CN101143857A - Benzoyl guanidine derivative, preparation method and medical use thereof - Google Patents
Benzoyl guanidine derivative, preparation method and medical use thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a class of benzoyl-guanidine derivatives (I) of trimetazidine coupling, a preparation method of the benzoyl-guanidine derivatives (I), medicinal composites containing the compounds and medicinal applications, and particularly, the invention is applied to drugs of curing the myocardial ischemia-reperfusion injury.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class trimetazidine link coupled benzoyl guanidine derivant, their preparation method, the medicinal compositions that contains these compounds and their medicinal use, particularly as resisting myocardial ischemia the purposes of reperfusion injury medicine.
Background technology
Na
+/ H
+Interchanger (Na
+/ H
+Exchanger is a kind ofly in many mammiferous various types of cells expressed protein to be arranged all NHE), and NHE can regulate internal pH (pH
i), and by discharging proton, move into sodium ion and regulate cell-volume.Having had 9 NHE hypotypes to be proved conclusively at present, is respectively NHE1～9, and they are distributed in each organ of human body.A large amount of experiment showed, that on mammiferous myocardial cell based on NHE-1, it plays an important role in the myocardial ischemia-reperfusion process.
The NHE-1 inhibitor is by suppressing Na
+/ H
+Too much Na is avoided in exchange
+Enter in the cell, and then make Na
+/ Ca
2+Exchange reduces, and prevents Ca
2+Excessively increase and cause cell contracture, necrosis.The NHE-1 inhibitor is also by suppressing Na
+/ H
+Exchange reduces intracellular Na
+Concentration descends osmotic pressure, prevents that moisture from entering in the cell, therefore can prevent or alleviate capillary endothelium swelling behind the ischemic, prevents necrocytosis.Because NHE-1 is non-activity in the normal myocardium cell, so the NHE-1 inhibitor only acts on ischemic area specifically, thereby side effect less (Chinese Pharmaceutical Journal, 2005,40 (5): 324-327).
To the structure activity relationship analysis revealed of all kinds of NHE-1 inhibitor, the acylguanidines part is very important for suppressing activity.NHE-1 inhibitor just under study for action contains fragrant first (alkane) acyl guanidine structure mostly at present.As: cariporide (Cariporide, HOE-642).
Cariporide
Trimetazidine (Trimetazidine) is a kind of metabolism class medicine, and it can suppress long-chain 3-keto acyl CoA thiolase by selectivity, reduces Fatty Acid Oxidation, activates glucose oxidase, thereby more effectively utilizes limited oxygen to produce ATP, improves myocardial ischemia.Before the patients of acute myocardial infarction thrombolysis or directly carry out the preceding trimetazidine that gives of percutaneous transluminal coronary angioplasty (PTCA), can improve clinical myocardial ischemia-reperfusion injury.The patient of bypass operation of coronary artery (CABG), the application of trimetazidine can reduce ischemical reperfusion injury, obviously improves the cardiac output of postoperative, reduces postoperative complication, the quality of making the life better (Chinese Medicine guide, 2003,5 (5): 341-342).
Trimetazidine
Summary of the invention
This research work obtains the subsidy (No.30672512) of state natural sciences fund.
The present invention is summing up existing NHE inhibitor structure activity relationship and is analyzing on the basis of cariporide constructional feature, the selection benzoyl guanidine is a parent nucleus, different positions at the female ring of benzoyl guanidine is introduced the trimetazidine with the reperfusion injury and protect of resisting myocardial ischemia, design and synthesize a series of novel cpds, through thrombocyte swelling test (Platelet Swelling Assay, PSA) show, The compounds of this invention all has certain restraining effect to NHE1, and it is active in the positive drug cariporide that the NHE1 of part of compounds suppresses.
Compound general formula I of the present invention is as follows:
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 or cyano group.These substituting groups can be single replacement, two replacement or three replacements;
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.
R
1Preferred representative: hydrogen or C
1～C
6Alkyl.
R
2Preferred representative: 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.
The acyl guanidine radicals preferably is in R
1The contraposition or the ortho position of base.
R
1More preferably representative: hydrogen or methyl;
R
2More preferably representative: nitro, trifluoromethyl, methylsulfonyl, sulfamyl or C
1～C
6Alkylamidoalkyl.
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I 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.
Part of compounds of the present invention is:
4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-1)
3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-2)
2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-3)
4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-4)
3-chloro-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-5)
4-chloro-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-6)
5-chloro-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-7)
3-chloro-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-8)
3-bromo-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-9)
4-bromo-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-10)
5-bromo-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-11)
3-bromo-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-12)
3-methoxyl group-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-13)
4-methoxyl group-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-14)
3-methoxyl group-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-15)
3-oxyethyl group-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-16)
3-nitro-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-17)
4-nitro-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-18)
5-nitro-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-19)
3-nitro-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-20)
3-nitro-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-21)
3-cyano group-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-22)
3-methylsulfonyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-23)
5-methylsulfonyl-2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-24)
3-methylsulfonyl-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-25)
3-sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-26)
3-first sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-27)
3-second sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-28)
3-third sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-29)
3-(piperidines-1-alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-30)
4-(piperidines-1-alkylsulfonyl)-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-31)
3-(4-methylpiperazine-1-alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-32)
3-(morpholine-1-alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-33)
3-(morpholine-1-alkylsulfonyl)-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-34)
3-(pyrroles-1-alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-35)
4-(pyrroles-1-alkylsulfonyl)-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-36)
3-(dimethylin alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-37)
3-(diethylin alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-38)
3-(dipropyl amido alkylsulfonyl)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-39)
3-acetamido-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-40)
4-acetamido-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-41)
3-benzoylamino-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-42)
3-(4-chloro-benzoyl amino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-43)
3-(4-brombenzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-44)
3-(2-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-45)
3-(4-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-46)
3-(4-nitrobenzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-47)
3-(4-nitrobenzamide base)-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-48)
3-(4-cyano group benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-49)
3-(4-methoxy benzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-50)
3-(4-toluyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-51)
3-(3-nitrobenzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-52)
3-(2-chloro-benzoyl amino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-53)
3-(2-brombenzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-54)
3-(2-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-55)
3-(2-nitrobenzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-56)
3-(2-methoxy benzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-57)
3-(2-toluyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-58)
3-(2-methyl-3-nitro benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride
(I-59)
3-(3,4-dichloro-benzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-60)
3-(2,4 dichloro benzene formamido-)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-61)
3-(3-chloro-4-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-62)
3-(2,4 difluorobenzene formamido-)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-63)
3-(2,3-dimethoxy benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-64)
3-(3,4-dimethoxy benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-65)
3-(3,4,5-trimethoxy-benzamide base)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride
(I-66)
The preparation method of general formula of the present invention (I) compound is as follows:
Work as 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 the time, synthetic route is as follows:
Work as R
2Representative: 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, C
1～C
6The alkylamino radical alkylsulfonyl time, synthetic route is as follows:
Wherein a, b, c, d, e, f and g represent reaction conditions:
A: reactant is N-bromo-succinimide, N-chlorosuccinimide; Initiator is benzoyl peroxide, azo
Bis-isobutyronitrile.
B: reactant is a trimetazidine; The disacidify agent be potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, saleratus,
Sodium bicarbonate, sodium methylate, sodium ethylate or two or more the mixture among them.
C:(1) reactant is free guanidine.
(2) reactant be ethanolic soln, the hydrogenchloride of methanol solution, the hydrogenchloride of hydrogenchloride ethyl acetate solution,
The tetrahydrofuran solution of hydrogenchloride, the aqueous solution of hydrogenchloride.
D:(1) reactant is a hydrogen; Catalyzer is 5%～10%Pd/C, Raney's nickel, platinum oxide.
Or: (2) reactant is iron powder, zinc powder; Catalyzer is hydrochloric acid, aqueous ammonium chloride solution or both mixtures.
E: reactant is C
1～C
4Alkyl acyl chloride, C
1～C
4Alkyl acid anhydrides, substituted benzoyl chloride, substituted benzoyl acid anhydrides.
F: catalyzer is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate; Solvent be the first alcohol and water mixed solvent,
The mixed solvent of second alcohol and water.
G: reactant is a guanidine; Condensing agent is dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylamino-propyl)
Carbodiimide hydrochloride (EDCI); Catalyzer is 4-Dimethylamino pyridine (DMAP) or 1-hydroxy benzo three
Azoles (HOBT).
Compound I I and V are prepared and get from commercial offers or by literature method.
The NHE1 of part of compounds of the present invention suppress active pharmacological testing and the result as follows:
For measuring The compounds of this invention to the active influence of NHE1, carried out the thrombocyte swelling test (Platelet SwellingAssay, PSA).(Platelet-rich plasma PRP) adds in the Sodium Propionate medium, and cell NHE is activated, H will to take from the thrombocyte enrichment blood plasma of rat
+Be transported to the extracellular, simultaneously Na in the cell
+Increase.This process has caused that the osmotic pressure of cell changes, and in order to recover normal osmotic pressure in the cell, extracellular fluid enters cell, causes cellular swelling.Hematoblastic this swelling has caused that optical density(OD) (OD) reduces.
With the positive contrast of cariporide, the NHE1 inhibition activity of target compound is assessed by PSA.Draw concentration-inhibiting rate curve, determine to suppress the drug level (IC50) of 50% cellular swelling.
People such as laboratory reference Rosskopf (Hypertens.1991,9 (3): method 231～237):
Only get rat eyeground blood 5mL/, add and contain in the plastic test tube of 0.25mLACD solution.The centrifugal 15min of (25 ℃) 150g gets 2/3 blood plasma under the room temperature, i.e. thrombocyte enrichment blood plasma (Platelet-rich plasma, PRP) be used for the thrombocyte swelling test (Platelet Swelling Assay, PSA).Ready thrombocyte must use in 4h.Dissolved with DMSO by the reagent thing, add the standard medium dilution, final DMSO content is all less than 10
-4Mol/L.6 groups of concentration of each drug test are measured three times for every group.(Optical density OD) is measured by many scanning spectrophotometers optical density(OD).175 μ L Sodium Propionate media and 25 μ L given the test agent or standard medium are added 96 orifice plates (1cm path length), be preheated to 37 ℃ after, add 50 μ L PRP.The OD value that is determined at the 550nm place changes, and every point of 7.5s record, writes down 2min altogether.
Method of calculation:
The variation of OD value meets the single index curve, and equation is
Wherein t represents the time, and unit is s; K is OD fall off rate constant, i.e. swelling rate constant.The control group k of dosing not
MaxValue is maximum swelling rate constant.With 10
-5Mol/L cariporide gained k
MinValue is as baseline control, characterizes non-NHE and activates the OD value that causes and change, and thinks that the activity of NHE1 reaches inhibition fully under this concentration.
The OD value that records is taken from right logarithm, is Y-axis with lnOD, and the time is that X-axis is done scatter diagram, and 42s carries out linear regression before getting, and the absolute value of gained slope is k.Deduction k
MinAfter k ' and k
Max' compare and obtain percentage rate constant (k%).To be subjected to the k% value of reagent thing under different concns is Y-axis, and its corresponding concentration is that X-axis is carried out nonlinear regression analysis (Graphpad Prism software) match S curve, and curve is calculated IC
50, promptly reduce the concentration of 50% thrombocyte swelling.
Calculation formula: k%=(k-k
Min)/(k
Max-k
Min) * 100%.
The result is as follows:
Table 1. part of compounds of the present invention suppresses the IC of NHE1
50Value
| Compound | IC 50(×10 -8M) |
| Cariporide | 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 structure of the compound that code name is represented in the last table is seen embodiment or " part of compounds of the present invention ".
The pharmacology test result shows, The compounds of this invention has in various degree restraining effect to rat NHE1, and therefore, compound of the present invention can be used for prevention or the relevant clinical disease of treatment myocardial ischemia-reperfusion injury.These illnesss comprise ischemia symptom, peripheral tissues's organ and limb ischemia, shock, the ischemic of irregular pulse, ventricle fibrosis, myocardial infarction, stenocardia, heart failure, congestive heart failure, myocardial ischemia, periphery and central nervous system ischemia symptom, apoplexy or pour into histoorgan acute and chronic injury, imbalance or the indirect sequelae that causes again.Compound of the present invention can also be used for the preservation of surgical operation and organ transplantation and transplant organ.
The present invention also provides a kind of pharmaceutical composition of treatment myocardial ischemia-reperfusion injury, wherein contains the compound of Formula I and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when benzoyl guanidine derivant of the present invention was used for the treatment of, the human dosage range was 2mg～2000mg/ days.Also can be according to the difference and the disease severity of formulation, using dosage exceeds this scope.
Embodiment
The preparation example of part active compound is as follows:
RY-l type melting point tube; Nicolet Impact410 type infrared spectrometer, the KBr compressing tablet;
1H-NMR BRUKERAM-500 type nuclear magnetic resonance analyser, interior mark TMS; HP1100 type mass spectrograph; Elemental analyser is a Carlo Erba1106 type.
Embodiment 1
The preparation of the preparation 4-bromomethyl-benzoic acid ethyl ester (III-1) of 4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-1)
The benzoyl peroxide of 4-tolyl acid ethyl ester (II-1) 1g (0.006mol), NBS1g (0.006mol) and catalytic amount is mixed with anhydrous tetracol phenixin 50ml, and stirring and refluxing 8h under the illumination filters, and filtrate decompression is concentrated into dried, obtains bromo-derivative III-1 (R
1=R
2=H, X=Br, halo (inferior) methyl and ester group relative position: contraposition) directly drop into the next step.The preparation of 4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-1)
Trimetazidine Hydrochloride 2g (5.9mmol) is mixed with the 40ml anhydrous acetonitrile, add triethylamine 4ml, reaction solution pH is 9, stirring at room, after treating that solid dissolves fully, dropping bromo-derivative III-1 is dissolved in the solution of 20ml anhydrous acetonitrile gained, drips and finishes, and is warming up to back flow reaction 5h, filter, boil off solvent, residue carries out silica gel column chromatography (eluent: sherwood oil/acetone=7: 1), obtain faint yellow oily thing.This oily matter is dissolved in acetone, feeds exsiccant HCl, obtain white solid IV-1 (R
1=R
2=H, trimetazidine link coupled (inferior) methyl and ester group relative position: contraposition) 2.3g (yield 77.8%), m.p.244～246 ℃.
1HNMR(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)，7.34(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)
IV-10.5g (1mmol) and free guanidine 0.5g (8.5mmol) are dropped among the anhydrous tetrahydro furan 20ml, back flow reaction 5h, the pressure reducing and steaming solvent, residue carries out silica gel column chromatography (eluent: sherwood oil: acetone=3: 1), get faint yellow oily thing 0.2g, use acetone solution, feed exsiccant HCl, filter, drying obtains white solid I-10.24g (46.7%), m.p.210～212 ℃.IR(cm
-1)：3362，3143，2990，2975，1703，1614，1603，1576，1499，1457，1270，1107(OCH
3)，812，754；
1HNMR(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＝8.0Hz)，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/z442[M+H]
+；Anal.Calcd.for?C
23H
35Cl
4N
5O
4：C47.03，H6.01，N11.92；Found：C47.05，H6.02，N11.95。
Embodiment 2
The preparation of preparation 3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) the ethyl benzoate hydrochloride (IV-2) of 3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-2)
With 3-tolyl acid ethyl ester (II-2) is raw material, and operation gets white solid IV-2 with III-1 and IV-1.Yield 47.8%, m.p.224～226 ℃.
1HNMR(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)
IV-21g (0.002mol) and free guanidine 1g (0.016mol) are dropped among the absolute Virahol 40ml, be warming up to back flow reaction 3h.Pressure reducing and steaming solvent, residue carry out big plate layer chromatography (developping agent: sherwood oil: acetone=1: 1), faint yellow oily thing 0.4g, with dry acetone dissolving, feed dry HCl, white powder solid I-2 (44.0%), m.p.80～83 ℃.IR(cm
-1)：3365，2931，2837，1706(C＝O)，1602，1568，1496，1463，1421，1280，1201，1099(OCH
3)，808，744；
1HNMR(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/z442[M+H]
+；Anal.Calcd.for?C
23H
35Cl
4N
5O
4：C47.03，H6.01，N11.92；Found：C47.13，H6.12，N11.85。
Embodiment 3
The preparation of 2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-3)
The preparation of 2-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-3)
With 2-tolyl acid ethyl ester (II-3) is raw material, and operation is with III-1 and IV-1, white solid IV-3, yield 56.0%, m.p.208～210 ℃.
1HNMR(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＝8.1Hz)，11.30(2H，bs，N
+H)。
With IV-3 is raw material, operates same I-2, white solid I-3, yield 30.5%, m.p.214～215 ℃.IR(cm
-1)：3367，3157，2925，2854，1712(C＝O)，1658，1600，1500，1460，1436，1274，1099(OCH
3)，802，757；
1HNMR(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/z442[M+H]
+；Anal.Calcd.for?C
23H
35Cl
4N
5O
4：C47.03，H6.01，N11.92；Found：C46.85，H6.00，N11.65。
Embodiment 4
The preparation of 4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-4)
The preparation of 4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) methyl benzoate hydrochloride (IV-4)
With 4-ethylamino benzonitrile acetoacetic ester (II-4) is raw material, and operation is with III-1 and IV-1, white solid IV-4, yield 66.0%, m.p.170～172 ℃.
1HNMR(500MHz，CDCl3)，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)，7.4l(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)。
With IV-4 is raw material, operates same I-2, the white powder solid, yield 52.8%, m.p.235～238 ℃.IR(cm
-1)：3396，2937，2818，1601，1529，1494，1346，1096，791，755；
1HNMR(500MHz，DMSO-d
6)，δ(ppm)：1.26(3H，d，CH3，J＝6.7Hz)，2.25～2.49(8H，m，
)，3.30～3.45(3H，m，CH
2，CH)，3.7l(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/z456[M+H]
+，478[M+Na]
+；Anal.Calcd.for?C
24H
37Cl
4N
5O
4：C47.93，H6.20，N11.65；Found：C47.71，H6.16，N11.59。
Embodiment 5
The preparation of 3-bromo-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-9)
The preparation of 3-bromo-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-9)
With 3-bromo-4-tolyl acid ethyl ester (II-9) is raw material, and operation is with III-1 and IV-1, white solid IV-9, yield 70.1%, m.p.189～192 ℃.
1HNMR(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，J
1＝8.0Hz，J
2＝1.5Hz)，8.07(1H，d，ArH，J＝1.6Hz)，12.75(2H，bs，N
+H)。
With IV-9 is raw material, operates same I-1, dry white solid I-9, yield 72.4%, m.p.244～246 ℃.IR(cm
-1)：3351，3112，2988，1704(C＝O)，1605，1574，1445，1421，1300，1253，1089(OCH
3)，751；
1HNMR(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/z520[M+H]
+；Ana1.Calcd.for?C
23H
34BrCl
4N
5O
4：C41.46，H5.14，N10.51；Found：C41.95，H5.56，N10.39。
Embodiment 6
The preparation of 3-nitro-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-17)
The preparation of 3-nitro-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate (IV-17)
The benzoyl peroxide of 3-nitro-4-methyl ethyl benzoate (II-17) 0.7g (0.003mol), NBS0.7g (0.003mol) and catalytic amount is dropped among the anhydrous tetracol phenixin 20ml, under the illumination, back flow reaction 3 days, filter, decompression is with the solvent evaporate to dryness, obtain bromo-derivative III-17, directly drop into the next step.
Trimetazidine Hydrochloride 1g (0.003mol) is dropped in the 40ml anhydrous acetonitrile, add triethylamine 4ml, reaction solution pH is 9, is stirred to solid under the room temperature and dissolves fully, drip bromo-derivative III-17 (on go on foot gained) and be dissolved in the solution of 10ml anhydrous acetonitrile gained, drip and finish, be warming up to 50 ℃ of reaction 3h, filter, filtrate boils off solvent, residue is with sherwood oil/acetone (7: 1) recrystallization, light yellow crystal IV-171.4g (85.0%), m.p.83～85 ℃.
1HNMR(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＝8.0Hz)，8.17(1H，dd，ArH，J
1＝8.0Hz，J
2＝1.6Hz)，8.44(1H，d，ArH，J＝1.5Hz)。
With IV-17 is raw material, operates same I-1, faint yellow solid, yield 79.0%, m.p.230～233 ℃.IR(cm
-1)：3401，3127，2956，1703(C＝O)，1620，1612，1543，1499，1460，1451，1345，(NO
2)，1160(OCH
3)，748；
1HNMR(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/z487[M+H]
+；Anal.Calcd.for?C
23H
34Cl
4N
6O
6.H
2O：C42.47，H5.58，N12.92；Found：C42.45，H6.07，N12.84。
Embodiment 7
The preparation of 4-nitro-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-18)
The preparation of 4-nitro-3-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-18)
With 3-methyl-4-ethyl nitrobenzoate (II-18) is raw material, and operation is with III-17 and IV-17, free alkali, logical dry HCl salify gets light yellow crystal IV-18 in acetone, yield 75.6%, m.p.205～207 ℃.
1HNMR(300MHz，DMSO-d
6)，δ(ppm)：1.35(3H，t，CH3，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)。
With IV-18 is raw material, operates same I-1, white solid I-18, yield 60.0%, m.p.220～224 ℃.IR(cm
-1)：3377，3137，2994，2840，1710(C＝O)，1602，1568，1531，1452，1350(NO
2)，1274，1101(OCH
3)，854，760；
1HNMR(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]
+；Ana1.Calcd.for?C
23H
33Cl
3N
6O
6.H
2O：C45.00，H5.75，N13.69；Found：C44.71，H5.74，N13.35。
Embodiment 8
The preparation of 3-nitro-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine (I-21)
The preparation of 3-nitro-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) methyl benzoate hydrochloride (IV-21)
With 3-nitro 4-ethylamino benzonitrile acetoacetic ester (II-21) is raw material, and operation is with III-17 and IV-17, after reaction finishes, filter, boil off solvent,, feed exsiccant HCl with acetic acid ethyl dissolution, the adularescent solid is separated out, filter, with the ethyl acetate washing, drying obtains white powder solid IV-21, yield 74.5%, m.p.185～186 ℃.
1HNMR(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＝8.0Hz)，8.53(1H，dd，ArH，J1＝8.0Hz，J
2＝1.5Hz)，8.89(1H，d，ArH，J＝1.5Hz)，12.80(2H，bs，N
+H)。
IV-2183g (0.006mol) and free guanidine 3g (0.05mol) are dropped among the anhydrous tetrahydro furan 60ml, be warming up to backflow, reaction 3h is concentrated into 1/2 volume with reaction solution, with the water dilution of 3 times of amounts, extract with methylene dichloride 15ml * 3, tell organic phase, anhydrous magnesium sulfate drying filters, boil off solvent and obtain yellow crystalline powder I-212.2g (yield 76.1%), m.p.135～136 ℃.IR(cm
-1)：3396，2937，2818，1680，1601，1494，1464，1416，1529，1345(NO
2)，1096(OCH
3)，1009，791，755；
1HNMR(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/z501[M+H
+]，523[M+Na]
+；Anal.Calcd.for?C
24H
32N
6O
6：C57.59，H6.44，N16.79；Found：C57.72，H6.51，N16.81。
Embodiment 9
The preparation of 3-methylsulfonyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine (I-23)
The preparation of 3-methylsulfonyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (IV-23)
The benzoyl peroxide of 3-methylsulfonyl-4-tolyl acid ethyl ester (II-23) 0.1g (0.0004mol), NBS0.1g (0.0005mol) and catalytic amount is dropped among the anhydrous tetracol phenixin 5ml; backflow 10h under the illumination; filter; decompression and solvent recovery; obtain bromo-derivative, not treated direct input the next step.
Trimetazidine Hydrochloride 0.15g (0.0005mol) is dropped among the anhydrous acetonitrile 5ml, drip triethylamine 1ml, be stirred to the solid dissolving, the bromo-derivative of step gained is warming up to backflow on the input, reaction 2h, filter, reclaim solvent, residue carries out silica gel column chromatography (eluent: sherwood oil: ethyl acetate=1: 1), faint yellow solid IV-230.15g (67.8%), m.p.130～137 ℃.
1HNMR(500MHz，CDCl
3)，δ(ppm)：2.23～2.73(8H，m，
)，3.43(5H，s，SO
2CH
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＝8.0Hz)，8.17(1H，dd，ArH，J
1＝8.0Hz，J
2＝2.0Hz)，8.72(1H，d，ArH，J＝2.0Hz)。
IV-230.1g (0.0002mol) and free guanidine 0.1g (0.002mol) are dropped in the 5ml anhydrous tetrahydro furan, be warming up to backflow, reaction 3h, the pressure reducing and steaming solvent, with the dilution of 10m1 water, stirring has solid to separate out, filter, vacuum-drying obtains white solid 0.08g (72.5%), m.p.180～185 ℃.IR(cm
-1)：3450，2999，2936，2803，1678(C＝O)，1607，1524，1497，1370，1303，1146，1095(OCH3)，786；
1HNMR(500MHz，DMSO-d
6)，δ(ppm)：2.33～2.69(8H，m，
)，3.48～3.50(5H，m，SO
2CH
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，J
1＝7.8Hz，J
2＝1.8Hz)，8.74(1H，d，ArH，J＝1.8Hz)；MS(ESI(+)70V)m/z520[M+H]
+，542[M+Na]
+，558[M+K]
+；Anal.Calcd.for?C
24H
33N
5O
6S：C55.48，H6.40，N13.48；Found：C55.54，H6.45，N13.45。
Embodiment 10
The preparation of 3-methylsulfonyl-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) benzoyl guanidine hydrochloride (I-25)
The preparation of 3-methylsulfonyl-4-(1-(4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) ethyl) methyl benzoate hydrochloride (IV-25)
With 3-methylsulfonyl-4-ethylamino benzonitrile acetoacetic ester (II-25) is raw material, and operation is with III-23 and IV-23, white solid IV-25, yield 77.0%, m.p.110～111 ℃.
1HNMR(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
2CH
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，J
1＝8.2Hz，J
2＝1.9Hz)，8.45(1H，d，ArH，J＝1.8Hz)，11.50(2H，bs，N
+H)。
With IV-25 is raw material, operates same I-21, and reaction is directly carried out column chromatography (eluent: sherwood oil: acetone=1: 1～1: 3) with reaction solution after finishing, faint yellow oily thing, be dissolved in dry acetone after, feed exsiccant HCl, white solid I-25, yield 61.0%, m.p.240～243 ℃.IR(cm
-1)：3401，3164，2988，1707(C＝O)，1604，1572，1469，1421，1308，1270，1148，1101(OCH
3)，758；
1HNMR(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/z534[M+H]
+；Anal.Calcd.for?C
25H
40Cl
5N
5O
6S：C41.94，H5.63，N9.78；Found：C41.78，H6.00，N9.62。
Embodiment 11
The preparation of 3-sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-26)
The preparation of 3-sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-26)
With 3-sulfamyl-4-tolyl acid ethyl ester (II-26) is raw material, and operation gets bromo-derivative with III-1 and IV-1.
Trimetazidine Hydrochloride 2.8g and KOH0.8g are dropped among the anhydrous acetonitrile 20ml, stir 1h down at 40 ℃, the bromo-derivative 2g of step gained is dissolved in the solution of 10ml acetonitrile gained in the dropping, drip and finish, be warming up to 70 ℃ of reaction 3h, filter, reclaim solvent, residue dissolves with anhydrous propanone, feeds exsiccant HCl, the adularescent solid is separated out, filter, with washing with acetone, drying, obtain white solid IV-262.0g (55.6%), m.p.241～242 ℃.
1HNMR(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，J
1＝8.0Hz，J
2＝1.7Hz)，8.49(1H，d，ArH，J＝1.7Hz)，9.65(1H，bs，N
+H)，11.75(1H，bs，N
+H)。
With IV-26 is raw material, operates same I-1, faint yellow solid I-26, yield 57.8%, m.p.218～220 ℃.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；
1HNMR(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/z521[M+H]
+，545[M+Na]
+；Anal.Calcd.for?C
23H
36Cl
4N
6O
6S.H
2O：C41.45，H5.44，N12.61；Found：C41.48，H5.76，N12.25.
Embodiment 12
The preparation of 3-third sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine hydrochloride (I-29)
The preparation of 3-third sulfamyl-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) ethyl benzoate hydrochloride (IV-29)
With 3-third sulfamyl-4-tolyl acid ethyl ester (II-29) is raw material, and operation is with III-26 and IV-26, white solid IV-29, yield 56.3%, m.p.229～231 ℃.
1HNMR(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，J1＝8.0Hz，J2＝1.7Hz)，8.69(1H，d，ArH，J＝1.7Hz)，11.35(2H，bs，N
+H)。
With IV-29 is raw material, operates same I-1, faint yellow solid I-29, yield 51.0%, m.p.229～231 ℃.IR(cm
-1)：3363，3110，2964，1698(C＝O)，1610，1584，1454，1334，1159(SO
2)，1106(OCH
3)，738；
1HNMR(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/z563[M+H]
+；Anal.Calcd.for?C
26H
41Cl
3N
6O
6S：C46.46，H6.15，N12.50；Found：C46.68，H6.14，N12.29。
Embodiment 13
The preparation of 3-acetamido-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) benzoyl guanidine (I-40):
The preparation of 3-nitro-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (VII-40)
The benzoyl peroxide of 3-nitro-4-methyl methyl benzoate (V-40) 30g (0.154mol), NBS30g (0.168mol) and catalytic amount is dropped among the anhydrous tetracol phenixin 100ml, backflow 36h under the illumination, filter, the evaporated under reduced pressure solvent, get bromo-derivative (VI-40) crude product, not treated direct input the next step.
Trimetazidine Hydrochloride 40g is dissolved in the 50ml water, stirring and dissolving, sodium hydroxide solution with 40% is regulated pH to 10～11, and ethyl acetate extraction three times (80ml * 3) merges organic layer, three times (150ml * 3) of saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying spends the night, and filters the evaporated under reduced pressure ethyl acetate, the trimetazidine that must dissociate is light yellow oil 24.6g.
Above-mentioned trimetazidine 24.6g (0.092mol) is dissolved in the 35ml anhydrous acetonitrile, the potassium carbonate powder 38.3g (0.28mol) that adds porphyrize, after being dissolved in the bromo-derivative crude product of gained of last step in the 20ml anhydrous acetonitrile, slowly splash in the reaction flask, add the potassium carbonate powder of porphyrize simultaneously, keeping the pH of reaction solution is 8, drip and finish, be warming up to 50 ℃ of reaction 4h, filter, boil off solvent, use ethyl acetate: acetone (1: 5) recrystallization, get faint yellow solid VII-4018.3g (26.1%), m.p.123 ℃～127 ℃.
1HNMR(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＝7.8Hz，)，8.16(1H，dd，ArH，J
1＝1.8Hz，J
2＝8.1Hz)，8.43(1H，d，ArH，J＝1.5Hz)。
The preparation of 3-amino-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (VIII-40)
In the 50ml three-necked bottle, add compound (VII-40) 1g (2.3mmol), be dissolved among the 50% ethanolic soln 12ml, add reduced iron powder 0.9g (16.1mmol), back flow reaction is 0.5 hour under the mechanical stirring, and reacting liquor while hot is filtered, filtrate concentrates, leave standstill crystallization, get faint yellow solid VIII-400.71g (76.3%), m.p.141 ℃～145 ℃.
1HNMR(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/z430.1[M+H]
+。The preparation of 3-acetamido-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (IX-40)
The anhydrous methylene chloride that adds compound (VIII-40) 0.5g (1.2mmol) and 5ml in the 25ml three-necked bottle, stirring and dissolving adds the 0.16ml triethylamine, cryosel is bathed and is cooled to below 0 ℃, slowly the anhydrous methylene chloride solution 2ml of dripping acetyl chloride 0.09g (1.2mmol) drips and finishes, reaction 5min.Reaction solution washs three times with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying filters, steaming desolventizes, yellow oil crude product 0.51g, column chromatography (eluent: sherwood oil: acetone=4: 1) separate white solid IX-400.2g (36.4%), m.p.119 ℃～121 ℃.
1HNMR(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＝7.8Hz)，7.67(1H，d，ArH，J＝7.8Hz)，8.87(1H，s，ArH)。The preparation of 3-acetamido-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid (X-40)
Add 0.2g (0.4mmol) compound (IX-40) in the 25ml eggplant-shape bottle, 60% methanol aqueous solution 10ml is heated to backflow, after the sample dissolution, add salt of wormwood 0.18g (1.3mmol), reacted 2 hours, remove methyl alcohol under reduced pressure, ice bath transfers pH to be about 7 (iso-electric points) with 2% dilute hydrochloric acid solution down, and white solid is separated out, and leaves standstill, filter, infrared lamp is oven dry down, gets white solid 0.16g (84.2%), m.p.127 ℃～128 ℃.
1HNMR(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＝7.8Hz)，8.84(1H，s，ArH)，10.65(1H，s，-CONH-)。
Getting compound (X-40) 0.16g (0.36mmol) is dissolved in the 2ml dry DMF, add I-hydroxybenzotriazole (HOBT) 0.047g (0.36mmol) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) 0.067g (0.36mmol), all after the dissolving, add free guanidine 0.05g (1.08mmol), stirring at room 5 hours.Pour reaction solution into ethyl acetate: in the mixing solutions of water (30ml:20ml), ethyl acetate extraction (20ml * 3).Merge the ester layer, saturated nacl aqueous solution washing (50ml * 3), anhydrous magnesium sulfate drying, filter, the filtrate decompression evaporate to dryness gets yellow oil, and (eluent: ethyl acetate: methyl alcohol: triethylamine=15:1:0.1) separate gets white solid 0.06g (35.3%) to column chromatography.m.p.180℃～182℃。IR(cm
-1)：3439，2935，2829，1670(C＝O)，1596，1569，1530，1419，1340，1274，1095(OCH
3)，1006，787；
1HNMR(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/z499.2[M+H]
+。
Embodiment 14
The preparation of 3-benzoylamino-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid guanidine (I-42)
The preparation of 3-benzoylamino-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (IX-42)
With compound (VIII-40) and Benzoyl chloride is raw material, and the method for similar compound IX-40 gets white solid IX-420.26g (41.9%), m.p.139 ℃～142 ℃.
1HNMR(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-)。
The preparation of 3-benzoylamino-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid (X-42)
With compound (IX-42) is raw material, and the method for similar compound IX-40 gets white solid (X-42) 0.18g (72.0%), m.p.141 ℃～143 ℃.
1HNMR(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-)。
With compound (X-42) is raw material, and the method for similar compound I-40 gets white solid I-42 (33.3%), m.p.220 ℃～
223℃。IR(cm
-1)：3442，3355，3230，2936，2823，1658(C＝O)，1569，1528，1462，1418，1340，1275，1094(OCH
3)，1004，707；
1H?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/z561.2[M+H]
+。
Embodiment 15
The preparation of 3-(2-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid guanidine (I-45):
The preparation of 3-(2-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (IX-45)
With compound (VIII-40) and o-fluoro-benzoyl chloride is raw material, and the method for similar compound IX-40 gets white solid IX-450.38g (59.4%), m.p.95 ℃～97 ℃.
1HNMR(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，-OCH3)，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-)。
The preparation of 3-(2-fluorobenzoyl amido)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid (X-45)
With compound (IX-45) is raw material, and the method for similar compound X-40 gets white solid X-450.3g (83.3%), m.p.130 ℃～132 ℃.
1HNMR (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-)..
With compounds X-45 is raw material, and the method for similar compound I-40 gets white solid I-45 (34.3%), m.p.210 ℃～212 ℃.IR(cm
-1)：3445，3363，3262，2932，2836，1667(C＝O)，1602，1571，1552，1415，1340，1280，1089(OCH
3)，1003，798；.
1HNMR(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/z579.1[M+H]
+。
Embodiment 16
The preparation of 3-(2-methyl-3-nitro benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid guanidine (I-59)
The preparation of 3-(2-methyl-3-nitro benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) methyl benzoate (IX-59)
In the 25ml eggplant-shape bottle, add 2-methyl-3-nitro phenylformic acid 0.4g (2.2mmol) and thionyl chloride 1.9ml, be heated to backflow, add 2 dry DMF, react after 12 hours the thionyl chloride evaporate to dryness, must yellow oil standby.
With compound VIII-40 and the above-mentioned 2-methyl-3-nitro Benzoyl chloride that makes is raw material, and the method for similar compound IX-40 gets white solid IX-590.28g (38.4%), m.p.65 ℃～66 ℃.
1HNMR (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, the-CONH-) preparation of .3-(2-methyl-3-nitro benzoylamino)-4-((4-(2,3,4-trimethoxy benzyl) piperazine-1-yl) methyl) phenylformic acid (X-59)
With Compound I X-59 is raw material, and the method for similar compound X-40 gets white solid X-590.17g (63.0%), m.p.124 ℃～125 ℃.
1HNMR (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-). with compounds X-59 is raw material, and the method for similar compound I-40 gets white solid I-59 (33.4%), m.p.215 ℃～216 ℃.IR(cm
-1)：3451，3403，3250，2933，2824，1668(C＝O)，1604，1577，1528，1430，1343，1276.1095(OCH
3)，1005，788；.
1HNMR(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/z620.4[M+H]
+。
Embodiment 17
Tablet
Get Compound I-25100mg and starch 200mg that embodiment 10 methods make, dextrin 100mg mixes, and makes wetting agent with an amount of 30% ethanol, makes softwood, and ordinary method is granulated, and adds an amount of Magnesium Stearate and mixes, and makes tablet.
Claims (8)
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. 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.
8. the purposes of claim 7 is ischemia symptom, peripheral tissues's organ and limb ischemia, shock, the ischemic of irregular pulse, ventricle fibrosis, myocardial infarction, stenocardia, heart failure, congestive heart failure, myocardial ischemia, periphery and central nervous system ischemia symptom, apoplexy or the histoorgan acute and chronic injury, imbalance or the indirect sequelae that cause of perfusion again with the NHE1 diseases associated wherein.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747292B (en) * | 2009-12-29 | 2011-07-20 | 中国药科大学 | Benzoylguanidine-trimetazidine conjugate, as well as preparation method and medical application thereof |
| CN102161619A (en) * | 2010-02-11 | 2011-08-24 | 成都自豪药业有限公司 | Ferulic acid Jiangtang compound salt as well as preparation method and application thereof |
| CN104447623A (en) * | 2013-09-25 | 2015-03-25 | 中国人民解放军第二军医大学 | Compound capable of protecting myocardium from ischemia reperfusion injury and application of compound |
-
2007
- 2007-10-15 CN CNB2007101332678A patent/CN100567278C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747292B (en) * | 2009-12-29 | 2011-07-20 | 中国药科大学 | Benzoylguanidine-trimetazidine conjugate, as well as preparation method and medical application thereof |
| CN102161619A (en) * | 2010-02-11 | 2011-08-24 | 成都自豪药业有限公司 | Ferulic acid Jiangtang compound salt as well as preparation method and application thereof |
| CN102161619B (en) * | 2010-02-11 | 2013-04-03 | 成都自豪药业有限公司 | Ferulic acid Jiangtang compound salt as well as preparation method and application thereof |
| CN104447623A (en) * | 2013-09-25 | 2015-03-25 | 中国人民解放军第二军医大学 | Compound capable of protecting myocardium from ischemia reperfusion injury and application of compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100567278C (en) | 2009-12-09 |
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