses compounds with the following structures as SGLT2 inhibitors:

Wherein, A is O, S, NH, (CH ₂ ) _n , n=0-3.

Chinese patent CN200380110040.1 discloses compounds with the following structures as SGLT2 inhibitors:

Wherein, A is a covalent bond, O, S, NH, (CH ₂ ) _n , n=1-3.

The invention discloses a class of halogenated phenylpropanediol derivatives as novel SGLT2 inhibitors, and these compounds can be used to prepare medicines for treating diabetes, especially type II diabetes.

Contents of the invention

An object of the present invention is to overcome the disadvantages and deficiencies of the prior art, and provide a compound with general formula I and a pharmaceutically acceptable prodrug ester thereof with good activity.

Another object of the present invention is to provide a process for the preparation of compounds of general formula I and pharmaceutically acceptable prodrug esters thereof.

Another object of the present invention is to provide the compound containing general formula I and its pharmaceutically acceptable prodrug ester for use in the treatment of diabetes.

The content of the present invention will now be specifically described in conjunction with the purpose of the present invention.

Compounds of the present invention having general formula I have the following structural formula:

Wherein, R ₁ is selected from a halogen substituent;

R ₂ is selected from C ₁ -C ₅ alkyl groups.

Compounds of general formula I below are preferred,

Wherein, R ₁ is selected from F, Cl substituent;

R ₂ is selected from methyl, ethyl, n-propyl.

More preferred compounds of general formula I have the following structure,

The compound of general formula I of the present invention is synthesized by the following route:

Compound II is treated with alkyllithium to obtain the corresponding aryl lithium III; nucleophilic addition of III to compound IV obtains V; compound V undergoes selective reduction and simultaneously removes the isopropylidene protecting group to obtain I; the aryl lithium selected From n-BuLi, sec-BuLi and t-BuLi. Wherein, R ₁ and R ₂ are as defined above.

The pharmaceutically acceptable prodrug ester of the compound of formula I described in the present invention includes the formation of any one or more hydroxyl groups in the molecule with acetyl groups, pivaloyl groups, various phosphoryl groups, carbamoyl groups, alkoxyformyl groups, etc. of esters.

The compound of the general formula I in the present invention has an inhibitory effect on SGLT2, and can be used as an active ingredient in the preparation of therapeutic drugs for diabetes. The activity of the compound of general formula I in the present invention is verified by receptor binding assay.

The compounds of general formula I according to the invention are effective over a fairly wide dosage range. For example, the daily dose is about in the range of 1mg-700mg/person, divided into one or several administrations. The actual dosage of the compound of general formula I of the present invention can be determined by a doctor according to relevant conditions.

detailed description

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

The preparation of embodiment 1I-1

Add 2.92g (10mmol) of compound II-1 into a 100mL dry round bottom flask, add a dry magnet and 30mL dry THF, and seal it with a rubber cork after purging with nitrogen. The flask was cooled to -78°C in liquid nitrogen-ethanol, and stirring was started. Slowly add 6.25mL (10mmol) of 1.6M n-BuLi n-hexane solution dropwise with a syringe. After the dropwise addition was complete, stirring was continued at this temperature for 1 hour. A solution of 1.44 g (10 mmol) of compound IV dissolved in 5 mL of dry THF was then added dropwise via syringe. After the dropwise addition, the reaction mixture was stirred at this temperature for 1 hour, then slowly warmed to room temperature, and stirred for 1 hour.

The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue obtained was subjected to neutral alumina column chromatography to obtain product V-1, a white solid, ESI-MS, m/z=367 ([M +Na] ⁺ ).

Dissolve 1.72g (5mmol) of compound V-1 in 10mL of dry dichloromethane, add 2.33g (20mmol) of Et ₃ SiH, stir, and slowly add 1.42g (10mmol) of BF ₃ ·Et ₂ O dropwise under cooling in an ice-water bath . After the dropwise addition, the reaction mixture was refluxed overnight under nitrogen protection.

The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain product I-1, a white solid, ESI-MS, m/z=311 ([M+Na] ⁺ ) .

The preparation of embodiment 2I-2

Add 3.09g (10mmol) of compound II-2 into a 100mL dry round bottom flask, add a dry magnet and 30mL dry THF, and seal it with a rubber cork after purging with nitrogen. The flask was cooled to -78°C in liquid nitrogen-ethanol, and stirring was started. Slowly add 7.7mL (10mmol) of 1.3M sec-BuLi n-hexane solution dropwise with a syringe. After the dropwise addition was complete, stirring was continued at this temperature for 1 hour. A solution of 1.44 g (10 mmol) of compound IV dissolved in 5 mL of dry THF was then added dropwise via syringe. After the dropwise addition, the reaction mixture was stirred at this temperature for 1 hour, then slowly warmed to room temperature, and stirred for 1 hour.

The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue obtained was subjected to neutral alumina column chromatography to obtain product V-2, a white solid, ESI-MS, m/z=383 ([M +Na] ⁺ ).

Dissolve 1.80g (5mmol) of compound V-2 in 10mL of dry dichloromethane, add 2.33g (20mmol) of Et ₃ SiH, stir, and slowly add 1.42g (10mmol) of BF ₃ ·Et ₂ O dropwise under cooling in an ice-water bath . After the dropwise addition, the reaction mixture was refluxed overnight under nitrogen protection.

The reaction mixture was poured into 200mL ice water, stirred, extracted with 100mL×3 dichloromethane,

The combined organic phases were washed with saturated brine and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain product I-2, a white solid, ESI-MS, m/z=327 ([M+Na] ⁺ ) .

Example 3-6

Referring to the operation steps of Example 1, the compounds listed in the following table were prepared.

The preparation of embodiment 7 reference compounds

In order to further illustrate the drug efficacy of the compound of the present invention, the present invention describes the compound D-1 which has not been published yet and is also designed by the applicant.

Its preparation method is as follows:

Add 2.76g (10mmol) of compound II-7 into a 100mL dry round bottom flask, add a dry magnet and 30mL dry THF, and seal it with a rubber cork after purging with nitrogen. The flask was cooled to -78°C in liquid nitrogen-ethanol, and stirring was started. Slowly add 7.7mL (10mmol) of 1.3M sec-BuLi n-hexane solution dropwise with a syringe. After the dropwise addition was complete, stirring was continued at this temperature for 1 hour. A solution of 1.44 g (10 mmol) of compound IV dissolved in 5 mL of dry THF was then added dropwise via syringe. After the dropwise addition, the reaction mixture was stirred at this temperature for 1 hour, then slowly warmed to room temperature, and stirred for 1 hour.

The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue obtained was subjected to neutral alumina column chromatography to obtain product V-7, a white solid, ESI-MS, m/z=349 ([M +Na] ⁺ ).

Dissolve 1.63g (5mmol) of compound V-7 in 10mL of dry dichloromethane, add 2.33g (20mmol) of Et ₃ SiH, stir, and slowly add 1.42g (10mmol) of BF ₃ ·Et ₂ O dropwise under cooling in an ice-water bath . After the dropwise addition, the reaction mixture was refluxed overnight under nitrogen protection.

The reaction mixture was poured into 200 mL of ice water, stirred, extracted with 100 mL×3 dichloromethane, the organic phases were combined, washed with saturated brine, and dried (Na ₂ SO ₄ ). After the desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain product D-1, a white solid, ESI-MS, m/z=293 ([M+Na] ⁺ ) .

Example 8

The IC ₅₀ values of the compounds described in the present invention and related compounds on the inhibition of SGLT2 are determined by reference to methods described in literature.

CHO cells stably expressing humanized SGLT2 were used as the carrier for the transport analysis, and [14C]-α-D-methylglucoside ([14C]-AMG) was used as the substrate for the transport analysis. CHO cells stably expressing humanized SGLT2 were inoculated on a 96-well plate and incubated at 37°C for 12 hours. Each well was washed with 200 μL of KRH-Na+ washing solution (containing 120 mM NaCl, 4.7 mM KCl, 1.2 mMMgCl2, 2.2 mMCaCl2, 10mMHEPESand1mMTris (pH=7.4)) was washed 3 times, then KRH-Na+ washing solution containing the compound to be tested or blank was added to each well, and 10 concentrations were set for each compound to be tested, and finally 100μL containing [14C]- Wash solution of AMG (10 μCi/mL). The 96-well plate was then incubated at 37°C for 1 hour, and then 100 μL of ice-cold stop solution (containing 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2 , 2.2 mM CaCl 2 , 10 mM HEPES, 1 mM Tris and 10 mM phlorizin (pH=7.4)) was added to each well. This stop solution was washed 5 times, 100 μL per well each time. Add 20 μL of ice-cold cell lysate (100 mM NaOH) to each well, then shake at a rate of 600 rpm for 5 minutes, then add 80 μL of Microscint40 liquid flash solution to each well, and then shake at a rate of 600 rpm for 5 minutes. Finally, the 96-well plate was counted on a MicroBetaTrilux liquid scintillation counter (PerkinElmer). Response curves were determined using an empirical four-parameter model to determine the half-inhibitory concentration, expressed as IC50.

The results are listed below.

The _IC50 value of some compounds of the present invention to SGLT2

Compound number _IC50 (hSGLT2, nM) Reference compound D-1 19.5 I-1 9.1 I-2 10.3 I-3 15.8 I-4 17.4 I-5 13.9 I-6 15.2

The above IC ₅₀ measurement results show that the compound of the present invention is a strong SGLT2 inhibitor and can be used to prepare drugs for treating type II diabetes.

Claims (2)

1. following compounds,

2. compound described in claim 1 and the pharmaceutically application of acceptable salt in preparation treatment diabetes medicament thereof.