CN102001971A - N-(4-guanidyl butyl) syringoylagmatine derivatives and pharmaceutical applications thereof - Google Patents
N-(4-guanidyl butyl) syringoylagmatine derivatives and pharmaceutical applications thereof Download PDFInfo
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Abstract
The invention relates to N-(4-guanidyl butyl) syringoylagmatine derivatives (I) and (II) and pharmaceutical applications thereof, relating to the field of pharmaceutical chemistry, wherein the definitions of Ar and n are illustrated in a specification. Pharmacology experiments prove that the N-(4-guanidyl butyl) syringoylagmatine derivatives can be used for treating or preventing diseases related to NHE 1 (Na+-H+Exchange isofonn 1), such as arrhythmia, coronary diseases, myocardial infarction, cardiac failure, angina, myocardial ischemia or acute and chronic organ injury caused by reperfusion injury, and the like.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class N-(4-guanidine radicals butyl) cloves amide derivatives, preparation method, and the pharmaceutical composition that contains them.
Background technology
Myocardial ischemia not only can cause stenocardia, when showing effect repeatedly and perfusion takes place again, also can cause myocardial cell's the damage and the disorder of heart function, mainly show as: the necrosis that irregular pulse, blood vessel injury even blood resides, myocardial function are lost, the acceleration ischemic causes the injury of myocardium cell, myocardial cell's oedema etc.Ischemic heart disease is the higher class cardiovascular disorder of sickness rate, diseases such as the myocardial infarction that myocardial ischemia can cause, stenocardia, irregular pulse, and the serious harm mankind's is healthy.At present, clinically diseases such as stenocardia that myocardial ischemia caused, irregular pulse are mainly adopted the symptomatic treatment scheme, the medicine of this respect has antianginal and anti-arrhythmia class medicine.Control medication to myocardial ischemia-reperfusion injury is limited to the fundamental research stage more, and research direction comprises free-radical scavengers, calcium ion retarding agent, neutrophil leucocyte inhibitor, Na
+/ H
+Medicines such as the potassium channel modulating agents of exchanger inhibitor, ATP sensitivity, nitric oxide donors and platelet suppressant drug (referring to Li Junpeng, Wang Yun. the new development of myocardial ischemia-reperfusion injury clinical prevention. medical research magazine .2007,36 (3): 17-19).Therefore, the medicine of ischemic heart disease becomes one of focus of world's drug research.
Na
+/ H
+Ion-exchanger (NHE) is a kind of important transmembrane protein that extensively is present in mammalian cell, and it keeps Na regulating intracellular ph value and cell-volume
+And Ca
2+Stable aspect plays an important role.Up to the present (NHE-1～NHE-10) be identified, wherein NHE-1 is a topmost hypotype in the cardiac muscle of mammal to existing 10 kinds of NHE hypotypes.The undue activation of NHE-1 will participate in forming a series of pathologic process,, stenocardia not normal as the rhythm of the heart, myocardial hypertrophy and heart failure etc.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, demonstrating has good protective action to myocardial ischemia-reperfusion injury.Because NHE-1 is non-activity in the normal myocardium cell, so the NHE1 inhibitor only acts on ischemic area specifically, thereby untoward reaction is less, and potential applicability in clinical practice is widely arranged.Since first NHE inhibitor guanamprazine in 1988 be proved myocardial ischemia-reperfusion injury had provide protection since; this compounds has caused showing great attention to of people and research enthusiasm; the discovery successively of a collection of specificity NHE-1 inhibitor quilt (referring to the thunder woods, Xu Yungen, Hua Weiyi .Na
+/ H
+Ion-exchanger inhibitor progress. Chinese Pharmaceutical Journal .2005,40 (5): 324-327).The NHE-1 selective depressant chemical structure type of having reported is mainly the acylguanidines class; the experimentation on animals result shows that they have good protective action to myocardial ischemia and reperfusion injury; can reduce the myocardial infarction case fatality rate, reduce infarct size and reduce ARR generation.Wherein Cariporide, Eniporide, Zoniporide, Sabiporide have entered the clinical study stage.But the clinical study of Cariporide and Eniporide does not obtain people's expected results (referring to Mentzer R M, Bartels C, Bolli R, et al.Sodium-hydrogen exchange inhibition by Cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting:results of the expedition study.The Annals of Thoracic Surgery.2008,85 (4): 1261-1270), the NHE-1 inhibitor of therefore seeking the new texture type just becomes work highly significant.
China's natural resources of Chinese medicinal materials is abundant, and clinical efficacy is definite, and its effective constituent structure is rich and varied, and the structure uniqueness is one of important source of lead compound.With the middle pharmaceutically active ingredient of determined curative effect as lead compound, utilize Modern Pharmaceutical Chemistry research principle that lead compound is carried out rational drug design, synthetic, therefrom filter out better efficacy, few side effects, new drug that bioavailability is high has important significance for theories and clinical value.
Motherwort Herb is the dry aerial parts of labiate Motherwort Herb (Leonurus heterophyllus Sweet), be the herbal species that Chinese Pharmacopoeia records, be used for treatment of diseases such as menoxenia, postpartum stasis of blood pain, cardiovascular and cerebrovascular diseases, hemopathy clinically.Studies show that in recent years, Motherwort Herb can obviously be improved myocardial ischemia, increase coronary flow, be improved heart function.Its provide protection to heart is owing to suppressed coronary disease patient's platelet aggregation; produce anti thrombotic action; and by remove that oxyradical performance antioxygenation produces (referring to Liu X-H; Xin H; Zhu Y-Z.More than a " mother-benefiting " herb:cardioprotective effect of Herbaleonuri.Acta Physiologica Sinica.2007,59 (5): 578-584).Syringic acid.delta.-guanidinobutyl ester (Leonurine) is the main effective constituent of performance drug action in the Chinese medicine Motherwort Herb, chemistry 4-hydroxyl-3 by name, and 5-dimethoxybenzoic acid 4-guanidine radicals butyl ester, existing synthetic, structural formula is as follows:
Pharmaceutical research shows that syringic acid.delta.-guanidinobutyl ester can improve the survival rate of ischemic myocardial cells, can reduce the rate that spills of lactic acid hydrogen enzyme (LDH), improves the activity of antioxidase, improves the superoxide dismutase activity, reduces the level of lipid peroxide mda.Yet the biological activity of syringic acid.delta.-guanidinobutyl ester and ester derivative thereof is not very strong, its reason may be to connect by ester bond in the molecular structure of syringic acid.delta.-guanidinobutyl ester and ester derivative thereof, ester group is syringic acid and two parts of guanidine radicals butanols by esterase hydrolyzed very easily in vivo, destroy the integrity of syringic acid.delta.-guanidinobutyl ester molecular structure, thereby lost its due biological activity.
Summary of the invention
The present invention with syringic acid.delta.-guanidinobutyl ester and agmatine molecule as guide's thing; according to bioisostere principle and principle of hybridization; with ester bond [N-(4-guanidine radicals butyl) the cloves acid amides in the alternative syringic acid.delta.-guanidinobutyl ester molecular structure of amido linkage; design and synthesize a series of N-(4-guanidine radicals butyl) cloves acid amides (Syringoylagmatine) analog derivative; these derivatives had both kept the platelet aggregation-against of syringic acid.delta.-guanidinobutyl ester; blood viscosity lowering; anti-oxidant; the effect of balance vasomotoricity and to the provide protection of ischemic myocardial cell; with the myocardium protecting action of agmatine, improve the biological activity of compound again.
Structural formula of compound of the present invention such as I or II:
Wherein Ar is phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-hydroxy 3-methoxybenzene base, 4-hydroxyl-3,5-Dimethoxyphenyl, 3-hydroxyl-4-p-methoxy-phenyl, halogenophenyl, 3-pyridyl, 3,4-dioxy methylene radical phenyl, 4-nitrophenyl, naphthalene nucleus-1-base, naphthalene nucleus-2-base, 6-methoxynaphthalene-1-base, 6-methoxynaphthalene-2-base, 6-hydroxyl base naphthalene-1-base, 6-hydroxyl naphthalene-2-base, furans-2-base, furans-3-base, thiophene-2-base or thiene-3-yl-; N=3 or 4.
Ar is preferably 4-hydroxyl-3,5-Dimethoxyphenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxyphenyl, 3-pyridyl in the general formula (I); Ar is preferably 4-hydroxy 3-methoxybenzene base or 4-hydroxy phenyl in the general formula (II).
Pharmacy acceptable salt that forms after formula I of the present invention or II compound and the sour addition and formula I or II compound have same pharmacology curative effect, hydrochloride, hydrobromate, vitriol, phosphoric acid salt, maleate, fumarate, succinate, lactic acid salt, citrate, mesylate, benzene sulfonate, tosilate, tartrate, ferulate or the nicotinate of these pharmacy acceptable salt preferred formula I or II compound.
Compound of the present invention can prepare with the following method:
The definition of Ar is the same.
With of the acid salt reaction of the above-mentioned product that makes, make the pharmacy acceptable salt of N-of the present invention (4-guanidine radicals butyl) cloves acid amides and analogue thereof with the mineral acid, organic acid and the polyprotonic acid that pharmaceutically allow.
The pharmacological testing and the result of following part of compounds of the present invention, compound code name corresponding compound of institute and structural formula are seen embodiment in the pharmacological testing.
One, NHE1 suppresses active mensuration (thrombocyte swelling experiment)
People (Hypertens, 1991,9 (3): method 231-237) such as laboratory reference Rosskopf.
(Platelet Swelling Assay PSA), with the positive contrast medicine of cariporide, carries out external NHE1 to institute's synthesising target compound and suppresses active preliminary screening to adopt the thrombocyte swelling model.The PSA test records the IC of part of compounds of the present invention and positive control drug
50Value sees Table 1.Test-results shows that compound of the present invention has certain NHE1 to suppress active, wherein compound L H
1, LH
2, LH
6, LH
10, LH
11And LH
12Activity significantly be better than syringic acid.delta.-guanidinobutyl ester and positive control drug cariporide.
Table 1 part of compounds of the present invention suppresses the IC of NHE1
50Value
| Compd | IC 50(M) | Compd | IC 50(M) |
| LH 1 | 9.28×10 -9 | LH 11 | 8.67×10 -8 |
| LH 2 | 8.46×10 -8 | LH 12 | 1.15×10 -7 |
| LH 6 | 4.65×10 -8 | LH 13 | 2.01×10 -4 |
| LH 7 | 8.60×10 -7 | LH 16 | 3.24×10 -5 |
| LH 8 | 5.14×10 -7 | LH 18 | 4.17×10 -5 |
| LH 9 | 1.24×10 -4 | Syringic acid.delta.-guanidinobutyl ester | 2.24×10 -5 |
| LH 10 | 1.52×10 -7 | Cariporide | 3.13×10 -7 |
Two .N-(4-guanidine radicals butyl) asafoetide acid amides (LH
1) provide protection of acute myocardial ischemia rat model is tested
Method: adopt coronary artery ligation to prepare the acute myocardial ischemia rat model, observe LH
1Before the rat model operation and operation back 0h, 0.5h, 1h, 2h, 3h, 5h are respectively organized the electrocardiogram(ECG S-T section of rat, myocardial damage scope (necrosis and ischemic scope), mda in the rat blood serum (MDA), serum lactic dehydrogenase (LDH) content, superoxide-dismutase (SOD), the active influence of creatine kinase (CK).
Get healthy Wistar rat, body weight is at 180-220g.With 3.5% chloral hydrate anesthesia (1ml/100g) fixing after, connect XD-7100 type electrocardiograph.Lead with II and to filter out 90 of electrocardiogram(ECG normal rats.Be divided into 6 groups at random: sham operated rats, model group, LH
1Low dose group (2.464mg/kg), LH
1Middle dosage group (4.928mg/kg), LH
1High dose group (9.856mg/kg), positive controls (hydrochloric acid syringic acid.delta.-guanidinobutyl ester 5mg/kg).
Behind the rat successive administration 7 days, etherization, lead with II earlier and write down each treated animal normal ECG, behind the left chest routine disinfection, open chest in a left side the 4th intercostal and expose heart, on the boundary and apex of the heart line of left auricle of heart and pulmonary conus, wear 60 surgical thread ligation, close chest, sham operated rats is only opened chest, expose the heart threading but not ligation coronary artery, postoperative abdominal injection benzylpenicillin sodium is protected from infection.Reject intraoperative death and modeling loser, 10 every group, male and female half and half.
Statistical procedures
The statistics of experimental data adopts SPSS12.0for windows software processing system.Measurement data adopts one-way analysis of variance, uses
Expression.
Electrocardiogram monitoring
Rat inserts limb electrode monitoring standard II and leads electrocardiogram(ECG, before the record operation and after the operation at once, 0.5,1,2,3 and 5h some time point electrocardiogram(ECG.LH
1The influence that coronary ligation is caused acute myocardial ischemia rat ECG-ST section sees Table 2.
Table 2.LH
1To coronary ligation cause acute myocardial ischemia rat ECG-ST section influence (
N=10)
Annotate: compare with sham operated rats,
#P＜0.05,
##P＜0.01; Compare * P＜0.05, * * P＜0.01 with model group
By table 2 as seen: model group and sham operated rats compare, and model group rat ECG ST section significantly improves, and the model copy success is described; Each medication group and model group relatively, each medication group rat ECG ST section significantly decreases after the trend, particularly modeling had significance to descend in 0.5 hour, and LH is described
1Cardiac muscle to rats with myocardial ischemia improves significantly.
The serum enzymatic determination
In operation back 24h, press 1ml/100g body weight intraperitoneal injection of anesthesia rat with 3.5% Chloral Hydrate, abdominal aortic blood then, anticoagulant heparin, centrifugal, get upper plasma, with 754 ultraviolet spectrophotometers in (440,660,532,550nm), blood plasma LDH, CK, MDA and SOD value are surveyed in the by specification operation respectively.LH
1The influence that coronary ligation is caused acute myocardial ischemia rat blood serum MDA, SOD content sees Table 3.LH
1The influence that coronary ligation is caused acute myocardial ischemia rat blood serum CK, LDH content sees Table 4.
Table 3.LH
1To coronary ligation cause acute myocardial ischemia rat blood serum MDA, SOD content influence (
N=10)
Annotate: compare #P＜0.05, ##P＜0.01 with sham operated rats; Compare * P＜0.05, * * P＜0.01 with model group
By table 3 as seen: model group and sham operated rats contrast, the content of MDA significantly raises in the rat blood serum, and SOD content significantly descends, and compares with sham operated rats, and significant difference is arranged, and the model copy success is described; LH
1The contrast of each dosage group and model group can reduce the content of MDA in the rat blood serum, the content of SOD in the rising rat blood serum, in, heavy dose of group effect is obvious.
Table 4.LH
1To coronary ligation cause acute myocardial ischemia rat blood serum CK, LDH content influence (
N=10)
Annotate: compare #P＜0.05, ##P＜0.01 with sham operated rats; Compare * P＜0.05, * * P＜0.01 with model group
By table 4 as seen: compare with sham operated rats, model group CK and LDH content raise, and significant difference is arranged; LH
1Each dosage group CK and LDH content have reduction trend, and particularly a large amount of groups have significant difference; The CK of positive drug group and LDH content and model group relatively have reduction trend.
The mensuration of myocardial infarction rate:
Perform the operation and put to death rat after 24 hours, open chest immediately, take out heart, from coronary sulcus excision atrium, at the bottom of the heart, get four from the apex of the heart altogether, every thick about 0.1cm, with the 1%TTC staining fluid 30min that in 37 ℃ of waters bath with thermostatic control, dyes, separate infarcted region, weigh, calculate the per-cent that infarcted region weight accounts for ventricular weight.LH
1The influence that coronary ligation is caused acute myocardial ischemia rat heart muscle infarct rate sees Table 5.
Table 5.LH
1To coronary ligation cause acute myocardial ischemia rat heart muscle infarct rate influence (
N=10)
Annotate: compare * P＜0.05, * * P＜0.01 with model group
By table 5 as seen: compare LH with model group
1Each dosage group can obviously reduce acute myocardial ischemia rat model myocardial infarction rate, and wherein heavy dose of group relatively has significant difference with model group.
Therefore, compound of the present invention can be used for treatment or prevention and NHE1 diseases associated.The described organ acute and chronic injury that causes with the preferred irregular pulse of NHE1 diseases associated, coronary heart disease, myocardial infarction, heart failure, stenocardia, myocardial ischemia or reperfusion injury.
Experimental study shows, compound of the present invention has significant protective effect to the ischemic myocardium of acute myocardial ischemia rat model due to the coronary artery ligation.
The present invention also provides a kind of pharmaceutical composition, wherein contains formula I of the present invention or formula II compound or its salt and pharmaceutically acceptable carrier.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 compound 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
Embodiment 1
N-(4-guanidine radicals butyl) asafoetide acid amides (Feruloylagmatine) (LH
1) synthetic
1.1N, the two tertbutyloxycarbonyl-methyl-isothioureas of N-synthetic
Reactions steps
In the 250mL three-necked bottle, add successively methyl-isourea (13.9g, 0.1mol), 30% solution of potassium carbonate 50mL, two tertbutyloxycarbonyl acid anhydrides (87.0g, 0.4mol), CH
2Cl
2100mL, behind the room temperature vigorous stirring reaction 24h, TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=4: 1] complete substantially (the product R of detection demonstration reaction
f=0.6), suction filtration, after organic phase water (50mL * 2) washing,, get white solid behind the reclaim under reduced pressure organic solvent through anhydrous sodium sulfate drying, separate with silicagel column, V (sherwood oil): V (ethyl acetate)=5: 1 is an eluent, collects product, behind the decompression and solvent recovery white solid 25.3g, receive 87.2%, m.p.121.5-123.3 ℃.
1.21-amido-4-(N
2, N
3-two tertbutyloxycarbonyls)-the guanidine radicals butane is synthetic
Reactions steps
In the 250mL three-necked bottle, add 1 successively, and the 4-butanediamine (11.0g, 120mmol), CH
2Cl
240mL slowly drips N, N-two tertbutyloxycarbonyl-methyl-isothiourea (8.7g, CH 30mmol)
2Cl
2(40mL) solution drips half earlier fast, slowly drips again, adds in about 2 hours.50 ℃ of insulation reaction 4h then, TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=4: 1] detect and show reaction (raw material R substantially fully
f=0.6, product R
f=0.1), suction filtration adds water 30mL in filtrate, shakes up the back branch and gets organic phase, water CH
2Cl
2(30mL * 3) extraction merges CH
2Cl
2Layer, after water (30mL * 2) washing, through anhydrous sodium sulfate drying, reclaim under reduced pressure CH
2Cl
2After colorless oil, separate with silicagel column, V (chloroform): V (triethylamine)=19: 1 be an eluent, collects product, must colorless oil 7.7g behind the decompression and solvent recovery, yield 77.8%.
1.3 (E)-3-(4-acetoxy-3-p-methoxy-phenyl) is acrylic acid synthetic
Reactions steps
In the 250mL three-necked bottle, add diacetyl oxide 10mL successively, 2 of the vitriol oils, behind the stirring at room 5min, with forulic acid (9.7g 50mmol) adds TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=1: 2] detect and show reaction (raw material R substantially fully
f=0.1, product R
f=0.4), add water 100mL, suction filtration, filter cake are dissolved in the 50mL salt of wormwood saturated aqueous solution, filter, it is about 4 that filtrate transfers to pH with 2mol/L hydrochloric acid, separates out white solid, suction filtration, washing, dry white solid 10.0g, yield 84.7%, m.p.193.5-194.3 ℃ of getting.
1.4 (E)-3-(4-acetoxy-3-p-methoxy-phenyl) vinylformic acid and tosic acid mix the synthetic of acid anhydride
Reactions steps
In the 250mL three-necked bottle, add successively (E)-3-(4-acetoxy-3-p-methoxy-phenyl) vinylformic acid (6g, 25mmol), CH
2Cl
2(40mL) extremely clarification after the stirring at room, add Anhydrous potassium carbonate (5g), TEBACl (0.1g), Tosyl chloride (4.8g then, 25mmol) solution becomes the oyster white suspension liquid, behind the room temperature reaction 2h, TLC[V (sherwood oil 60～90): V (ethyl acetate)=1: 1 is developping agent] detect and show that Tosyl chloride disappears substantially, get solution A, standby.
1.5 (E)-4-(N
2, N
3-two tertbutyloxycarbonyl guanidine butyl)-3-(4-acetoxy-3-p-methoxy-phenyl) acrylamide
Reactions steps
With 1-amido-4-(N
2, N
3-two tertbutyloxycarbonyls)-(7.0g 21mmol) is dissolved in CH to the guanidine radicals butane
2Cl
2(40mL), stir and down this drips of solution to be added in 1.4 the solution A, add back restir reaction 4h under room temperature, TLC[V (sherwood oil 60～90): V (ethyl acetate)=1: 1 be a developping agent] detect and show complete substantially (the product R of reaction
f=0.5), adds water 50mL, divide and get organic phase, water CH
2Cl
2(30mL * 3) extraction merges CH
2Cl
2Layer, after water (20mL * 2) washing, through anhydrous sodium sulfate drying, reclaim under reduced pressure CH
2Cl
2After oily matter, separate with silicagel column, V (sherwood oil): V (ethyl acetate)=3: 2 be an eluent, collects product, must white crystal 7.1g behind the decompression and solvent recovery, yield 61.2%, m.p.112.2-112.7 ℃.
1H-NMR(CDCl
3，400MHz)δ：11.48(s，1H，NH)，8.42(s，1H，NH)，6.86(s，1H，NH)，7.57(d，J＝16.0Hz，1H，ArCH＝)，7.09(d，J＝8.0Hz，1H，ArH)，7.07(s，1H，ArH)，7.02(d，J＝8.0Hz，1H，ArH)，6.45(d，J＝16.0Hz，1H，CH＝)，3.84(s，3H，OCH
3)，3.44(m，4H，2×NCH
2)，2.32(s，3H，CH
3CO)，1.62(m，4H，CH
2CH
2)，1.48(s，9H，C(CH
3)
3)，1.50(s，9H，C(CH
3)
3)；
13C-NMR(CDCl
3，100MHz)δ：168.8，165.2，163.4，156.4，153.2，151.2，140.7，139.6，134.1，123.0，121.5，120.4，111.5，83.2，79.4，55.8，40.3，39.5，28.2，28.0，27.2，25.7，20.6；IR(KBr，cm
-1)υ：3322.0，2977.1，2940.1，1726.7，1633.8，1566.0，1510.9，1414.3，1369.6，1331.2，1264.0，1131.9，846.0，808.8；ESI-MS?for?C
27H
40N
4O
8：m/z548.97(M
++H)。
1.6 hydrochloric acid N-(4-guanidine radicals butyl) asafoetide acid amides (Feruloylagmatine) (LH
1) synthetic
Reactions steps
In the 250mL three-necked bottle, add (E)-4-(N successively
2, N
3-two tertbutyloxycarbonyl guanidine radicals)-(6.5g, 12mmol), (0.6g, 15mmol), water (10mL), solution is faint yellow settled solution to 1-(4-acetoxy-3-methoxyl group cinnamyl amido) butane for methyl alcohol (10mL), sodium hydroxide.Behind the stirring at room 12h, TLC[V (sherwood oil 60～90): V (ethyl acetate)=1: 2 is as developping agent] detect and show (the raw material R that reacts completely
f=0.5, product R
f=0.1), logical then CO
2Regulate pH to 8～9, decompression and solvent recovery adds water 30mL, with ethyl acetate (30mL * 3) extraction, the combined ethyl acetate layer, after water (20mL * 2) washing, through anhydrous sodium sulfate drying, reclaim under reduced pressure is to 15ml, add methyl alcohol 10ml, transfer pH to 2～3 with concentrated hydrochloric acid, after 4h is stirred in backflow, TLC[V (methyl alcohol): V (ethyl acetate)=1: 4] complete substantially (the raw material R of detection demonstration reaction
f=0.6, product R
f=0.1), decompression and solvent recovery, cooling, suction filtration, ethyl acetate washing, the dry yellow crystal 2 .2g of hydrochloric acid N-(4-guanidine radicals butyl) asafoetide acid amides, yield 81.5%, m.p.177.2-177.3 ℃ of getting.
1H-NMR (DMSO-d
6, 400MHz) δ: 8.11 (s, 1H, NH) (D
2O disappears), 7.84 (s, 1H, OH) (D
2O disappears), 7.31 (d, J=16.0Hz, 1H, ArCH=), 7.11 (d, J=1.6Hz, 1H, ArH), 6.98 (dd, J=8.0,1.6Hz, 1H, ArH), 6.81 (d, J=8.0Hz, 1H, ArH), 6.48 (d, J=16.0Hz, 1H, CH=), 3.79 (s, 3H, OCH
3), 3.17 (m, 2H, NCH
2), 3.13 (m, 2H, NCH
2), 1.48 (s, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 165.9,157.5,148.7,148.2,139.2,126.8,121.9,119.5,116.1,111.2,56.0,40.8,38.5,26.8,26.5; IR (KBr, cm
-1) υ: 3331.4,3175.4,2946.0,1662.1,1597.4,1519.5,1428.3,1277.6,1162.8,1206.9,1031.5,876.0,805.8; ESI-MS for C
15H
12N
4O
3: m/z 307.12 (M
++ H).
Embodiment 2
(E)-N-(4-guanidine butyl)-3-(4-hydroxy phenyl) acrylamide (LH
2)
By embodiment 1 similar method operate (E)-N-(4-guanidine butyl)-3-(4-hydroxy phenyl) acrylamide light yellow crystal, m.p.222.6-223.2 ℃;
1H-NMR (DMSO-d
6, 300MHz) δ: 7.90 (s, 1H, OH), 7.46 (s, 1H, NH), 7.19 (d, J=15.9Hz, 1H, ArCH=), 7.08 (d, J=8.4Hz, 2H, ArH), 6.11 (d, J=8.4Hz, 2H, ArH), 6.05 (d, J=15.9Hz, 1H, CH=), 3.16 (m, 2H, NCH
2), 3.09 (m, 2H, NCH
2), 1.46 (s, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 75MHz) δ: 170.7,167.4,157.5,141.1,130.1,119.1,119.0,113.5,40.9,38.4,26.9,26.4; IR (KBr, cm
-1) υ: 3327.5,2934.1,1652.4,1600.0,1446.7,1366.9,1306.9,1222.9,1166.3,1138.4,983.1,831.6; ESI-MS for C
14H
20N
4O
2: m/z 277.29 (M
++ H).
Embodiment 3
N-(4-guanidine butyl)-4-hydroxybenzamide (LH
3)
By embodiment 1 similar method operate N-(4-guanidine butyl)-4-hydroxybenzamide white crystal, m.p.189.3-192.1 ℃;
1H-NMR (DMSO-d
6, 300MHz) δ: 7.87 (s, 1H, NH), 7.50 (d, J=8.4Hz, 2H, ArH), 6.36 (d, J=8.4Hz, 2H, ArH), 3.20 (br s, 2H, NCH
2), 3.12 (br s, 2H, NCH
2), 1.47 (m, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 75MHz) δ: 170.0,167.5,157.6,129.4,118.5,117.3,40.9,38.6,27.2,26.5; IR (KBr, cm
-1) υ: 3333.1,2945.6,2869.0,1679.5,1629.6,1587.2,1545.4,1489.1,1317.6,1286.1,1241.4,1207.5,1171.2,847.5; ESI-MSfor C
12H
18N
4O
2: m/z 251.20 (M
++ H).
Embodiment 4
N-(4-guanidine butyl)-4-hydroxy 3-methoxybenzene methane amide (LH
4)
By embodiment 1 similar method operate N-(4-guanidine butyl)-4-hydroxy 3-methoxybenzene methane amide white crystal, m.p.159.9-160.5 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.48 (s, 1H, NH), 7.90 (s, 1H, OH), 7.39 (s, 1H, ArCH=), 7.30 (d, J=8.0Hz, 1H, ArH), 6.80 (d, J=8.0Hz, 1H, ArH), 3.70 (s, 3H, OCH
3), 3.15 (t, J=6.0Hz, 2H, NCH
2), 3.12 (t, J=6.0Hz, 2H, NCH
2), 1.45～1.37 (m, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.4,157.5,149.8,147.4,125.5,121.1,115.1,111.7,56.1,40.8,38.6,26.6,26.4; IR (KBr, cm
-1) υ: 3347.3,2956.2,2872.1,1690.0,1660.2,1599.5,1547.6,1482.0,1294.1,1223.8,1178.2,1027.0,832.6,775.3; ESI-MS forC
13H
20N
4O
3: m/z 281.16 (M
++ H).
Embodiment 5
N-(4-guanidine butyl)-3-hydroxyl-4-methoxy benzamide (LH
5)
By embodiment 1 similar method operate N-(4-guanidine butyl)-3-hydroxyl-4-methoxy benzamide white crystal, m.p.187.5-188.7 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.37 (s, 1H, NH), 7.93 (s, 1H, OH), 7.51 (s, 1H, NH), 7.26～7.28 (m, 2H, ArH), 6.84 (d, J=8.0Hz, 1H, ArH), 3.69 (s, 3H, OCH
3), 3.10～3.12 (m, 2H, NCH
2), 3.06～3.07 (m, 2H, NCH
2), 1.37～1.44 (m, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.5,157.6,150.4,146.3,127.3,119.1,115.1,111.5,56.0,40.8,31.2,26.6,26.4; IR (KBr, cm
-1) υ: 3427.1,3355.4,2926.8,1624.9,1568.3,1534.9,1495.1,1396.1,1337.7,1296.8,1220.5,1114.7,1018.6,869.0,754.9; ESI-MSfor C
13H
20N
4O
3: m/z 281.17 (M
++ H).
Embodiment 6
N-(4-guanidine butyl)-4-hydroxyl-3,5-dimethoxy benzamide (LH
6)
By embodiment 1 similar method operate N-(4-guanidine butyl)-4-hydroxyl-3,5-dimethoxy benzamide white crystal, m.p.162.5-163.7 ℃;
1H-NMR (DMSO-d
6, 300MHz) δ: 8.92 (s, 1H, NH), 8.42 (s, 1H, OH), 7.66 (s, 1H, NH), 7.18 (s, 2H, ArH), 3.80 (s, 6H, OCH
3), 3.25～3.27 (m, 2H, NCH
2), 3.14 (m, 2H, NCH
2), 1.53 (m, 4H, CH
2CH
2);
13C-NMR (DMSO-d
6, 75MHz) δ: 166.7,157.3,147.9,138.9,124.6,105.5,56.6,41.0,39.1,26.8,26.4; IR (KBr, cm
-1) υ: 3425.6,3125.6,2940.3,1666.2,1592.7,1513.4,1462.6,1415.5,1334.6,1234.9,1127.6,1016.5,865.9,770.5,714.5; ESI-MS for C
14H
22N
4O
4: m/z 311.10 (M
++ H).
Embodiment 7
N-(4-guanidine butyl)-4-methoxy benzamide hydrochloride (LH
7)
By embodiment 1 similar method operate N-(4-guanidine butyl)-4-methoxy benzamide hydrochloride white crystal, m.p.178.9-179.9 ℃;
1H NMR (D
2O, 300MHz) δ: 7.64 (d, J=8.4Hz, 2H, ArH), 6.97 (d, J=8.4Hz, 2H, ArH), 3.78 (s, 3H, OCH
3), 3.29 (br s, 2H, NCH
2), 3.11 (br s, 2H, NCH
2), 1.55 (m, 4H, CH
2CH
2);
13C-NMR (D
2O, 75MHz) δ: 169.7,161.9,161.8,129.0,125.9,113.9,55.5,40.8,39.3,25.9,25.4; IR (KBr, cm
-1) υ: 3289.1,1657.6,1555.3,1505.2,1379.4,1337.1,1302.2,1257.7,1182.6,1114.1,1025.8,966.6,846.9,765.6; ESI-Mass forC
13H
20N
4O
2: m/z265.15 (M
++ H).
Embodiment 8
N-(4-guanidine butyl)-3,4-methylene-dioxy benzamide hydrochloride salt (LH
8)
By embodiment 1 similar method operate N-(4-guanidine butyl)-3,4-methylene-dioxy benzamide hydrochloride salt white crystal, m.p.122.8-123.7 ℃;
1H NMR (D
2O, 300MHz) δ: 7.19 (d, J=7.8Hz, 1H, ArH), 7.06 (s, 1H, ArH), 6.80 (d, J=7.8Hz, 1H, ArH), 5.92 (s, 2H, OCH
2O), 3.25 (br s, 2H, NCH
2), 3.10 (br s, 2H, NCH
2), 1.53 (m, 4H, CH
2CH
2);
13C-NMR (D
2O, 75MHz) δ: 169.0,156.6,150.1,147.4,127.4,122.2,108.1,107.1,102.0,40.9,39.3,25.9,25.5; IR (KBr, cm
-1) υ: 3333.5,2950.5,2873.3,1762.3,1677.9,1635.5,1582.8,1549.4,1493.9,1435.8,1356.3,1290.3,1256.2,1164.8,1119.3,1092.9,1034.1,917.2,758.2; ESI-Mass forC
13H
18N
4O
3: m/z279.21 (M
++ H).
Embodiment 9
N-(4-guanidine butyl)-4-nitrobenzamide hydrochloride (LH
9)
By embodiment 1 similar method operate N-(4-guanidine butyl)-4-nitrobenzamide hydrochloride white crystal, m.p.197.1-198.3 ℃;
1H NMR (D
2O, 300MHz) δ: 7.98 (d, J=8.7Hz, 2H, ArH), 7.63 (d, J=8.7Hz, 2H, ArH), 3.20 (br s, 2H, NCH
2), 3.05 (br s, 2H, NCH
2), 1.47 (m, 4H, CH
2CH
2);
13C-NMR (D
2O, 75MHz) δ: 167.5,156.6,148.9,139.2,128.2,123.6,40.8,39.5,25.7,25.4; IR (KBr, cm
-1) υ: 3322.2,2948.1,1651.5,1524.6,1347.8,1163.3,1108.9,868.5,717.4; ESI-Mass for C
12H
17N
5O
3: m/z280.20 (M
++ H).
Embodiment 10
N-(4-guanidine butyl)-niacinamide hydrochloride (LH
10)
By embodiment 1 similar method operate N-(4-guanidine butyl)-niacinamide hydrochloride white crystal, m.p.201.4-202.3 ℃;
1H NMR (D
2O, 300MHz) δ: 9.11 (s, 1H, ArH), 8.90～8.85 (m, 2H, ArH), 8.17～8.12 (m, 1H, ArH), 3.43 (t, J=6.0Hz, 2H, NCH
2), 3.19 (t, J=6.0Hz, 2H, NCH
2), 1.64～1.61 (m, 4H, CH
2CH
2);
13C-NMR (D
2O, 75MHz) δ: 164.1,156.7,145.1,143.4,140.8,133.7,127.7,40.8,39.8,25.5,25.4; IR (KBr, cm
-1) υ: 3329.4,2940.4,2522.6,1644.0,1533.7,1468.9,1342.1,1301.4,1251.4,1141.8,1046.7,731; ESI-Mass for C
11H
17N
5O
3: m/z236.18 (M
++ H).
Embodiment 11
N-(3-guanidine radicals propyl group) asafoetide acid amides (LH
11) synthetic
11.11-amido-3-(N
2, N
3-two tertbutyloxycarbonyls)-guanidine radicals propane synthetic
Reactions steps
In the 250mL three-necked bottle, add 1 successively, and the 3-propylene diamine (18.0g, 240mmol), CH
2Cl
2Solution 40mL, be warming up to 50 ℃ after, slowly drip N, N-two tertbutyloxycarbonyl-methyl-isothiourea (18.0g, CH 60mmol)
2Cl
2Solution 40mL, behind reaction 4h under this temperature, TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=4: 1] complete substantially (the raw material R of detection demonstration reaction
f=0.6, product R
f=0.1), adds water 30mL, use CH
2Cl
2(30mL * 3) extraction merges CH
2Cl
2Layer, water (30mL * 2) washing be after anhydrous sodium sulfate drying, reclaim under reduced pressure CH
2Cl
2After colorless oil, separate with silicagel column, V (chloroform): V (triethylamine)=19: 1 be an eluent, collects elutriant, must 1-amido-3-(N behind the decompression and solvent recovery
2, N
3-two tertbutyloxycarbonyls)-and guanidine radicals propane 15.3g, yield 75.1%.
11.2 (E)-3-(N
2, N
3-two tertbutyloxycarbonyl guanidine propyl group)-3-(4-acetoxy-3-p-methoxy-phenyl) acrylamide synthetic
Reactions steps
With 1-amido-3-(N
2, N
3-two tertbutyloxycarbonyls)-(7.0g 20mmol) is dissolved in CH to guanidine radicals propane
2Cl
2(40mL), stir down this drips of solution be added in the solution A of embodiment 1.4,, behind the stirring at room 4h, TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=1: 1] detect and show (the product R that reacts completely
f=0.5), adds water 30mL, divide and get organic phase, water CH
2Cl
2(30mL * 3) extraction merges CH
2Cl
2Layer, after water (20mL * 2) washing, through anhydrous sodium sulfate drying, reclaim under reduced pressure CH
2Cl
2After oily matter, separate with silicagel column, V (sherwood oil): V (ethyl acetate)=3: 2 be an eluent, collects elutriant, must white crystal 7.0g behind the decompression and solvent recovery, yield 60.1%, m.p.109.8-111.8 ℃.
1H-NMR(CDCl
3，400MHz)δ：11.46(s，1H，NH)，8.52(s，1H，NH)，7.80(s，1H，NH)，7.73(d，J＝16.0Hz，1H，ArCH＝)，7.09(m，2H，ArH)，7.03(d，J＝8.0Hz，1H，ArH)，6.48(d，J＝16.0Hz，1H，CH＝)，3.89(s，3H，OCH
3)，3.52(m，2H，NCH
2)，3.41(m，2H，NCH
2)，2.33(s，3H，CH
3CO)，1.73(m，4H，CH
2CH
2)，1.52(s，9H，C(CH
3)
3)，1.50(s，9H，C(CH
3)
3)；
13C?NMR(CDCl
3，100MHz)δ：168.8，165.6，162.9，157.3，153.1，151.2，140.6，139.8，134.2，122.9，121.8，120.6，111.4，83.5，79.4，55.8，37.0，35.3，30.1，28.4，28.0，20.6；IR(KBr，cm
-1)υ：3339.4，2973.7，1767.0，1726.6，1645.1，1512.1，1365.2，1331.1，1261.8，1130.4，846.9，807.7；ESI-MS?for?C
26H
38N
4O
8：m/z535.03(M
++H)。
11.3 hydrochloric acid N-(3-guanidine radicals propyl group) asafoetide acid amides (LH
11) synthetic
Reactions steps
In the 250mL three-necked bottle, add (E)-3-(N successively
2, N
3-two tertbutyloxycarbonyl guanidine propyl group)-and 3-(4-acetoxy-3-p-methoxy-phenyl) acrylamide (6g, 11mmol), methyl alcohol (10mL), (0.7g, 17mmol), water (10mL), solution are faint yellow settled solution to sodium hydroxide.Behind the stirring at room 12h, TLC[V (60～90 ℃ of sherwood oils): V (ethyl acetate)=1: 2 is as developping agent] detect and show (the raw material R that reacts completely
f=0.5, product R
f=0.1), logical then CO
2Regulate pH to 8～9, decompression and solvent recovery adds water 30mL, with ethyl acetate (30mL * 3) extraction, the combined ethyl acetate layer, after water (20mL * 2) washing, through anhydrous sodium sulfate drying, reclaim under reduced pressure is to 15ml, add methyl alcohol 10ml, transfer pH to 2～3 with concentrated hydrochloric acid, after 4h is stirred in backflow, TLC[V (methyl alcohol): V (ethyl acetate)=1: 4] complete substantially (the raw material R of detection demonstration reaction
f=0.6, product R
f=0.1), decompression and solvent recovery, cooling, suction filtration, ethyl acetate washing, the dry yellow solid 2.3g that gets, yield is 70.1%, m.p.173.5-174.2 ℃.
1H-NMR (DMSO-d
6, 400MHz) δ: 8.26 (s, 1H, NH) (D
2O disappears), 7.89 (s, 1H, OH) (D
2O disappears), 7.33 (d, J=15.6Hz, 1H, ArCH=), 7.11 (d, J=1.6Hz, 1H, ArH), 6.99 (dd, J=8.4,1.6Hz, 1H, ArH), 6.83 (d, J=8.4Hz, 1H, ArH), 6.52 (d, J=15.6Hz, 1H, CH=), 3.78 (s, 3H, OCH
3), 3.21 (m, 4H, NCH
2), 1.63～1.66 (m, 2H, CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.0,157.5,148.7,148.2,139.3,126.8,121.8,119.4,116.1,111.3,56.0,38.9,36.5,29.2; IR (KBr, cm
-1) υ: 3396.2,3172.6,2923.8,2845.0,1673.4,1643.5,1594.3,1519.5,1470.8,1356.6,1257.4,1166.8,1121.5,1026.9,975.7,847.1,815.7; ESI-MS for C
14H
20N
4O
3: m/z 293.13 (M
++ H).
Embodiment 12
N-(3-guanidine propyl group)-4-hydroxyl-3,5-dimethoxy benzamide (LH
12)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-4-hydroxyl-3,5-dimethoxy benzamide white crystal, m.p.285.2～287 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 7.83 (s, 1H, NH), 7.41 (s, 1H, OH), 7.04 (s, 2H, ArH), 3.57 (s, 6H, OCH
3), 3.01 (m, 4H, NCH
2), 1.48～1.50 (m, 2H, CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.6,157.4,147.5,138.4,123.9,105.4,56.6,38.9,37.0,28.8; IR (KBr, cm
-1) υ: 3401.5,3367.3,3071.5,2933.1,2867.4,1670.2,1645.6,1609.8,1477.0,1330.9,1233.6,1113.0,749.0; ESI-MS for C
13H
20N
4O
4: m/z 297.08 (M
++ H).
Embodiment 13
N-(3-guanidine propyl group)-4-hydroxy 3-methoxybenzene methane amide (LH
13)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-4-hydroxy 3-methoxybenzene methane amide white crystal, m.p.151.8-152.4 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.45 (s, 1H, NH), 7.81 (s, 1H, OH), 7.44 (d, J=1.6Hz, 1H, ArH), 7.36 (dd, J=8.4,1.6Hz, 1H, ArH), 6.82 (d, J=8.4,1H, ArH), 3.78 (s, 3H, OCH
3), 3.26 (br s, 2H, NCH
2), 3.17～3.12 (m, 2H, NCH
2), 1.66～1.71 (m, 2H, CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.7,157.3,149.9,147.5,125.7,121.2,115.2,111.7,56.1,38.9,36.9,29.1; IR (KBr, cm
-1) υ: 3337.7,3174.6,2971.4,1637.8,1605.8,1494.1,1300.1,1265.2,1221.1,1131.4,1027.7,878.3,776.8; ESI-MS forC
12H
18N
4O
3: m/z 267.19 (M
++ H).
Embodiment 14
N-(3-guanidine propyl group)-3-hydroxyl-4-methoxy benzamide (LH
14)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-3-hydroxyl-4-methoxy benzamide white crystal, m.p.153.7-155.1 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.75 (s, 1H, OH), 7.12 (s, H, ArH=), 6.78 (d, J=8.0Hz, 1H, ArH), 6.66 (d, J=8.0Hz, 1H, ArH), 3.68 (s, 3H, OCH
3), 3.25～3.28 (m, 2H, NCH
2), 3.15～3.17 (m, 2H, NCH
2), 1.64～1.67 (m, 2H, CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 168.0,157.7,156.7,153.3,128.4,116.6,111.7,110.8,55.6,38.5,36.7,29.1; IR (KBr, cm
-1) υ: 3377.0,3229.6,2958.4,1666.1,1634.6,1560.3,1495.2,1296.0,1262.1,1222.4,1126.7,1022.8,810.5,755.9; ESI-MS for C
12H
18N
4O
3: m/z 267.15 (M
++ H).
Embodiment 15
N-(3-guanidine propyl group)-4-hydroxybenzamide (LH
15)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-4-hydroxybenzamide white crystal, m.p.170.5-171.7 ℃;
1H-NMR (DMSO-d
6, 400MHz) δ: 8.31 (s, 1H, OH), 8.02 (s, 1H, NH), 7.69 (d, J=8.4Hz, 2H, ArH=), 6.72 (d, J=8.4Hz, 2H, ArH), 3.23～3.27 (m, 2H, NCH
2), 3.08～3.11 (m, 2H, NCH
2), 1.66～1.69 (m, 2H, CH
2);
13C-NMR (DMSO-d
6, 100MHz) δ: 166.7,160.6,157.5,129.5,125.1,115.0,39.5,36.8,29.0; IR (KBr, cm
-1) υ: 3418.5,1637.8,1560.7,1504.6,1411.5,1313.2,1277.5,1249.4,845.7; ESI-MS for C
11H
16N
4O
2: m/z 237.14 (M
++ H).
Embodiment 16
N-(3-guanidine propyl group)-3,4-methylene-dioxy benzamide hydrochloride salt (LH
16)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-3,4-methylene-dioxy benzamide hydrochloride salt white crystal, m.p.130.2-131.4 ℃;
1H NMR (D
2O, 400MHz) δ: 7.20 (d, J=8.4Hz, 1H, ArH), 7.05 (s, 1H, ArH), 6.78 (d, J=8.4Hz, 1H, ArH), 5.92 (s, 2H, OCH
2O), 3.31 (t, J=6.8Hz, 2H, NCH
2), 3.16 (t, J=6.8Hz, 2H, NCH
2), 1.76～1.83 (m, 2H, CH
2CH
2CH
2);
13C-NMR (D
2O, 100MHz) δ: 169.4,156.7,150.2,147.3,127.2,122.2,108.1,107.1,101.9,38.8,37.0,27.7; IR (KBr, cm
-1) υ: 3325.0,1678.8,1547.2,1484.0,1438.7,1358.6,1306.7,1257.6,1173.9,1125.2,1096.5,1037.4,929.5,811.0,758.9,585.9; ESI-Mass for C
12H
16N
4O
3: m/z265.17 (M
++ H).
Embodiment 17
N-(3-guanidine propyl group)-4-methoxy benzamide (LH
17)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-4-methoxy benzamide white crystal, m.p.130.4-131.1 ℃;
1H NMR (DMSO-d
6, 300MHz) δ: 7.87 (d, J=8.1Hz, 2H, ArH), 6.95 (d, J=8.4Hz 2H, ArH), 3.73 (s, 3H, OCH
3), 3.24 (br s, 2H, NCH
2), 3.04 (br s, 2H, NCH
2), 1.63 (m, 2H, CH
2CH
2CH
2);
13C-NMR (DMSO-d
6, 75MHz) δ: 166.3,161.8,158.1,129.4,127.2,113.8,55.7,39.6,37.3,29.2; IR (KBr, cm
-1) υ: 3259.9,1613.8,1549.6,1504.8,1382.2,1257.4,1210.1,1179.8,1031.1,878.9,839.6,768.8,693.7,608.8; ESI-Massfor C
12H
18N
4O
2: m/z 251.24 (M
++ H).
Embodiment 18
N-(3-guanidine propyl group)-4-nitrobenzamide hydrochloride (LH
18)
By embodiment 11 similar approach operate N-(3-guanidine propyl group)-4-nitrobenzamide hydrochloride white crystal, m.p.166.7-168.1 ℃;
1H NMR (D
2O, 300MHz) δ: 8.15 (d, J=7.2Hz, 2H, ArH), 7.78 (d, J=7.2Hz, 1H, ArH), 3.39 (br s, 2H, NCH
2), 3.23 (t, J=6.6Hz, 2H, NCH
2), 1.83～1.87 (m, 2H, CH
2CH
2CH
2);
13C-NMR (
D2O, 75MHz) δ: 168.2,156.7,149.1,139.2,128.2,123.7,38.7,37.2,27.6; IR (KBr, cm
-1) υ: 3406.1,3170.6,2872.4,1722.5,1648.6,1541.5,1520.0,1482.6,1353.4,1301.0,1259.1,1135.2,1053.6,868.0,840.9,715.9; ESI-Mass forC
11H
15N
5O
3: m/z 266.16 (M
++ H).
Claims (7)
1. general formula (I) or compound (II) or its pharmacy acceptable salt:
Wherein Ar is phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-hydroxy 3-methoxybenzene base, 4-hydroxyl-3,5-Dimethoxyphenyl, 3-hydroxyl-4-p-methoxy-phenyl, halogenophenyl, 3-pyridyl, 3,4-dioxy methylene radical phenyl, 4-nitrophenyl, naphthalene nucleus-1-base, naphthalene nucleus-2-base, 6-methoxynaphthalene-1-base, 6-methoxynaphthalene-2-base, 6-hydroxyl base naphthalene-1-base, 6-hydroxyl naphthalene-2-base, furans-2-base, furans-3-base, thiophene-2-base or thiene-3-yl-; N=3 or 4.
2. Ar is a 4-hydroxyl-3 in the compound of claim 1 or its pharmacy acceptable salt, its formula of (I), 5-Dimethoxyphenyl, 4-p-methoxy-phenyl, 3,4-dioxy methylene radical phenyl or 3-pyridyl.
3. Ar is 4-hydroxy 3-methoxybenzene base or 4-hydroxy phenyl in the compound of claim 1 or its pharmacy acceptable salt, its formula of (II).
4. the compound of claim 1 or its pharmacy acceptable salt, wherein said salt are general formula (I) or (II) hydrochloride, hydrobromate, vitriol, phosphoric acid salt, maleate, fumarate, succinate, lactic acid salt, citrate, mesylate, benzene sulfonate, tosilate, tartrate, ferulate or the nicotinate of compound.
5. pharmaceutical composition wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
6. the compound of claim 1 or its pharmacy acceptable salt are used to prepare the purposes of the medicine of treatment or prevention and NHE1 diseases associated.
7. the purposes of claim 6 is the organ acute and chronic injury that irregular pulse, coronary heart disease, myocardial infarction, heart failure, stenocardia, myocardial ischemia or reperfusion injury cause with the NHE1 diseases associated wherein.
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| CN112773784A (en) * | 2021-02-23 | 2021-05-11 | 贵州中医药大学 | Medicine for resisting pressure overload myocardial hypertrophy and ventricular remodeling and application thereof |
| CN115073329A (en) * | 2021-03-12 | 2022-09-20 | 中国海洋大学 | Novel leonurine derivative and preparation method and application thereof |
| CN115317474A (en) * | 2021-05-10 | 2022-11-11 | 中国海洋大学 | Application of benzoylguanidine derivative in preparation of medicine for preventing and treating nervous system diseases or cardiovascular system diseases |
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| CN110872240A (en) * | 2019-12-05 | 2020-03-10 | 天津理工大学 | Method for extracting guanidine alkaloid of scorpion and scorpion alkaloid A and/or scorpion and scorpion alkaloid B in scorpion and medical application |
| CN110872240B (en) * | 2019-12-05 | 2022-03-08 | 天津理工大学 | Method for extracting guanidine alkaloid of scorpion and scorpion alkaloid A and/or scorpion and scorpion alkaloid B in scorpion and medical application |
| CN112773784A (en) * | 2021-02-23 | 2021-05-11 | 贵州中医药大学 | Medicine for resisting pressure overload myocardial hypertrophy and ventricular remodeling and application thereof |
| CN115073329A (en) * | 2021-03-12 | 2022-09-20 | 中国海洋大学 | Novel leonurine derivative and preparation method and application thereof |
| CN115068462A (en) * | 2021-03-12 | 2022-09-20 | 中国海洋大学 | Application of novel leonurine marine derivative in preparation of medicines for preventing and treating inflammatory diseases or allergy |
| CN115073329B (en) * | 2021-03-12 | 2024-01-26 | 中国海洋大学 | Novel leonurine derivative and preparation method and application thereof |
| CN115317474A (en) * | 2021-05-10 | 2022-11-11 | 中国海洋大学 | Application of benzoylguanidine derivative in preparation of medicine for preventing and treating nervous system diseases or cardiovascular system diseases |
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| CN102001971B (en) | 2013-01-02 |
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