CN100567278C - Benzoylguanidine derivatives, their preparation methods and their medicinal uses - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry, in particular to a class of trimetazidine-coupled benzoylguanidine derivatives (I), their preparation methods, pharmaceutical compositions containing these compounds and their medical uses, especially as Use of anti-myocardial ischemia-reperfusion injury drugs.

Description

Benzoylguanidine derivatives, their preparation methods and their medicinal uses

technical field

The present invention relates to the field of medicinal chemistry, in particular to a class of trimetazidine-coupled benzoylguanidine derivatives, their preparation methods, pharmaceutical compositions containing these compounds and their medical uses, especially as anti-myocardial ischemia The use of drugs for blood reperfusion injury.

Background technique

Na ⁺ /H ⁺ exchanger (Na ⁺ /H ⁺ exchanger, NHE) is a protein expressed in various types of cells in many mammals. NHE can regulate intracellular pH (pH _i ) and excrete protons , move in sodium ions to regulate cell volume. So far, nine subtypes of NHE have been confirmed, namely NHE1-9, which are distributed in various organs of the human body. A large number of experiments have proved that NHE-1 is mainly present in mammalian cardiomyocytes, which plays an important role in the process of myocardial ischemia-reperfusion.

NHE-1 inhibitors prevent excessive Na ⁺ from entering cells by inhibiting Na ⁺ /H ⁺ exchange, thereby reducing Na ⁺ /Ca ²⁺ exchange and preventing excessive increase of Ca ²⁺ from causing cell contracture and necrosis. NHE-1 inhibitors can also reduce the intracellular Na ⁺ concentration by inhibiting Na ⁺ /H ⁺ exchange, reduce the osmotic pressure, and prevent water from entering the cell, so it can prevent or reduce the swelling of microvascular endothelial cells after ischemia and prevent cell necrosis . Since NHE-1 is inactive in normal cardiomyocytes, NHE-1 inhibitors only specifically act on the ischemic area, so side effects are small (Chinese Journal of Pharmaceutical Sciences, 2005, 40(5): 324-327) .

The structure-activity relationship analysis of various NHE-1 inhibitors showed that the acylguanidine moiety is very important for the inhibitory activity. Most of the NHE-1 inhibitors currently under study contain arylmethanoylguanidine structures. Such as: Cariporide (Cariporide, HOE-642).

Caliber

Trimetazidine is a metabolic drug that can reduce fatty acid oxidation and activate glucose oxidation by selectively inhibiting long-chain 3-ketoacyl-CoA thiolase, thereby more efficiently utilizing limited oxygen to generate ATP, Improve myocardial ischemia. Administering trimetazidine before thrombolysis or directly before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction can improve clinical myocardial ischemia-reperfusion injury. In patients with coronary artery bypass grafting (CABG), the application of trimetazidine can reduce ischemia-reperfusion injury, significantly increase postoperative cardiac output, reduce surgical complications, and improve quality of life (Chinese Medicine Guide, 2003 , 5(5):341-342).

trimetazidine

Contents of the invention

This research work was supported by the National Natural Science Foundation of China (No.30672512).

In the present invention, on the basis of summarizing the structure-activity relationship of existing NHE inhibitors and analyzing the structural characteristics of cariporide, benzoylguanidine is selected as the mother nucleus, and anti-myocardial ischemia is introduced into different positions of the benzoylguanidine mother ring. Trimetazidine for reperfusion injury, designed and synthesized a series of novel compounds, the platelet swelling test (Platelet Swelling Assay, PSA) shows that the compounds of the present invention have a certain inhibitory effect on NHE1, and the NHE1 inhibitory activity of some compounds is obvious Better than the active drug Cariporide.

Compound general formula I of the present invention is as follows:

Wherein R ¹ represents: hydrogen, C ₁ ~C ₆ alkyl, C ₂ ~C ₁₀ alkoxyalkyl, phenyl or phenyl substituted by the following groups: halogen, C ₁ ~C ₆ alkoxy, nitro or cyano. These substituents may be monosubstituted, disubstituted or trisubstituted;

R ² represents: hydrogen, chlorine, bromine, fluorine, C ₁ ~C ₆ alkoxy, allyloxy, nitro, trifluoromethyl, cyano, C ₁ ~C ₆ alkylsulfonyl, sulfamoyl , C ₁ -C ₆ alkylaminosulfonyl, allylaminosulfonyl, morpholin-1-ylsulfonyl, piperidin-1-ylsulfonyl, 4-methylpiperidin-1-ylsulfonyl, Pyrrol-1-ylsulfonyl, C ₁ ~C ₆ alkylamide, benzamide or benzamide substituted by the following groups: halogen, C ₁ ~C ₆ alkyl, hydroxyl, C ₁ ~C ₆ alkoxy, nitro, cyano, C ₁ -C ₆ alkylsulfonyl or C ₁ -C ₆ alkylaminosulfonyl.

R ¹ preferably represents: hydrogen or C ₁ -C ₆ alkyl.

^R preferably represents: hydrogen, chlorine, fluorine, nitro, trifluoromethyl, methanesulfonyl, ethylsulfonyl, sulfamoyl, morpholin-1-ylsulfonyl, piperidin-1-ylsulfonyl, 4 -Methylpiperidin-1-ylsulfonyl, C ₁ ~C ₆ alkylamide, benzamide or benzamide substituted by the following groups: halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₄ alkoxy, nitro, cyano, C ₁ ~C ₃ alkylsulfonyl or C ₁ ~C ₃ alkylaminosulfonyl.

The acylguanidine group is preferably in the para or ortho position to the R ^group .

R ¹ more preferably represents: hydrogen or methyl;

R ² more preferably represents: nitro, trifluoromethyl, methanesulfonyl, sulfamoyl or C ₁ -C ₆ alkylamide.

According to the present invention, pharmaceutically acceptable salts include the acid addition salts formed by the compound of general formula I and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, Acetic, maleic, methanesulfonic, benzenesulfonic, p-toluenesulfonic, ferulic, or niacin.

Some compounds of the present invention are:

4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-1)

3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-2)

2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-3)

4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-4)

3-Chloro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-5)

4-Chloro-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-6)

5-Chloro-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-7)

3-Chloro-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-8)

3-Bromo-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-9)

4-Bromo-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-10)

5-Bromo-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-11)

3-Bromo-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-12)

3-Methoxy-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-13)

4-Methoxy-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-14)

3-Methoxy-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-15)

3-Ethoxy-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-16)

3-nitro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-17)

4-nitro-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-18)

5-nitro-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-19)

3-Nitro-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-20)

3-Nitro-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-21)

3-cyano-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-22)

3-Methanesulfonyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-23)

5-Methanesulfonyl-2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-24)

3-Methanesulfonyl-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-25)

3-sulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-26)

3-Methanesulfonyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-27)

3-Ethsulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-28)

3-Alanylsulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-29)

3-(piperidine-1-sulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -30)

4-(piperidine-1-sulfonyl)-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -31)

3-(4-Methylpiperazin-1-sulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine salt Salt (I-32)

3-(morpholine-1-sulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -33)

3-(Morpholine-1-sulfonyl)-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-34)

3-(pyrrole-1-sulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I- 35)

4-(pyrrole-1-sulfonyl)-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I- 36)

3-(Dimethylaminosulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I- 37)

3-(Diethylaminosulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I- 38)

3-(Dipropylaminosulfonyl)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-39 )

3-Acetamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-40)

4-Acetamido-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-41)

3-Benzamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-42)

3-(4-chlorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -43)

3-(4-bromobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -44)

3-(2-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -45)

3-(4-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -46)

3-(4-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-47)

3-(4-nitrobenzamido)-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride Salt (I-48)

3-(4-cyanobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-49)

3-(4-methoxybenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-50)

3-(4-methylbenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-51)

3-(3-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-52)

3-(2-Chlorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -53)

3-(2-Bromobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -54)

3-(2-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I -55)

3-(2-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-56)

3-(2-methoxybenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-57)

3-(2-methylbenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride ( I-58)

3-(2-Methyl-3-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoyl Guanidine Hydrochloride (I-59)

3-(3,4-Dichlorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride Salt (I-60)

3-(2,4-Dichlorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride Salt (I-61)

3-(3-Chloro-4-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine salt Salt (I-62)

3-(2,4-Difluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride Salt (I-63)

3-(2,3-Dimethoxybenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine Hydrochloride (I-64)

3-(3,4-dimethoxybenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine Hydrochloride (I-65)

3-(3,4,5-trimethoxybenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoyl Guanidine Hydrochloride (I-66)

The preparation method of general formula (I) compound of the present invention is as follows:

When R ² represents: hydrogen, chlorine, bromine, fluorine, C ₁ ~C ₆ alkoxy, allyloxy, nitro, trifluoromethyl, cyano, C ₁ ~C ₆ alkylsulfonyl, sulfamoyl Acyl, C ₁ to C ₆ alkylaminosulfonyl, allylaminosulfonyl, morpholin-1-ylsulfonyl, piperidin-1-ylsulfonyl, 4-methylpiperidin-1-ylsulfonyl , Pyrrol-1-ylsulfonyl, the synthetic route is as follows:

When R ² represents: C ₁ ~ C ₆ alkyl amido, benzamide or benzamide substituted by the following groups: halogen, C ₁ ~ C ₆ alkyl, hydroxyl, C ₁ ~ C ₆ alkoxy When the group, nitro group, cyano group, C ₁ ~C ₆ alkylsulfonyl group, C ₁ ~C ₆ alkylaminosulfonyl group, the synthetic route is as follows:

where a, b, c, d, e, f and g represent the reaction conditions:

a: The reactants are N-bromosuccinimide and N-chlorosuccinimide; the initiators are benzoyl peroxide and azobisisobutyronitrile.

b: The reactant is trimetazidine; the acid removal agent is potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium methylate, sodium ethylate, or two or more of them A mixture of two or more.

c: (1) The reactant is free guanidine.

(2) The reactant is methanol solution of hydrogen chloride, ethanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, aqueous solution of hydrogen chloride.

d: (1) The reactant is hydrogen; the catalyst is 5% to 10% Pd/C, Raney nickel, and platinum oxide.

Or: (2) The reactant is iron powder, zinc powder; the catalyst is hydrochloric acid, ammonium chloride aqueous solution, or a mixture of the two.

e: The reactants are C ₁ -C ₄ alkyl acid chlorides, C ₁ -C ₄ alkyl acid anhydrides, substituted benzoyl chlorides, and substituted benzoic anhydrides.

f: The catalyst is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate; the solvent is a mixed solvent of methanol and water, or a mixed solvent of ethanol and water.

g: The reactant is guanidine; the condensing agent is dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); catalyst It is 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBT).

Compounds II and V were obtained from commercial sources or prepared according to literature methods.

The pharmacological tests and results of the NHE1 inhibitory activity of some compounds of the present invention are as follows:

In order to determine the effect of the compounds of the present invention on NHE1 activity, platelet swelling assay (Platelet Swelling Assay, PSA) was carried out. When platelet-rich plasma (PRP) from rats was added to sodium propionate medium, cellular NHE was activated, H ⁺ was transported outside the cells, and intracellular Na ⁺ increased. This process causes a change in the osmotic pressure of the cells. In order to restore the normal osmotic pressure in the cells, extracellular fluid enters the cells, causing the cells to swell. This swelling of platelets causes a decrease in optical density (OD).

Using cariporide as a positive control, the NHE1 inhibitory activity of the target compound was evaluated by PSA. Concentration-inhibition rate curves were drawn to determine the drug concentration (IC ₅₀ ) that inhibited 50% of cell swelling.

The experiment refers to the method of Rosskopf et al. (Hypertens.1991, 9(3): 231-237):

Take 5 mL of fundus blood from rats and add it to a plastic test tube containing 0.25 mL of ACD solution. Centrifuge at 150 g for 15 min at room temperature (25° C.), and take the upper 2/3 of the plasma, that is, platelet-rich plasma (Platelet-rich plasma, PRP) for platelet swelling assay (Platelet Swelling Assay, PSA). The prepared platelets must be used within 4 hours. The test drugs were dissolved in DMSO, added to standard media for dilution, and the final DMSO content was less than 10 ^-4 mol/L. Six groups of concentrations were tested for each drug, and each group was determined three times. Optical density (OD) was measured by a multi-scan spectrophotometer. Add 175 μL sodium propionate medium and 25 μL test sample or standard medium to a 96-well plate (1 cm path length), preheat to 37°C, then add 50 μL PRP. Measure the change of OD value at 550nm, and record a point every 7.5s for a total of 2 minutes.

Calculation method;

The change of OD value conforms to a single exponential curve, and the equation is OD _(t) =OD _(t=0) e ^-kt . Among them, t represents the time, and the unit is s; k is the OD decrease rate constant, that is, the swelling rate constant. The k _max value of the untreated control group was the maximum swelling rate constant. The k _min value obtained by 10 ^-5 mol/L cariporide was used as the baseline control to characterize the change of OD value caused by non-NHE activation, and the activity of NHE1 was considered to be completely inhibited at this concentration.

Take the natural logarithm of the measured OD value, make a scatter diagram with lnOD as the Y axis and time as the X axis, and take the first 42s for linear regression, and the absolute value of the obtained slope is k. The percent rate constant (k%) of k' after subtracting k _min is compared with k _max '. Take the k% value of the test drug at different concentrations as the Y axis, and the corresponding concentration as the X axis to perform nonlinear regression analysis (Graphpad Prism software) to fit the S curve, and calculate the IC ₅₀ of the curve, which is 50% reduction The concentration of platelet swelling.

Calculation formula: k%=(kk _min )/(k _max -k _min )×100%.

The result is as follows:

Table 1. IC ₅₀ values of some compounds of the present invention inhibiting NHE1

compound IC₅₀(×10^-8M) Caliber 6.50 trimetazidine 620

I-1 3.64 I-2 3.65 I-3 1.11 I-4 4.05 I-9 24.8 I-17 0.36 I-18 1.42 I-21 1.87 I-23 1.50 I-25 0.248 I-26 1.15 I-29 115

The structures of the compounds represented by the codes in the above table are shown in the examples or "partial compounds of the present invention".

The results of pharmacological tests show that the compounds of the present invention have different degrees of inhibitory effects on rat NHE1, therefore, the compounds of the present invention can be used to prevent or treat clinical conditions related to myocardial ischemia-reperfusion injury. These conditions include arrhythmia, ventricular fibrosis, myocardial infarction, angina pectoris, heart failure, congestive heart failure, myocardial ischemia, peripheral and central nervous system ischemic symptoms, stroke ischemic symptoms, peripheral tissue organs and limb ischemia, Acute and chronic injury, disorder or indirect sequelae of tissues and organs caused by shock, ischemia or reperfusion. The compounds of the present invention can also be used in surgery and organ transplantation and preservation of transplanted organs.

The present invention also provides a pharmaceutical composition for treating myocardial ischemia-reperfusion injury, which contains a therapeutically effective amount of the compound of general formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of common pharmaceutical preparations such as ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, oral liquids, and injections.

Generally, when the benzoylguanidine derivatives of the present invention are used for treatment, the human dose ranges from 2 mg to 2000 mg/day. Depending on the dosage form and the severity of the disease, the dosage may exceed this range.

Detailed ways

Examples of the preparation of some active compounds are as follows:

RY-1 melting point tube; Nicolet Impact 410 infrared spectrometer, KBr pellet; ¹ H-NMR BRUKERAM-500 nuclear magnetic resonance instrument, internal standard TMS; HP1100 mass spectrometer; Carlo Erba 1106 element analyzer.

Example 1

Preparation of 4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-1)

Preparation of ethyl 4-bromomethylbenzoate (III-1)

Mix 1 g (0.006 mol) of ethyl 4-methylbenzoate (II-1), 1 g (0.006 mol) of NBS and a catalytic amount of benzoyl peroxide with 50 ml of anhydrous carbon tetrachloride, stir and reflux for 8 hours under light , filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the bromide III-1 (R ¹ =R ² =H, X = Br, the relative position of the halogenated (hypo)methyl group and the ester group: para position) and directly put it into the next reaction .

Preparation of ethyl 4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-1)

Mix 2g (5.9mmol) of trimetazidine hydrochloride with 40ml of anhydrous acetonitrile, add 4ml of triethylamine, the pH of the reaction solution is 9, stir at room temperature, after the solid is completely dissolved, add bromide III-1 dropwise and dissolve in 20ml of anhydrous The solution obtained from water and acetonitrile was added to the solution, heated to reflux for 5 hours, filtered, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent: petroleum ether/acetone=7:1) to obtain a light yellow oil. Dissolve the oil in acetone and pass through dry HCl to obtain white solid IV-1 (R ¹ =R ² =H, relative position of trimetazidine-coupled (hypo)methyl group and ester group: para position) 2.3g (77.8% yield), mp 244-246°C.

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.21(2H，s，CH₂)，4.32～4.37(4H，m，COOCH₂-，CH₂)，6.87(1H，d，ArH，J＝8.7Hz)，734(1H，d，ArH，J＝8.4Hz)，7.76(2H，d，ArH，J＝8,0Hz)，7.98～8.00(2H，d，ArH，J＝8.0Hz)，11.70(1H，bs，N⁺H) ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.32 (3H, t, CH ₃ , J=7.1Hz), 3.10～3.65 (8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.21 (2H, s, CH ₂ ), 4.32～4.37 (4H, m, COOCH ₂ -, CH ₂ ), 6.87 (1H, d, ArH, J=8.7Hz), 734 (1H, d, ArH, J=8.4Hz), 7.76 (2H, d, ArH, J=8,0Hz) , 7.98～8.00 (2H, d, ArH, J=8.0Hz), 11.70 (1H, bs, N ⁺ H)

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.23(2H，s，CH₂)，4.41(2H，s，CH₂)，6.87(1H，d，ArH，J＝8.7Hz)，7.35(1H，d，ArH，J＝8.6Hz)，7.84(2H，d，ArH，J＝g.0Hz)，8.27(2H，d，ArH，J＝8.2Hz)，8.69(3H，bs，NH)，8.92(3H，bs，NH)，12.38(2H，bs，NH)；MS(ESI(+)70V)m/z 442[M+H]⁺；Anal.Calcd.for C₂₃H₃₅ClaN₅O₄：C 47.03，H 6.01，N 11.92；Found：C 47.05，H 6.02，N 11.95。Put IV-10.5g (1mmol) and free guanidine 0.5g (8.5mmol) into 20ml of anhydrous tetrahydrofuran, reflux for 5h, evaporate the solvent under reduced pressure, and carry out silica gel column chromatography (eluent: petroleum ether: acetone =3:1), to obtain 0.2 g of a pale yellow oil, which was dissolved in acetone, passed through dry HCl, filtered, and dried to obtain a white solid I-10.24 g (46.7%), mp 210-212°C. IR (cm ^-1 ): 3362, 3143, 2990, 2975, 1703, 1614, 1603, 1576, 1499, 1457, 1270, 1107 (OCH ₃ ), 812, 754; ¹ HNMR (300MHz, DMSO-d ₆ ), δ(ppm): 3.30～3.68(8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.23 (2H, s, CH ₂ ), 4.41 (2H, s, CH ₂ ), 6.87 (1H, d, ArH, J=8.7Hz), 7.35 (1H, d, ArH, J=8.6Hz), 7.84 (2H, d, ArH, J=g.0Hz), 8.27 (2H, d , ArH, J=8.2Hz), 8.69 (3H, bs, NH), 8.92 (3H, bs, NH), 12.38 (2H, bs, NH); MS (ESI (+) 70V) m/z 442 [M +H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₅ ClaN ₅ O ₄ : C 47.03, H 6.01, N 11.92; Found: C 47.05, H 6.02, N 11.95.

Example 2

Preparation of 3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-2)

Preparation of ethyl 3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-2)

)，3.75(3H，s，OCH₃)，3.77(3H，s，OCH₃)，3.81(3H，s，OCH₃)，4.20(2H，s，CH₂)，4.33(2H，q，COOCH₂-，J＝7.1Hz)，4.40(2H，s，CH₂)，6.86(1H，d，ArH，J＝8.7Hz)，7.37(1H，d，ArH，J＝8.7Hz)，7.58～7.61(1H，m，ArH)，7.99～8.01(2H，m，ArH)，8.21(1H，s，ArH)，12.25(2H，bs，N⁺H)Using ethyl 3-methylbenzoate (II-2) as raw material, the operation was the same as III-1 and IV-1 to obtain white solid IV-2. Yield 47.8%, mp 224-226°C. ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.33 (3H, t, CH ₃ , J=7.1Hz), 3.30～3.65 (8H, m,

), 3.75 (3H, s, OCH ₃ ), 3.77 (3H, s, OCH ₃ ), 3.81 (3H, s, OCH ₃ ), 4.20 (2H, s, CH ₂ ), 4.33 (2H, q, COOCH ₂ -, J=7.1Hz), 4.40(2H, s, CH ₂ ), 6.86(1H, d, ArH, J=8.7Hz), 7.37(1H, d, ArH, J=8.7Hz), 7.58～7.61( 1H, m, ArH), 7.99～8.01 (2H, m, ArH), 8.21 (1H, s, ArH), 12.25 (2H, bs, N ⁺ H)

)，3.75(3H，s，OCH₃)，3.77(3H，s，OCH₃)，3.81(3H，s，OCH₃)，4.21(2H，s，CH₂)，4.40(2H，s，CH₂)，6.79(1H，d，ArH，J＝8.6Hz)，6.98(1H，d，ArH，J＝8.6Hz)，7.40～7.42(1H，m，ArH)，7.48～7.49(2H，m，ArH)，7.80(3H，bs，NH)，8.04(1H，s，ArH)，8.84(3H，bs，NH)；MS(ESI(+)70V)m/z 442[M+H]⁺；Anal.Calcd.for C₂₃H₃₅Cl₄N₅O₄：C47.03，H 6.01，N 11.92；Found：C 47.13，H 6.12，N 11.85。Put IV-21g (0.002mol) and free guanidine 1g (0.016mol) into 40ml of absolute isopropanol, heat up to reflux for 3h. The solvent was evaporated under reduced pressure, and the residue was subjected to large-plate chromatography (developing solvent: petroleum ether: acetone = 1:1) to obtain 0.4 g of a light yellow oil, which was dissolved in dry acetone and passed through dry HCl to obtain a white powder solid I -2 (44.0%), mp 80-83°C. IR (cm ^-1 ): 3365, 2931, 2837, 1706 (C=O), 1602, 1568, 1496, 1463, 1421, 1280, 1201, 1099 (OCH ₃ ), 808, 744; ¹ HNMR (300MHz, DMSO -d ₆ ), δ(ppm): 3.164～3.46(8H, m,

), 3.75 (3H, s, OCH ₃ ), 3.77 (3H, s, OCH ₃ ), 3.81 (3H, s, OCH ₃ ), 4.21 (2H, s, CH ₂ ), 4.40 (2H, s, CH ₂ ), 6.79 (1H, d, ArH, J=8.6Hz), 6.98 (1H, d, ArH, J=8.6Hz), 7.40~7.42 (1H, m, ArH), 7.48~7.49 (2H, m, ArH ), 7.80 (3H, bs, NH), 8.04 (1H, s, ArH), 8.84 (3H, bs, NH); MS (ESI (+) 70V) m/z 442[M+H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₅ Cl ₄ N ₅ O ₄ : C 47.03, H 6.01, N 11.92; Found: C 47.13, H 6.12, N 11.85.

Example 3

Preparation of 2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-3)

Preparation of ethyl 2-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-3)

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.25(2H，s，CH₂)，4.33(2H，q，COOCH₂-，J＝7.1Hz)，4.65(2H，s，CH₂)，6.89(1H，d，J＝8.7Hz，ArH)，7.33(1H，d，J＝8.7Hz，ArH)，7.61～7.79(3H，m，ArH)，8.01(1H，d，ArH，J＝8.1Hz)，11.30(2H，bs，N⁺H)。Using ethyl 2-methylbenzoate (II-3) as the raw material, the procedure was the same as III-1 and IV-1 to obtain white solid IV-3 with a yield of 56.0%, mp 208-210°C. ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.36 (3H, t, CH ₃ , J=7.1Hz), 3.20～3.71 (8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.25 (2H, s, CH ₂ ), 4.33 (2H, q, COOCH ₂ -, J=7.1Hz), 4.65(2H, s, CH ₂ ), 6.89(1H, d, J=8.7Hz, ArH), 7.33(1H, d, J=8.7Hz, ArH), 7.61～7.79( 3H, m, ArH), 8.01 (1H, d, ArH, J = 8.1 Hz), 11.30 (2H, bs, N ⁺ H).

)，3.74(3H，s，OCH₃)，3.80(3H，s，OCH₃)，3.85(3H，s，OCH₃)，4.18(2H，s，CH₂)，4.57(2H，s，CH₂)，6.86(1H，d，ArH，J＝8.7Hz)，6.95～7.05(2H，m，ArH)，7.31(1H，d，ArH，J＝8.6Hz)，7.58(3H，bs，NH)，7.71～7.78(1H，m，ArH)，7.95～8.05(1H，m，ArH)，8.59(3H，bs，NH)，12.11(2H，bs，NH)；MS(ESI(+)70V)m/z 442[M+H]⁺；Anal.Calcd.for C₂₃H₃₅Cl₄N₅O₄：C 47.03，H 6.01，N 11.92；Found：C 46.85，H 6.00，N 11.65。Using IV-3 as raw material, the operation was the same as that of I-2 to obtain white solid I-3 with a yield of 30.5%, mp 214-215°C. IR (cm ^-1 ): 3367, 3157, 2925, 2854, 1712 (C=O), 1658, 1600, 1500, 1460, 1436, 1274, 1099 (OCH ₃ ), 802, 757; ¹ HNMR (500MHz, DMSO -d ₆ ), δ(ppm): 3.25～3.71(8H, m,

), 3.74 (3H, s, OCH ₃ ), 3.80 (3H, s, OCH ₃ ), 3.85 (3H, s, OCH ₃ ), 4.18 (2H, s, CH ₂ ), 4.57 (2H, s, CH ₂ ), 6.86 (1H, d, ArH, J=8.7Hz), 6.95～7.05 (2H, m, ArH), 7.31 (1H, d, ArH, J=8.6Hz), 7.58 (3H, bs, NH), 7.71～7.78(1H, m, ArH), 7.95～8.05(1H, m, ArH), 8.59(3H, bs, NH), 12.11(2H, bs, NH); MS(ESI(+)70V)m/ z 442 [M+H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₅ Cl ₄ N ₅ O ₄ : C 47.03, H 6.01, N 11.92; Found: C 46.85, H 6.00, N 11.65.

Example 4

Preparation of 4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-4)

Preparation of methyl 4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoate hydrochloride (IV-4)

)，3.83(3H，s，OCH₃)，3.87(3H，s，OCH₃)，3.98(3H，s，OCH₃)，4.11～4.35(3H，m，CH₂，CH)，4.40(2H，q，COOCH₂-，J＝7.1Hz)，6.73(1H，d，ArH，J＝8.6Hz)，7.41(1H，d，ArH，J＝8.6Hz)，7.80(2H，d，ArH，J＝8.2Hz)，8.13(2H，d，ArH，J＝8.1Hz)，1306(1H，bs，N⁺H)，13.75(1H，bs，N⁺H)。Using ethyl 4-ethylbenzoate (II-4) as the raw material, the procedure was the same as III-1 and IV-1 to obtain white solid IV-4 with a yield of 66.0%, mp 170-172°C. ¹ HNMR (500MHz, CDCl ₃ ), δ (ppm): 1.40 (3H, t, CH ₃ , J=7.1Hz), 1.90 (3H, d, CH ₃ , J=7.5Hz), 3.10～3.56 (8H, m,

), 3.83 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 3.98 (3H, s, OCH ₃ ), 4.11～4.35 (3H, m, CH ₂ , CH), 4.40 (2H, q, COOCH ₂ -, J=7.1Hz), 6.73 (1H, d, ArH, J=8.6Hz), 7.41 (1H, d, ArH, J=8.6Hz), 7.80 (2H, d, ArH, J= 8.2 Hz), 8.13 (2H, d, ArH, J=8.1 Hz), 1306 (1H, bs, N ⁺ H), 13.75 (1H, bs, N ⁺ H).

)，3.30～3.45(3H，m，CH₂，CH)，3.71(3H，s，OCH₃)，3.74(3H，s，OCH₃)，3.75(3H，s，OCH₃)，6.72(1H，d，ArH，J＝8.6Hz)，6.92(1H，d，ArH，J＝8.6Hz)，7.27(2H，d，ArH，J＝8.2Hz)，7.68(3H，bs，NH)，7.99(2H，d，ArH，J＝8.2Hz)；MS(ESI(+)70V)m/z 456[M+H]⁺，478[M+Na]⁺；Anal.Calcd.for C₂₄H₃₇Cl₄N₅O₄：C 47.93，H 6.20，N11.65；Found：C 47.71，H 6.16，N 11.59。Using IV-4 as the raw material, the operation is the same as that of I-2 to obtain a white powder solid with a yield of 52.8% and mp 235-238°C. IR (cm ^-1 ): 3396, 2937, 2818, 1601, 1529, 1494, 1346, 1096, 791, 755; ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.26 (3H, d, CH ₃ , J＝6.7Hz), 2.25～2.49(8H, m,

), 3.30～3.45 (3H, m, CH ₂ , CH), 3.71 (3H, s, OCH ₃ ), 3.74 (3H, s, OCH ₃ ), 3.75 (3H, s, OCH ₃ ), 6.72 (1H, d, ArH, J=8.6Hz), 6.92 (1H, d, ArH, J=8.6Hz), 7.27 (2H, d, ArH, J=8.2Hz), 7.68 (3H, bs, NH), 7.99 (2H , d, ArH, J=8.2Hz); MS (ESI(+)70V) m/z 456[M+H] ⁺ , 478[M+Na] ⁺ ; Anal.Calcd.for C ₂₄ H ₃₇ Cl ₄ N ₅ O ₄ : C 47.93, H 6.20, N 11.65; Found: C 47.71, H 6.16, N 11.59.

Example 5

Preparation of 3-bromo-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-9)

Preparation of ethyl 3-bromo-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-9)

)，3.38(2H，s，CH₂)，3.56(2H，s，CH₂)，3.74(3H，s，OCH₃)，3.77(6H，s，OCH₃)，4.33(2H，q，COOCH₂-，J＝7.1Hz)，6.74(1H，d，ArH，J＝8.6Hz)，6.95(1H，d，ArH，J＝8.5Hz)，7.61(1H，d，ArH，J＝8.0Hz)，7.92(1H，dd，ArH，J₁＝8.0Hz，J₂＝1.5Hz)，8.07(1H，d，ArH，J＝1.6Hz)，12.75(2H，bs，N⁺H)。Using ethyl 3-bromo-4-methylbenzoate (II-9) as the raw material, the procedure was the same as III-1 and IV-1 to obtain white solid IV-9 with a yield of 70.1%, mp 189-192°C. ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.32 (3H, t, CH ₃ , J=7.1Hz), 2.38～2.51 (8H, m,

), 3.38 (2H, s, CH ₂ ), 3.56 (2H, s, CH ₂ ), 3.74 (3H, s, OCH ₃ ), 3.77 (6H, s, OCH ₃ ), 4.33 (2H, q, COOCH ₂ -, J = 7.1Hz), 6.74 (1H, d, ArH, J = 8.6Hz), 6.95 (1H, d, ArH, J = 8.5Hz), 7.61 (1H, d, ArH, J = 8.0Hz), 7.92 (1H, dd, ArH, _J1 = 8.0 Hz, _J2 = 1.5 Hz), 8.07 (1H, d, ArH, J = 1.6 Hz), 12.75 (2H, bs, N ⁺ H).

)，3.79(3H，s，OCH₃)，3.84(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.04(2H，s，CH₂)，4.24(2H，s，CH₂)，6.90(1H，d，ArH，J＝8.7Hz)，7.36(1H，d，ArH，J＝8.7Hz)，7.88(1H，d，ArH，J＝8.1Hz)，8.26(1H，dd，ArH，J＝8.1Hz J＝1.7Hz)，8.46(1H，d，ArH，J＝1.4Hz)，8.74(3H，bs，NH)，12.41(2H，bs，NH)；MS(ESI(+)70V)m/z520[M+H]⁺；Anal.Calcd.for C₂₃H₃₄BrCl₄N₅O₄：C 41.46，H 5.14，N 10.51；Found：C 41.95，H 5.56，N10.39。Using IV-9 as the raw material, the operation is the same as that of I-1, and the white solid I-9 is obtained by drying, the yield is 72.4%, and the mp is 244-246°C. IR (cm ^-1 ): 3351, 3112, 2988, 1704 (C=O), 1605, 1574, 1445, 1421, 1300, 1253, 1089 (OCH ₃ ), 751; ¹ HNMR (500MHz, DMSO-d ₆ ) , δ (ppm): 2.95 ~ 3.61 (8H, m,

), 3.79 (3H, s, OCH ₃ ), 3.84 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.04 (2H, s, CH ₂ ), 4.24 (2H, s, CH ₂ ), 6.90 (1H, d, ArH, J=8.7Hz), 7.36 (1H, d, ArH, J=8.7Hz), 7.88 (1H, d, ArH, J=8.1Hz), 8.26 (1H, dd, ArH, J=8.1Hz J=1.7Hz), 8.46 (1H, d, ArH, J=1.4Hz), 8.74 (3H, bs, NH), 12.41 (2H, bs, NH); MS (ESI(+) 70V) m/z 520[M+H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₄ BrCl ₄ N ₅ O ₄ : C 41.46, H 5.14, N 10.51; Found: C 41.95, H 5.56, N 10.39.

Example 6

Preparation of 3-nitro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-17)

Preparation of ethyl 3-nitro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (IV-17)

Put 0.7g (0.003mol) of ethyl 3-nitro-4-methylbenzoate (II-17), 0.7g (0.003mol) of NBS and catalytic amount of benzoyl peroxide into 20ml of anhydrous carbon tetrachloride , under light, reflux for 3 days, filter, and evaporate the solvent to dryness under reduced pressure to obtain bromide III-17, which is directly put into the next step reaction.

)，3.46(2H，s，CH₂)，3.80(2H，s，CH₂)，3.84(3H，s，OCH₃)，3.86(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.41(2H，q，COOCH₂-，J＝7.2Hz)，6.62(1H，d，ArH，J＝8.6Hz)，6.97(1H，d，ArH，J＝8.1Hz)，7.71(1H，d，ArH，J＝8.0Hz)，8.17(1H，dd，ArH，J₁＝8.0Hz，J₂＝1.6Hz)，8.44(1H，d，ArH，J＝1.5Hz)。Put 1 g (0.003 mol) of trimetazidine hydrochloride into 40 ml of anhydrous acetonitrile, add 4 ml of triethylamine, the pH of the reaction solution is 9, stir at room temperature until the solid is completely dissolved, add bromide III-17 (obtained in the previous step) dropwise Dissolve the solution obtained by dissolving in 10ml of anhydrous acetonitrile, after dripping, raise the temperature to 50°C for 3h, filter, evaporate the filtrate to remove the solvent, and recrystallize the residue with petroleum ether/acetone (7:1) to obtain light yellow crystal IV-171.4g (85.0%), mp83-85°C. ¹ HNMR (500MHz, CDCl ₃ ), δ (ppm): 1.41 (3H, t, CH ₃ , J=7.2Hz), 2.35～2.75 (8H, m,

), 3.46 (2H, s, CH ₂ ), 3.80 (2H, s, CH ₂ ), 3.84 (3H, s, OCH ₃ ), 3.86 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.41 (2H, q, COOCH ₂ -, J=7.2Hz), 6.62 (1H, d, ArH, J=8.6Hz), 6.97 (1H, d, ArH, J=8.1Hz), 7.71 (1H, d, ArH, J=8.0 Hz), 8.17 (1H, dd, ArH, J ₁ =8.0 Hz, J ₂ =1.6 Hz), 8.44 (1H, d, ArH, J=1.5 Hz).

)，3.77(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，3.94(2H，s，CH₂)，4.20(2H，s，CH₂)，6.88(1H，d，ArH，J＝8.7Hz)，7.26(1H，d，ArH，J＝8.6Hz)，7.93(1H，d，ArH，J＝8.1Hz)，8.47(1H，dd，ArH，J＝8.0Hz，J＝1.7Hz)，8.64(1H，d，ArH，J＝1.7Hz)，8.50(3H，bs，NH)，8.70(3H，bs，NH)，9.94(1H，bs，NH)，12.36(1H，bs，NH)；MS(ESI(+)70V)m/z 487[M+H]⁺；Anal.Calcd.for C₂₃H₃₄Cl₄N₆O₆.H₂O：C 42.47，H 5.58，N12.92；Found：C 42.45，H 6.07，N 12.84。Using IV-17 as the raw material, the operation is the same as that of I-1 to obtain a light yellow solid with a yield of 79.0% and mp 230-233°C. IR (cm ^-1 ): 3401, 3127, 2956, 1703 (C=O), 1620, 1612, 1543, 1499, 1460, 1451, 1345, (NO ₂ ), 1160 (OCH ₃ ), 748; ¹ HNMR ( 500MHz, CDCl ₃ ), δ(ppm): 2.53～3.29(8H, m,

), 3.77 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 3.94 (2H, s, CH ₂ ), 4.20 (2H, s, CH ₂ ), 6.88 (1H, d, ArH, J=8.7Hz), 7.26 (1H, d, ArH, J=8.6Hz), 7.93 (1H, d, ArH, J=8.1Hz), 8.47 (1H, dd, ArH, J=8.0Hz, J=1.7Hz), 8.64(1H, d, ArH, J=1.7Hz), 8.50(3H, bs, NH), 8.70(3H, bs, NH), 9.94(1H, bs , NH), 12.36 (1H, bs, NH); MS (ESI(+)70V) m/z 487[M+H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₄ Cl ₄ N ₆ O ₆ .H ₂ O: C 42.47, H 5.58, N 12.92; Found: C 42.45, H 6.07, N 12.84.

Example 7

Preparation of 4-nitro-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-18)

Preparation of ethyl 4-nitro-3-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-18)

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.22(2H，s，CH₂)，4.26(2H，s，CH₂)，4.37(2H，q，COOCH₂-，J＝7.1Hz)，6.88(1H，d，ArH，J＝8.8Hz)，7.34(1H，d，ArH，J＝8.7Hz)，8.13(1H，d，ArH，J＝8.6Hz)，8.23(1H，dd，ArH，J＝8.5Hz，J＝2.3Hz)，8.32(1H，d，ArH，J＝2.2Hz)，9.75(1H，bs，N⁺H)，11.80(1H，bs，N⁺H)。Using 3-methyl-4-nitrobenzoic acid ethyl ester (II-18) as the raw material, the operation is the same as III-17 and IV-17 to obtain the free base, and dry HCl in acetone to form a salt to obtain light yellow crystal IV- 18. Yield 75.6%, mp 205-207°C. ¹ HNMR (300MHz, DMSO-d ₆ ), δ (ppm): 1.35 (3H, t, CH ₃ , J=7.1Hz), 3.09～3.65 (8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.22 (2H, s, CH ₂ ), 4.26 (2H, s, CH ₂ ), 4.37 (2H, q, COOCH ₂ -, J=7.1Hz), 6.88 (1H, d, ArH, J=8.8Hz), 7.34 (1H, d, ArH, J=8.7Hz), 8.13 (1H, d, ArH, J=8.6Hz), 8.23 (1H, dd, ArH, J=8.5Hz, J=2.3Hz), 8.32 (1H, d, ArH, J=2.2Hz), 9.75 (1H, bs, N ⁺ H), 11.80 (1H, bs, N ⁺ H).

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.09(2H，s，CH₂)，4.21(2H，s，CH₂)，6.88(1H，d，ArH，J＝8.7Hz)，7.34(1H，d，ArH，J＝8.7Hz)，8.17(1H，d，ArH，J＝8.6Hz)，8.30(1H，dd，ArH，J＝8.5Hz，J＝1.7Hz)，8.49(1H，s，ArH)，8.80(5H，bs，NH)，10.75(1H，bs，NH)，12.67(1H，bs，NH)；MS(ESI(+)70V)m/z487[M+H]⁺；Anal.Calcd.for C₂₃H₃₃Cl₃N₆O₆.H₂O：C 45.00，H 5.75，N 13.69；Found：C 44.71，H5.74，N 13.35。Using IV-18 as raw material, the operation was the same as that of I-1 to obtain white solid I-18 with a yield of 60.0%, mp 220-224°C. IR (cm ^-1 ): 3377, 3137, 2994, 2840, 1710 (C=O), 1602, 1568, 1531, 1452, 1350 (NO ₂ ), 1274, 1101 (OCH ₃ ), 854, 760; ¹ HNMR (300MHz, DMSO-d ₆ ), δ(ppm): 2.75～3.41(8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.09 (2H, s, CH ₂ ), 4.21 (2H, s, CH ₂ ), 6.88 (1H, d, ArH, J=8.7Hz), 7.34 (1H, d, ArH, J=8.7Hz), 8.17 (1H, d, ArH, J=8.6Hz), 8.30 (1H, dd, ArH, J=8.5Hz, J=1.7Hz), 8.49 (1H, s, ArH), 8.80 (5H, bs, NH), 10.75 (1H, bs, NH), 12.67 (1H, bs, NH); MS (ESI(+)70V)m/z487[M+H] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₃ Cl ₃ N ₆ O ₆ .H ₂ O: C 45.00, H 5.75, N 13.69; Found: C 44.71 , H5.74, N 13.35.

Example 8

Preparation of 3-nitro-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine (I-21)

Preparation of 3-nitro-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)methyl benzoate hydrochloride (IV-21)

)，3.85(3H，s，OCH₃)，3.87(3H，s，OCH₃)，3.99(3H，s，OCH₃)，4.29～4.33(3H，m，CH₂，CH)，4.44(2H，q，COOCH₂-，J＝7.1Hz)，6.72(1H，d，ArH，J＝8.5Hz)，7.40(1H，d，ArH，J＝8.6Hz)，8.44(1H，d，ArH，J＝8.0Hz)，8.53(1H，dd，ArH，J₁＝8.0Hz，J₂＝1.5Hz)，8.89(1H，d，ArH，J＝1.5Hz)，12.80(2H，bs，N⁺H)。Using ethyl 3-nitro4-ethylbenzoate (II-21) as raw material, the operation is the same as III-17 and IV-17. After the reaction is completed, filter, evaporate the solvent, dissolve in ethyl acetate, and pass into In the dried HCl, a white solid precipitated, filtered, washed with ethyl acetate, and dried to obtain IV-21 as a white powder solid, yield 74.5%, mp 185-186°C. ¹ HNMR (500MHz, CDCl ₃ ), δ(ppm): 1.43 (3H, t, CH ₃ , J=7.0Hz), 1.89 (3H, d, CH ₃ , J=7.4Hz), 3.50～3.95 (8H, m,

), 3.85 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 3.99 (3H, s, OCH ₃ ), 4.29～4.33 (3H, m, CH ₂ , CH), 4.44 (2H, q, COOCH ₂ -, J=7.1Hz), 6.72 (1H, d, ArH, J=8.5Hz), 7.40 (1H, d, ArH, J=8.6Hz), 8.44 (1H, d, ArH, J= 8.0 Hz), 8.53 (1H, dd, ArH, _J1 = 8.0 Hz, _J2 = 1.5 Hz), 8.89 (1H, d, ArH, J = 1.5 Hz), 12.80 (2H, bs, N ⁺ H).

)，3.16(2H，s，CH₂)，3.71(3H，s，OCH₃)，3.73(3H，s，OCH₃)，3.75(3H，s，OCH₃)，4.22(1H，q，CH，J＝7.3Hz)，6.72(1H，d，ArH，J＝8.6Hz)，6.91(1H，d，ArH，J＝8.6Hz)，7.78(1H，d，ArH，J＝8.0Hz)，7.90(4H，bs，NH)，8.21(1H，dd，ArH，J＝8.1Hz，J＝1.6Hz)，8.30(1H，d，ArH，J＝1.6Hz)；MS(ESI(+)70V)m/z 501[M+H⁺]，523[M+Na]⁺；Anal.Calcd.for C₂₄H₃₂N₆O₆：C 57.59，H 6.44，N16.79；Found：C 57.72，H 6.51，N 16.81。Put IV-2183g (0.006mol) and 3g (0.05mol) of free guanidine into 60ml of anhydrous tetrahydrofuran, raise the temperature to reflux, react for 3h, concentrate the reaction solution to 1/2 volume, dilute with 3 times the amount of water, dilute with two Extract with 15ml×3 methyl chloride, separate the organic phase, dry over anhydrous magnesium sulfate, filter, evaporate the solvent to obtain 12.2g (yield 76.1%) of yellow crystalline powder I-2, mp135～136°C. IR (cm ^-1 ): 3396, 2937, 2818, 1680, 1601, 1494, 1464, 1416, 1529, 1345 (NO ₂ ), 1096 (OCH ₃ ), 1009, 791, 755; ¹ HNMR (500MHz, DMSO- d ₆ ), δ(ppm): 1.32 (3H, d, CH ₃ , J=7.2Hz), 2.20～2.45 (8H, m,

), 3.16 (2H, s, CH ₂ ), 3.71 (3H, s, OCH ₃ ), 3.73 (3H, s, OCH ₃ ), 3.75 (3H, s, OCH ₃ ), 4.22 (1H, q, CH, J=7.3Hz), 6.72 (1H, d, ArH, J=8.6Hz), 6.91 (1H, d, ArH, J=8.6Hz), 7.78 (1H, d, ArH, J=8.0Hz), 7.90 ( 4H, bs, NH), 8.21 (1H, dd, ArH, J=8.1Hz, J=1.6Hz), 8.30 (1H, d, ArH, J=1.6Hz); MS (ESI(+)70V)m/ z 501[M+H ⁺ ], 523[M+Na] ⁺ ; Anal.Calcd.for C ₂₄ H ₃₂ N ₆ O ₆ : C 57.59, H 6.44, N 16.79; Found: C 57.72, H 6.51, N 16.81.

Example 9

Preparation of 3-methylsulfonyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine (I-23)

Preparation of methyl 3-methylsulfonyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (IV-23)

Put 0.1g (0.0004mol) of ethyl 3-methylsulfonyl-4-methylbenzoate (II-23), 0.1g (0.0005mol) of NBS and a catalytic amount of benzoyl peroxide into anhydrous carbon tetrachloride 5ml, reflux under light for 10h, filter, and recover the solvent under reduced pressure to obtain bromide, which is directly put into the next step reaction without treatment.

)，3.43(5H，s，SO₂CH₃，CH₂)，3.83(3H，s，OCH₃)，3.84(3H，s，OCH₃)，3.85(3H，s，OCH₃)，3.93(3H，s，COOCH₃)，3.95(2H，s，CH₂)，6.61(1H，d，ArH，J＝8.5Hz)，6.95(1H，d，ArH，J＝8.5Hz)，7.49(1H，d，ArH，J＝8.0Hz)，8.17(1H，dd，ArH，J₁＝8.0Hz，J₂＝2.0Hz)，8.72(1H，d，ArH，J＝2.0Hz)。Put 0.15g (0.0005mol) of trimetazidine hydrochloride into 5ml of anhydrous acetonitrile, dropwise add 1ml of triethylamine, stir until the solid dissolves, put in the bromide obtained in the previous step, heat up to reflux, react for 2h, filter, and recover the solvent , and the residue was subjected to silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 30.15 g (67.8%) of light yellow solid IV-2, mp 130-137°C. ¹ HNMR (500MHz, CDCl ₃ ), δ (ppm): 2.23～2.73 (8H, m,

), 3.43 (5H, s, SO ₂ CH ₃ , CH ₂ ), 3.83 (3H, s, OCH ₃ ), 3.84 (3H, s, OCH ₃ ), 3.85 (3H, s, OCH ₃ ), 3.93 (3H , s, COOCH ₃ ), 3.95 (2H, s, CH ₂ ), 6.61 (1H, d, ArH, J=8.5Hz), 6.95 (1H, d, ArH, J=8.5Hz), 7.49 (1H, d , ArH, J=8.0 Hz), 8.17 (1H, dd, ArH, J ₁ =8.0 Hz, J ₂ =2.0 Hz), 8.72 (1H, d, ArH, J=2.0 Hz).

)，3.48～3.50(5H，m，SO₂CH₃，CH₂)，3.78(3H，s，OCH₃)，3.81(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.92(2H，s，CH₂)，6.80(1H，d，ArH，J＝8.6Hz)，7.01(1H，d，ArH，J＝8.5Hz)，7.62(1H，d，ArH，J＝7.9Hz)，8.31(1H，dd，ArH，J₁＝7.8Hz，J₂＝1.8Hz)，8.74(1H，d，ArH，J＝1.8Hz)；MS(ESI(+)70V)m/z 520[M+H]⁺，542[M+Na]⁺，558[M+K]⁺；Anal.Calcd.for C₂₄H₃₃N₅O₆S：C 55.48，H 6.40，N 13.48；Found：C 55.54，H 6.45，N 13.45。Put 0.1g (0.0002mol) of IV-230 and 0.1g (0.002mol) of free guanidine into 5ml of anhydrous tetrahydrofuran, raise the temperature to reflux, react for 3h, distill off the solvent under reduced pressure, dilute with 10ml of water, stir to precipitate solids, filter, After vacuum drying, 0.08 g (72.5%) of white solid was obtained, mp 180-185°C. IR (cm ^-1 ): 3450, 2999, 2936, 2803, 1678 (C=O), 1607, 1524, 1497, 1370, 1303, 1146, 1095 (OCH ₃ ), 786; ¹ HNMR (500MHz, DMSO-d ₆ ), δ(ppm): 2.33～2.69(8H, m,

), 3.48～3.50 (5H, m, SO ₂ CH ₃ , CH ₂ ), 3.78 (3H, s, OCH ₃ ), 3.81 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.92 (2H, s, CH ₂ ), 6.80 (1H, d, ArH, J=8.6Hz), 7.01 (1H, d, ArH, J=8.5Hz), 7.62 (1H, d, ArH, J=7.9Hz) , 8.31 (1H, dd, ArH, _J1 = 7.8Hz, _J2 = 1.8Hz), 8.74 (1H, d, ArH, J = 1.8Hz); MS (ESI (+) 70V) m/z 520 [M +H] ⁺ , 542[M+Na] ⁺ , 558[M+K] ⁺ ; Anal.Calcd.for C ₂₄ H ₃₃ N ₅ O ₆ S: C 55.48, H 6.40, N 13.48; Found: C 55.54, H 6.45, N 13.45.

Example 10

3-Methanesulfonyl-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)benzoylguanidine hydrochloride (I-25) preparation

3-Methanesulfonyl-4-(1-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl)methyl benzoate hydrochloride (IV-25) preparation

)，3.29(2H，s，CH₂)，3.36(3H，s，SO₂CH₃)，3.72(3H，s，OCH₃)，3.75(3H，s，OCH₃)，3.76(3H，s，OCH₃)，3.89(3H，s，COOCH₃)，4.35(1H，q，CH，J＝6.4Hz)，6.74(1H，d，ArH，J＝8.6Hz)，6.94(1H，d，ArH，J＝8.6Hz)，7.99(1H，d，ArH，J＝8.2Hz)，8.24(1H，dd，ArH，J₁＝8.2Hz，J₂＝1.9Hz)，8.45(1H，d，ArH，J＝1.8Hz)，11.50(2H，bs，N⁺H)。Using ethyl 3-methylsulfonyl-4-ethylbenzoate (II-25) as raw material, the operation was the same as III-23 and IV-23 to obtain white solid IV-25, yield 77.0%, mp110～111℃. ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.27 (3H, d, CH ₃ , J=6.4Hz), 2.30～2.78 (8H, m,

), 3.29 (2H, s, CH ₂ ), 3.36 (3H, s, SO ₂ CH ₃ ), 3.72 (3H, s, OCH ₃ ), 3.75 (3H, s, OCH ₃ ), 3.76 (3H, s, OCH ₃ ), 3.89 (3H, s, COOCH ₃ ), 4.35 (1H, q, CH, J=6.4Hz), 6.74 (1H, d, ArH, J=8.6Hz), 6.94 (1H, d, ArH, J = 8.6Hz), 7.99 (1H, d, ArH, J = 8.2Hz), 8.24 (1H, dd, ArH, _J1 = 8.2Hz, _J2 = 1.9Hz), 8.45 (1H, d, ArH, J = 1.8 Hz), 11.50 (2H, bs, N ⁺ H).

)，3.49(3H，s，CH₃)，3.75(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.86(3H，s，OCH₃)，4.20～4.40(3H，m，CH₂，CH)，6.87(1H，d，ArH，J＝8.6Hz)，7.33(1H，d，ArH，J＝8.6Hz)，8.30(2H，bs，NH)，8.64～8.67(2H，m，ArH)，8.81(1H，s，ArH)，8.85(3H，bs，NH)，11.45(1H，bs，NH)，12.73(1H，bs，NH)；MS(ESI(+)70V)m/z 534[M+H]⁺；Anal.Calcd.for C₂₅H₄₀Cl₅N₅O₆S：C 41.94，H5.63，N 9.78；Found：C 41.78，H 6.00，N 9.62。Using IV-25 as the raw material, the operation is the same as that of I-21. After the reaction, the reaction solution is directly subjected to column chromatography (eluent: petroleum ether: acetone = 1:1～1:3) to obtain a light yellow oil, dissolved in After drying the acetone, pass through dry HCl to obtain white solid I-25, yield 61.0%, mp 240-243°C. IR (cm ^-1 ): 3401, 3164, 2988, 1707 (C=O), 1604, 1572, 1469, 1421, 1308, 1270, 1148, 1101 (OCH ₃ ), 758; ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 1.64 (3H, d, CH ₃ , J=6.8Hz), 2.80～3.57 (8H, m,

), 3.49 (3H, s, CH ₃ ), 3.75 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.86 (3H, s, OCH ₃ ), 4.20～4.40 (3H, m, CH ₂ , CH), 6.87 (1H, d, ArH, J=8.6Hz), 7.33 (1H, d, ArH, J=8.6Hz), 8.30 (2H, bs, NH), 8.64～8.67 (2H, m , ArH), 8.81(1H, s, ArH), 8.85(3H, bs, NH), 11.45(1H, bs, NH), 12.73(1H, bs, NH); MS(ESI(+)70V)m/ z 534 [M+H] ⁺ ; Anal. Calcd. for C ₂₅ H ₄₀ Cl ₅ N ₅ O ₆ S: C 41.94, H 5.63, N 9.78; Found: C 41.78, H 6.00, N 9.62.

Example 11

Preparation of 3-sulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-26)

Preparation of ethyl 3-sulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-26)

Using ethyl 3-sulfamoyl-4-methylbenzoate (II-26) as raw material, the operation is the same as III-1 and IV-1 to obtain bromide.

)，3.78(3H，s，OCH₃)，3.83(3H，s，OCH₃)，3.86(3H，s，OCH₃)，4.20(2H，s，CH₂)，4.25(2H，s，CH₂)，4.34(2H，q，COOCH₂-，J＝7.1Hz)，6.89(1H，d，ArH，J＝8.6Hz)，7.34(1H，d，ArH，J＝8.6Hz)，8.00(1H，d，ArH，J＝8.0Hz)，8.15(1H，dd，ArH，J₁＝8.0Hz，J₂＝1.7Hz)，8.49(1H，d，ArH，J＝1.7Hz)，9.65(1H，bs，N⁺H)，11.75(1H，bs，N⁺H)。Put 2.8g of trimetazidine hydrochloride and 0.8g of KOH into 20ml of anhydrous acetonitrile, stir at 40°C for 1h, add dropwise the solution obtained by dissolving 2g of the bromide obtained in the previous step in 10ml of acetonitrile, and heat up to 70°C React for 3 hours, filter, recover the solvent, dissolve the residue with anhydrous acetone, pass through dry HCl, a white solid precipitates, filter, wash with acetone, and dry to obtain a white solid IV-262.0g (55.6%), mp241～242 ℃. ¹ HNMR (300MHz, DMSO-d ₆ ), δ (ppm): 1.20 (3H, t, CH ₃ , J=7.1Hz), 2.75～3.50 (8H, m,

), 3.78 (3H, s, OCH ₃ ), 3.83 (3H, s, OCH ₃ ), 3.86 (3H, s, OCH ₃ ), 4.20 (2H, s, CH ₂ ), 4.25 (2H, s, CH ₂ ), 4.34 (2H, q, COOCH ₂ -, J=7.1Hz), 6.89 (1H, d, ArH, J=8.6Hz), 7.34 (1H, d, ArH, J=8.6Hz), 8.00 (1H, d, ArH, J = 8.0Hz), 8.15 (1H, dd, ArH, _J1 = 8.0Hz, _J2 = 1.7Hz), 8.49 (1H, d, ArH, J = 1.7Hz), 9.65 (1H, bs , N ⁺ H), 11.75 (1H, bs, N ⁺ H).

)，3.76(3H，s，OCH₃)，3.82(3H，s，OCH₃)，3.88(3H，s，OCH₃)，4.26(2H，s，CH₂)，4.49(2H，s，CH₂)，6.88(1H，d，ArH，J＝8.7Hz)，7.32(1H，d，ArH，J＝8.7Hz)，7.75(bs，NH)，8.11(1H，d，ArH，J＝8.0Hz)，8.57(1H，dd，ArH，J＝8.0Hz，J＝1.8Hz)，8.60(1H，d，ArH，J＝1.8Hz)，8.80(bs，NH)，12.40(bs，NH)；MS(ESI(+)70V)m/z 521[M+H]⁺，545[M+Na]⁺；Anal.Calcd.for C₂₃H₃₆Cl₄N₆O₆S.H₂O：C 41.45，H5.44，N 12.61；Found：C 41.48，H 5.76，N 12.25.Using IV-26 as the raw material, the operation was the same as that of I-1 to obtain I-26 as a light yellow solid with a yield of 57.8%, mp 218-220°C. IR (cm ^-1 ): 3358, 3137, 2994, 1706 (C=O), 1603, 1584, 1498, 1454, 1436, 1344, 1266, 1161 (SO ₂ ), 1106, 1090 (OCH ₃ ), 858, 757; ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 3.10～3.42 (8H, m,

), 3.76 (3H, s, OCH ₃ ), 3.82 (3H, s, OCH ₃ ), 3.88 (3H, s, OCH ₃ ), 4.26 (2H, s, CH ₂ ), 4.49 (2H, s, CH ₂ ), 6.88 (1H, d, ArH, J=8.7Hz), 7.32 (1H, d, ArH, J=8.7Hz), 7.75 (bs, NH), 8.11 (1H, d, ArH, J=8.0Hz) , 8.57 (1H, dd, ArH, J=8.0Hz, J=1.8Hz), 8.60 (1H, d, ArH, J=1.8Hz), 8.80 (bs, NH), 12.40 (bs, NH); MS ( ESI (+)70V) m/z 521[M+H] ⁺ , 545[M+Na] ⁺ ; Anal. Calcd. for C ₂₃ H ₃₆ Cl ₄ N ₆ O ₆ SH ₂ O: C 41.45, H5.44 , N 12.61; Found: C 41.48, H 5.76, N 12.25.

Example 12

Preparation of 3-propylsulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine hydrochloride (I-29)

Preparation of ethyl 3-propylsulfamoyl-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate hydrochloride (IV-29)

)，2.74(2H，m，CH₂)，3.50(2H，s，CH₂)，3.84(3H，s，OCH₃)，3.85(3H，s，OCH₃)，3.86(3H，s，OCH₃)，3.95(2H，s，CH₂)，4.41(2H，q，COOCH₂-，J＝7.1Hz)6.62(1H，d，ArH，J＝8.5Hz)，6.93(1H，d，ArH，J＝8.3Hz)，7.36(1H，d，ArH，J＝7.9Hz)，8.12(1H，dd，ArH，J₁＝8.0Hz，J₂＝1.7Hz)，8.69(1H，d，ArH，J＝1.7Hz)，11.35(2H，bs，N⁺H)。Using ethyl 3-propylsulfamoyl-4-methylbenzoate (II-29) as raw material, the operation was the same as III-26 and IV-26 to obtain white solid IV-29 with a yield of 56.3%, mp229～231°C . ¹ HNMR (500MHz, CDCl ₃ ), δ (ppm): 0.87 (3H, t, CH ₃ , J=7.3Hz), 1.40 (3H, t, CH ₃ , J=7.1Hz), 1.42～1.48 (2H, m, CH ₂ ), 2.20～2.66 (8H, m,

), 2.74 (2H, m, CH ₂ ), 3.50 (2H, s, CH ₂ ), 3.84 (3H, s, OCH ₃ ), 3.85 (3H, s, OCH ₃ ), 3.86 (3H, s, OCH ₃ ), 3.95 (2H, s, CH ₂ ), 4.41 (2H, q, COOCH ₂ -, J=7.1Hz), 6.62 (1H, d, ArH, J=8.5Hz), 6.93 (1H, d, ArH, J = 8.3Hz), 7.36 (1H, d, ArH, J = 7.9Hz), 8.12 (1H, dd, ArH, J ₁ = 8.0Hz, J ₂ = 1.7Hz), 8.69 (1H, d, ArH, J = 1.7Hz), 11.35 (2H, bs, N ⁺ H).

)，3.77(3H，s，OCH₃)，3.81(3H，s，OCH₃)，3.87(3H，s，OCH₃)，4.22～4.40(4H，m，CH₂，CH₂)，6.89(1H，d，ArH，J＝8.8Hz)，7.35(1H，d，ArH，J＝8.7Hz)，8.05(1H，bs，NH)，8.10～8.15(1H，m，ArH)，8.49(1H，d，ArH，J＝1.7Hz)，8.58(1H，dd，ArH，J₁＝8.1Hz，J₂＝1.8Hz)，8.76(5H，bs，NH)，11.05(1H，bs，NH)，12.25(1H，bs，NH)；MS(ESI(+)70V)m/z563[M+H]⁺；Anal.Calcd.for C₂₆H₄₁Cl₃N₆O₆S：C 46.46，H 6.15，N 12.50；Found：C 46.68，H 6.14，N12.29。Using IV-29 as the raw material, the operation was the same as that of I-1 to obtain I-29 as a light yellow solid with a yield of 51.0% and mp229-231°C. IR (cm ^-1 ): 3363, 3110, 2964, 1698 (C=O), 1610, 1584, 1454, 1334, 1159 (SO ₂ ), 1106 (OCH ₃ ), 738; ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 0.77 (3H, t, CH ₃ , J=7.3Hz), 2.11 (2H, m, CH ₂ ), 2.76～2.80 (2H, m, CH ₂ ), 3.00～3.50 (8H ,s,

), 3.77 (3H, s, OCH ₃ ), 3.81 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 4.22～4.40 (4H, m, CH ₂ , CH ₂ ), 6.89 (1H , d, ArH, J=8.8Hz), 7.35(1H, d, ArH, J=8.7Hz), 8.05(1H, bs, NH), 8.10～8.15(1H, m, ArH), 8.49(1H, d , ArH, J=1.7Hz), 8.58 (1H, dd, ArH, J ₁ =8.1Hz, J ₂ =1.8Hz), 8.76 (5H, bs, NH), 11.05 (1H, bs, NH), 12.25 ( 1H, bs, NH); MS (ESI (+) 70V) m/z 563 [M+H] ⁺ ; Anal. Calcd. for C ₂₆ H ₄₁ Cl ₃ N ₆ O ₆ S: C 46.46, H 6.15, N 12.50 ; Found: C 46.68, H 6.14, N 12.29.

Example 13

Preparation of 3-acetamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoylguanidine (I-40):

Preparation of methyl 3-nitro-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (VII-40)

3-nitro-4-methylbenzoic acid methyl ester (V-40) 30g (0.154mol), NBS 30g (0.168mol) and catalytic amount of benzoyl peroxide are dropped into anhydrous carbon tetrachloride 100ml, Reflux for 36 hours under light, filter, and evaporate the solvent under reduced pressure to obtain a crude bromide (VI-40), which is directly put into the next reaction without treatment.

Dissolve 40g of trimetazidine hydrochloride in 50ml of water, stir to dissolve, adjust the pH to 10-11 with 40% sodium hydroxide solution, extract three times with ethyl acetate (80ml×3), combine the organic layers, and saturated aqueous sodium chloride solution Wash three times (150ml×3), dry overnight with anhydrous sodium sulfate, filter, and evaporate ethyl acetate to dryness under reduced pressure to obtain free trimetazidine as light yellow oil 24.6g.

)，3.50(2H，s，-CH₂)，3.81(2H，s，-CH₂)，3.84(3H，s，-OCH₃)，3.86(3H，s，-OCH₃)，3.87(3H，s，-OCH₃)，3.94(3H，s，-COOCH₃)，6.62(1H，d，ArH，J＝8.4Hz)，7.01(1H，d，ArH，J＝8.7Hz)，7.71(1H，d，ArH，J＝7.8Hz，)，8.16(1H，dd，ArH，J₁＝1.8Hz，J₂＝8.1Hz)，8.43(1H，d，ArH，J＝1.5Hz)。Dissolve 24.6g (0.092mol) of the above-mentioned trimetazidine in 35ml of anhydrous acetonitrile, add 38.3g (0.28mol) of finely ground potassium carbonate powder, and dissolve the crude bromide obtained in the previous step in 20ml of anhydrous acetonitrile , slowly drop into the reaction flask, and at the same time, add fine potassium carbonate powder to keep the pH of the reaction solution at 8. After dropping, heat up to 50°C for 4 hours, filter, evaporate the solvent, and use ethyl acetate: acetone (1 : 5) Recrystallized to obtain 18.3 g (26.1%) of light yellow solid VII-40, mp 123°C-127°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.42～2.54 (8H, m,

), 3.50 (2H, s, -CH ₂ ), 3.81 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.86 (3H, s, -OCH ₃ ), 3.87 (3H, s, -OCH ₃ ), 3.94 (3H, s, -COOCH ₃ ), 6.62 (1H, d, ArH, J=8.4Hz), 7.01 (1H, d, ArH, J=8.7Hz), 7.71 (1H, d, ArH, J = 7.8 Hz, ), 8.16 (1H, dd, ArH, J ₁ = 1.8 Hz, J ₂ = 8.1 Hz), 8.43 (1H, d, ArH, J = 1.5 Hz).

Preparation of methyl 3-amino-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (VIII-40)

)，3.50(3H，s，-COOCH₃)，3.81～3.86(13H，m，3×-OCH₃，2×-CH₂)，4.82～4.85(2H，bs，NH₂)，6.60(1H，d，ArH，J＝8.4Hz)，6.99(1H，d，ArH，J＝8.1Hz)，7.25～7.26(2H，m，ArH)，7.29(1H，m，ArH)；MS(ESI(+)70V)m/z 430.1[M+H]⁺。In a 50ml three-necked flask, add 1g (2.3mmol) of compound (VII-40), dissolve it in 12ml of 50% ethanol solution, add 0.9g (16.1mmol) of reduced iron powder, and reflux for 0.5 hours under mechanical stirring. Filtrate hot, concentrate the filtrate, and stand for crystallization to obtain 000.71 g (76.3%) of light yellow solid VIII-4, mp 141°C-145°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.40～2.60 (8H, m,

), 3.50 (3H, s, -COOCH ₃ ), 3.81～3.86 (13H, m, 3×-OCH ₃ , 2×-CH ₂ ), 4.82～4.85 (2H, bs, NH ₂ ), 6.60 (1H, d, ArH, J=8.4Hz), 6.99(1H, d, ArH, J=8.1Hz), 7.25～7.26(2H, m, ArH), 7.29(1H, m, ArH); MS(ESI(+) 70V) m/z 430.1 [M+H] ⁺ .

Preparation of methyl 3-acetamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (IX-40)

)，3.48(3H，s，-COOCH₃)，3.69(2H，s，-CH₂)，3.85(2H，s，-CH₂)，3.86(3H，s，-OCH₃)，3.88(3H，s，-OCH₃)，3.89(3H，s，-OCH₃)，6.63(1H，d，ArH，J＝8.7Hz)，6.98(1H，d，ArH，J＝8.4Hz)，7.13(1H，d，ArH，J＝7.8Hz)，7.67(1H，d，ArH，J＝7.8Hz)，8.87(1H，s，ArH)。Add 0.5g (1.2mmol) of compound (VIII-40) and 5ml of anhydrous dichloromethane into a 25ml three-necked flask, stir to dissolve, add 0.16ml of triethylamine, cool in an ice-salt bath to below 0°C, and slowly add ethyl alcohol dropwise. Acyl chloride 0.09g (1.2mmol) in anhydrous dichloromethane solution 2ml, dropwise, react for 5min. The reaction solution was washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 0.51 g of a crude yellow oil, which was separated by column chromatography (eluent: petroleum ether: acetone = 4:1) to obtain White solid IX-400.2g (36.4%), mp 119°C～121°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.15 (3H, s, -COCH ₃ ), 2.48～2.52 (8H, m,

), 3.48 (3H, s, -COOCH ₃ ), 3.69 (2H, s, -CH ₂ ), 3.85 (2H, s, -CH ₂ ), 3.86 (3H, s, -OCH ₃ ), 3.88 (3H, s, -OCH ₃ ), 3.89 (3H, s, -OCH ₃ ), 6.63 (1H, d, ArH, J=8.7Hz), 6.98 (1H, d, ArH, J=8.4Hz), 7.13 (1H, d, ArH, J=7.8 Hz), 7.67 (1H, d, ArH, J=7.8 Hz), 8.87 (1H, s, ArH).

Preparation of 3-acetamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoic acid (X-40)

)，3.65(2H，s，-CH₂)，3.71(2H，s，-CH₂)，3.84(3H，s，-OCH₃)，3.85(3H，s，-OCH₃)，3.88(3H，s，-OCH₃)，5.65(6.65(1H，d，ArH，J＝8.7Hz)，7.05(1H，d，ArH，J＝8.7Hz)，7.14(1H，d，ArH，J＝7.8Hz)，7.71(1H，d，ArH，J＝7.8Hz)，8.84(1H，s，ArH)，10.65(1H，s，-CONH-)。Add 0.2g (0.4mmol) compound (IX-40) in the 25ml eggplant-shaped bottle, 10ml of 60% aqueous methanol solution, heat to reflux, after the sample dissolves, add potassium carbonate 0.18g (1.3mmol), react for 2 hours, evaporate under reduced pressure In addition to methanol, use 2% dilute hydrochloric acid solution to adjust the pH to about 7 (isoelectric point) in an ice bath, a white solid is precipitated, left to stand, filtered, and dried under an infrared lamp to obtain 0.16 g (84.2%) of a white solid, mp127 ℃～128℃. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.09 (3H, s, -COCH ₃ ), 2.35～2.70 (8H, m,

), 3.65 (2H, s, -CH ₂ ), 3.71 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.85 (3H, s, -OCH ₃ ), 3.88 (3H, s, -OCH ₃ ), 5.65 (6.65 (1H, d, ArH, J=8.7Hz), 7.05 (1H, d, ArH, J=8.7Hz), 7.14 (1H, d, ArH, J=7.8Hz) , 7.71 (1H, d, ArH, J = 7.8 Hz), 8.84 (1H, s, ArH), 10.65 (1H, s, -CONH-).

)，3.40(2H，s，-CH₂)，3.57(2H，s，-CH₂)，3.72(3H，s，-OCH₃)，3.76(6H，s，2×-OCH₃)，5.5～6.5(1H，bs，NH)，6.75(1H，d，ArH，J＝8.6Hz)，6.96(1H，d，ArH，J＝8.6Hz)，7.19(1H，d，ArH，J＝7.8Hz)，7.72(1H，d，ArH，J＝7.8Hz)，8.54(1H，s，ArH)，7.30～8.50(3H，bs，NH)，10.47(1H，s，-CONH-)；MS(ESI(+)70V)m/z 499.2[M+H]⁺。Dissolve 0.16g (0.36mmol) of compound (X-40) in 2ml of anhydrous DMF, add 0.047g (0.36mmol) of 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-di After 0.067 g (0.36 mmol) of methylaminopropyl) carbodiimide hydrochloride (EDCI) was completely dissolved, 0.05 g (1.08 mmol) of free guanidine was added and stirred at room temperature for 5 hours. The reaction solution was poured into a mixed solution of ethyl acetate:water (30ml:20ml), and extracted with ethyl acetate (20ml×3). The ester layers were combined, washed with saturated sodium chloride solution (50ml×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a yellow oil, which was subjected to column chromatography (eluent: ethyl acetate: methanol: triethyl acetate) Amine=15:1:0.1) to obtain 0.06 g (35.3%) of white solid. mp180℃～182℃. IR (cm ^-1 ): 3439, 2935, 2829, 1670 (C=O), 1596, 1569, 1530, 1419, 1340, 1274, 1095 (OCH ₃ ), 1006, 787; ¹ HNMR (500MHz, DMSO-d ₆ ), δ (ppm): 2.06 (3H, s, -COCH ₃ ), 2.22～2.48 (8H, m,

), 3.40 (2H, s, -CH ₂ ), 3.57 (2H, s, -CH ₂ ), 3.72 (3H, s, -OCH ₃ ), 3.76 (6H, s, 2×-OCH ₃ ), 5.5～ 6.5 (1H, bs, NH), 6.75 (1H, d, ArH, J=8.6Hz), 6.96 (1H, d, ArH, J=8.6Hz), 7.19 (1H, d, ArH, J=7.8Hz) , 7.72 (1H, d, ArH, J=7.8Hz), 8.54 (1H, s, ArH), 7.30～8.50 (3H, bs, NH), 10.47 (1H, s, -CONH-); MS (ESI ( +)70V) m/z 499.2[M+H] ⁺ .

Example 14

Preparation of 3-benzamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)guanidine benzoate (I-42)

Preparation of 3-benzamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)methyl benzoate (IX-42)

)，3.50(2H，s，-CH₂)，3.67(2H，s，-CH₂)，3.85(3H，s，-OCH₃)，3.86(3H，s，-OCH₃)，3.88(3H，s，-OCH₃)，3.91(3H，s，-COOCH₃)，6.63(1H，d，ArH，J＝8.4Hz)，6.95(1H，d，ArH，J＝8.7Hz)，7.21(1H，d，ArH，J＝7.8Hz)，7.43～7.48(2H，m，ArH)，7.54～7.56(1H，m，ArH)，7.73(1H，d，ArH，J＝7.8Hz)，7.99～8.02(2H，m，ArH)，9.07(1H，s，ArH)，11.46(1H，s，-CONH-)。Using compound (VIII-40) and benzoyl chloride as raw materials, a white solid IX-420.26g (41.9%) was obtained in a similar manner to compound IX-40, mp 139°C-142°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.26～2.60 (8H, m,

), 3.50 (2H, s, -CH ₂ ), 3.67 (2H, s, -CH ₂ ), 3.85 (3H, s, -OCH ₃ ), 3.86 (3H, s, -OCH ₃ ), 3.88 (3H, s, -OCH ₃ ), 3.91 (3H, s, -COOCH ₃ ), 6.63 (1H, d, ArH, J=8.4Hz), 6.95 (1H, d, ArH, J=8.7Hz), 7.21 (1H, d, ArH, J=7.8Hz), 7.43～7.48(2H, m, ArH), 7.54～7.56(1H, m, ArH), 7.73(1H, d, ArH, J=7.8Hz), 7.99～8.02( 2H, m, ArH), 9.07 (1H, s, ArH), 11.46 (1H, s, -CONH-).

Preparation of 3-benzamido-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoic acid (X-42)

)，3.71(2H，s，-CH₂)，3.74(2H，s，-CH₂)，3.84(3H，s，-OCH₃)，3.85(3H，s，-OCH₃)，3.89(3H，s，-OCH₃)，6.66(1H，d，ArH，J＝8.7Hz)，7.05(1H，d，ArH，J＝8.7Hz)，7.22(1H，d，ArH，J＝8.1Hz)，7.39～7.44(2H，m，ArH)，7.51～7.56(1H，m，ArH)，7.72(1H，d，ArH，J＝7.8Hz)，7.94～7.96(2H，m，ArH)，9.08(1H，s，ArH)，11.30(1H，s，-CONH-)。Using compound (IX-42) as a raw material, the method was similar to compound IX-40 to obtain 0.18 g (72.0%) of white solid (X-42), mp 141°C-143°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.40～2.70 (8H, m,

), 3.71 (2H, s, -CH ₂ ), 3.74 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.85 (3H, s, -OCH ₃ ), 3.89 (3H, s, -OCH ₃ ), 6.66 (1H, d, ArH, J=8.7Hz), 7.05 (1H, d, ArH, J=8.7Hz), 7.22 (1H, d, ArH, J=8.1Hz), 7.39 ～7.44(2H, m, ArH), 7.51～7.56(1H, m, ArH), 7.72(1H, d, ArH, J=7.8Hz), 7.94～7.96(2H, m, ArH), 9.08(1H, s, ArH), 11.30 (1H, s, -CONH-).

)，3.52(2H，s，-CH₂)，3.62(2H，s，-CH₂)，3.86(3H，s，-OCH₃)，3.87(3H，s，-OCH₃)，3.89(3H，s，-OCH₃)，6.64(1H，d，ArH，J＝8.7Hz)，6.97(1H，d，ArH，J＝8.4Hz)，7.22(1H，d，ArH，J＝7.8Hz)，7.46～7.51(2H，m，ArH)，7.56～7.60(1H，m，ArH)，7.88(1H，d，ArH，J＝7.8Hz)，7.97～7.99(2H，m，ArH)，8.72(1H，s，ArH)，11.51(1H，s，-CONH-)；MS(ESI(+)70V)m/z 561.2[M+H]⁺。Using compound (X-42) as a raw material, a white solid I-42 (33.3%) was obtained in a similar manner to compound I-40, mp 220°C-223°C. IR (cm ^-1 ): 3442, 3355, 3230, 2936, 2823, 1658 (C=O), 1569, 1528, 1462, 1418, 1340, 1275, 1094 (OCH ₃ ), 1004, 707; ¹ H NMR ( 300MHz, CDCl ₃ ), δ(ppm): 2.40～2.68(8H, s,

), 3.52 (2H, s, -CH ₂ ), 3.62 (2H, s, -CH ₂ ), 3.86 (3H, s, -OCH ₃ ), 3.87 (3H, s, -OCH ₃ ), 3.89 (3H, s, -OCH ₃ ), 6.64 (1H, d, ArH, J=8.7Hz), 6.97 (1H, d, ArH, J=8.4Hz), 7.22 (1H, d, ArH, J=7.8Hz), 7.46 ～7.51(2H, m, ArH), 7.56～7.60(1H, m, ArH), 7.88(1H, d, ArH, J=7.8Hz), 7.97～7.99(2H, m, ArH), 8.72(1H, s, ArH), 11.51 (1H, s, -CONH-); MS (ESI (+) 70V) m/z 561.2 [M+H] ⁺ .

Example 15

3-(2-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)guanidine benzoate (I-45) preparation:

Methyl 3-(2-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoate (IX-45) preparation of

Using compound (VIII-40) and o-fluorobenzoyl chloride as raw materials, the method was similar to that of compound IX-40 to obtain 50.38 g (59.4%) of white solid IX-4, mp 95°C-97°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.22～2.48 (8H, m, ), 3.38 (2H, s-CH ₂ ), 3.59 (2H, s, -CH ₂ ), 3.80 (3H, s, -OCH ₃ ), 3.81 (3H, s, -OCH ₃ ), 3.82 (3H, s , -OCH ₃ ), 3.87 (3H, s, -COOCH ₃ ), 6.58 (1H, d, ArH, J=8.7Hz), 7.08 (1H, d, ArH, J=8.7Hz), 7.17 (1H, d , ArH, J=7.8Hz), 7.26～7.28(2H, m, ArH), 7.45～7.49(1H, m, ArH), 7.70(1H, d, ArH, J=7.8Hz), 7.98～8.03(1H , m, ArH), 9.00 (1H, s, ArH). 11.20 (1H, s, -CONH-).

Preparation of 3-(2-fluorobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoic acid (X-45)

)，3.60(2H，s-CH₂)，3.66(2H，s，-CH₂)，3.84(3H，s，-OCH₃)，3.88(3H，s，-OCH₃)，4.08(3H，s，-OCH₃)，6.66(1H，d，ArH，J＝8.4Hz)，7.08(1H，d，ArH，J＝8.4Hz)，7.22(1H，d，ArH，J＝7.8Hz)，7.29～7.32(2H，m，ArH)，7.47～7.54(1H，m，ArH)，7.79(1H，d，ArH，J＝7.8Hz)，8.04～8.09(1H，m，ArH)，9.03(1H，s，ArH)，10.98(1H，s，-CONH-)。.Using compound (IX-45) as raw material, the method was similar to that of compound X-40 to obtain 50.3g (83.3%) of white solid X-4, mp130℃～132℃. ¹ HNMR (300MHz, CDCl ₃ ), δ(ppm): 2.40～2.78(8H, m,

), 3.60 (2H, s-CH ₂ ), 3.66 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.88 (3H, s, -OCH ₃ ), 4.08 (3H, s , -OCH ₃ ), 6.66 (1H, d, ArH, J=8.4Hz), 7.08 (1H, d, ArH, J=8.4Hz), 7.22 (1H, d, ArH, J=7.8Hz), 7.29～ 7.32(2H, m, ArH), 7.47～7.54(1H, m, ArH), 7.79(1H, d, ArH, J=7.8Hz), 8.04～8.09(1H, m, ArH), 9.03(1H, s , ArH), 10.98 (1H, s, -CONH-). .

Using compound X-45 as a raw material, a white solid I-45 (34.3%) was obtained in a similar manner to compound I-40, mp 210°C-212°C. IR (cm ^-1 ): 3445, 3363, 3262, 2932, 2836, 1667 (C=O), 1602, 1571, 1552, 1415, 1340, 1280, 1089 (OCH ₃ ), 1003, 798; ^.1 HNMR ( 300MHz, CDCl ₃ ), δ(ppm): 2.41～2.44(8H, s, ), 3.43 (2H, s, -CH ₂ ), 3.60 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.86 (3H, s, -OCH ₃ ), 3.87 (3H, s, -OCH ₃ ), 6.62 (1H, d, ArH, J=8.7Hz), 6.95 (1H, d, ArH, J=8.4Hz), 7.21 (1H, d, ArH, J=8.1Hz), 7.28 ～7.33(2H, m, ArH), 7.51～7.56(1H, m, ArH), 7.86(1H, d, ArH, J=7.8Hz), 7.95～7.96(1H, m, ArH), 8.54(1H, s, ArH), 11.24 (1H, s, -CONH-); MS (ESI (+) 70V) m/z 579.1 [M+H] ⁺ .

Example 16

3-(2-Methyl-3-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)guanidine benzoate Preparation of (I-59)

3-(2-Methyl-3-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoic acid methyl Preparation of ester (IX-59)

In a 25ml eggplant-shaped bottle, add 0.4g (2.2mmol) of 2-methyl-3-nitrobenzoic acid and 1.9ml of thionyl chloride, heat to reflux, add 2 drops of anhydrous DMF, react for 12 hours and dichloromethane The sulfoxide was evaporated to dryness to obtain a yellow oil for later use.

)，2.66(3H，s，-CH₃)，3.33(2H，s，-CH₂)，3.65(2H，s，-CH₂)，3.84(3H，s，-OCH₃)，3.85(3H，s，-OCH₃)，3.87(3H，s，-OCH₃)，3.93(3H，s，-COOCH₃)，6.61(1H，d，ArH，J＝8.5Hz)，6.88(1H，d，ArH，J＝8.5Hz)，7.20(1H，d，ArH，J＝7.9Hz)，7.35～7.41(1H，m，ArH)，7.70～7.78(2H，m，ArH)，7.91(1H，d，ArH，J＝8.1Hz)，9.07(1H，s，ArH)，11.69(1H，s，-CONH-).Using compound VIII-40 and the above-prepared 2-methyl-3-nitrobenzoyl chloride as raw materials, a white solid IX-590.28g (38.4%) was obtained in a similar manner to compound IX-40, mp65℃～66℃ . ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.17～2.47 (8H, s,

), 2.66 (3H, s, -CH ₃ ), 3.33 (2H, s, -CH ₂ ), 3.65 (2H, s, -CH ₂ ), 3.84 (3H, s, -OCH ₃ ), 3.85 (3H, s, -OCH ₃ ), 3.87 (3H, s, -OCH ₃ ), 3.93 (3H, s, -COOCH ₃ ), 6.61 (1H, d, ArH, J=8.5Hz), 6.88 (1H, d, ArH , J=8.5Hz), 7.20(1H, d, ArH, J=7.9Hz), 7.35～7.41(1H, m, ArH), 7.70～7.78(2H, m, ArH), 7.91(1H, d, ArH , J=8.1Hz), 9.07 (1H, s, ArH), 11.69 (1H, s, -CONH-).

3-(2-methyl-3-nitrobenzamido)-4-((4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)methyl)benzoic acid ( X-59) Preparation

)，2.61(3H，s，-CH₃)，3.55(2H，s，-CH₂)，3.67(2H，s，-CH₂)，3.85～3.93(9H，m，-OCH₃)，6.63(1H，d，ArH，J＝8.7Hz)，6.96(1H，d，ArH，J＝8.4Hz)，7.17(1H，d，ArH，J＝7.8Hz)，7.30～7.35(1H，m，ArH)，7.68～7.75(2H，m，ArH)，7.86(1H，d，ArH，J＝8.1Hz)，8.97(1H，s，ArH)，11.38(1H，s，-CONH-).Using compound IX-59 as a raw material, the method was similar to that of compound X-40 to obtain 90.17 g (63.0%) of white solid X-5, mp 124°C-125°C. ¹ HNMR (300MHz, CDCl ₃ ), δ (ppm): 2.30～2.56 (8H, s,

), 2.61 (3H, s, -CH ₃ ), 3.55 (2H, s, -CH ₂ ), 3.67 (2H, s, -CH ₂ ), 3.85～3.93 (9H, m, -OCH ₃ ), 6.63 ( 1H, d, ArH, J=8.7Hz), 6.96 (1H, d, ArH, J=8.4Hz), 7.17 (1H, d, ArH, J=7.8Hz), 7.30～7.35 (1H, m, ArH) , 7.68～7.75 (2H, m, ArH), 7.86 (1H, d, ArH, J=8.1Hz), 8.97 (1H, s, ArH), 11.38 (1H, s, -CONH-).

)，2.68(3H，s，-CH₃)，3.32(2H，s，-CH₂)，3.63(2H，s，-CH₂)，3.84～3.86(9H，m，-OCH₃)，6.61(1H，，d，ArH，J＝8.7Hz)，6.87(1H，d，ArH，J＝8.4Hz)，7.20(1H，d，ArH，J＝8.1Hz)，7.40～7.45(1H，m，ArH)，7.70～7.73(1H，，m，ArH)，7.87～7.89(1H，m，ArH)，7.94(1H，d，ArH，J＝8.4Hz)，8.62(1H，s，ArH)，11.75(1H，s，-CONH-)；MS(ESI(+)70V)m/z 620.4[M+H]⁺。Using compound X-59 as a raw material, a white solid I-59 (33.4%) was obtained in a similar manner to compound I-40, mp 215°C-216°C. IR (cm ^-1 ): 3451, 3403, 3250, 2933, 2824, 1668 (C=O), 1604, 1577, 1528, 1430, 1343, 1276, 1095 (OCH ₃ ), 1005, 788; ^.1 HNMR ( 300MHz, CDCl ₃ ), δ(ppm): 2.38～2.42(8H, s,

), 2.68 (3H, s, -CH ₃ ), 3.32 (2H, s, -CH ₂ ), 3.63 (2H, s, -CH ₂ ), 3.84～3.86 (9H, m, -OCH ₃ ), 6.61 ( 1H,, d, ArH, J=8.7Hz), 6.87 (1H, d, ArH, J=8.4Hz), 7.20 (1H, d, ArH, J=8.1Hz), 7.40～7.45 (1H, m, ArH ), 7.70~7.73 (1H,, m, ArH), 7.87~7.89 (1H, m, ArH), 7.94 (1H, d, ArH, J=8.4Hz), 8.62 (1H, s, ArH), 11.75 ( 1H, s, -CONH-); MS (ESI (+) 70V) m/z 620.4 [M+H] ⁺ .

Example 17

tablet

Mix 100 mg of compound I-25 prepared by the method in Example 10 with 200 mg of starch and 100 mg of dextrin, use an appropriate amount of 30% ethanol as a wetting agent to make a soft material, granulate in a conventional manner, add an appropriate amount of magnesium stearate and mix to prepare tablet.

Claims (7)

1, the compound of general formula (I) or its pharmacy acceptable salt:

R wherein ¹Representative: hydrogen, C ₁～C ₆Alkyl, C ₂～C ₁₀Alkoxyalkyl, phenyl, or the phenyl that replaces by following groups: halogen, C ₁～C ₆Alkoxyl group, nitro, cyano group;

R ²Representative: hydrogen, chlorine, bromine, fluorine, C ₁～C ₆Alkoxyl group, allyloxy, nitro, trifluoromethyl, cyano group, C ₁～C ₆Alkyl sulphonyl, sulfamyl, C ₁～C ₆Alkylamino radical alkylsulfonyl, allyl amido alkylsulfonyl, morpholine-1-base alkylsulfonyl, piperidines-1-base alkylsulfonyl, 4-methyl piperidine-1-base alkylsulfonyl, pyrroles-1-base alkylsulfonyl, C ₁～C ₆Alkylamidoalkyl, benzoylamino, or the benzoylamino that replaces by following groups: halogen, C ₁～C ₆Alkyl, hydroxyl, C ₁～C ₆Alkoxyl group, nitro, cyano group, C ₁～C ₆Alkyl sulphonyl or C ₁～C ₆The alkylamino radical alkylsulfonyl.

2, the compound of claim 1 or its pharmacy acceptable salt, wherein R ¹Represent hydrogen or C ₁～C ₆Alkyl.

3, the compound of claim 1 or its pharmacy acceptable salt, wherein R ²Represent hydrogen, chlorine, fluorine, nitro, trifluoromethyl, methylsulfonyl, ethylsulfonyl, sulfamyl, morpholine-1-base alkylsulfonyl, piperidines-1-base alkylsulfonyl, 4-methyl piperidine-1-base alkylsulfonyl, C ₁～C ₆Alkylamidoalkyl, benzoylamino, or the benzoylamino that replaces by following groups: halogen, C ₁～C ₆Alkyl, C ₁～C ₄Alkoxyl group, nitro, cyano group, C ₁～C ₃Alkyl sulphonyl or C ₁～C ₃The alkylamino radical alkylsulfonyl.

4, the compound of claim 1 or its pharmacy acceptable salt, wherein the acyl guanidine radicals is in R ¹The contraposition or the ortho position of base.

5, the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, forulic acid or nicotinic acid.

6, a kind of pharmaceutical composition wherein contains general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.

7, the general formula of claim 1 (I) compound or its pharmacy acceptable salt purposes in the medicine of preparation prevention or treatment and NHE1 diseases associated.