CN114539129B - Allylamine bifunctional compound and application thereof - Google Patents

Allylamine bifunctional compound and application thereof Download PDF

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CN114539129B
CN114539129B CN202011291425.4A CN202011291425A CN114539129B CN 114539129 B CN114539129 B CN 114539129B CN 202011291425 A CN202011291425 A CN 202011291425A CN 114539129 B CN114539129 B CN 114539129B
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amino
allyl
methoxyphenyl
propan
yloxy
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CN114539129A (en
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贾立军
李剑
倪帅帅
陈鑫
刘倩
杨晞
张军千
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East China University of Science and Technology
Longhua Hospital Affiliated to Shanghai University of TCM
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East China University of Science and Technology
Longhua Hospital Affiliated to Shanghai University of TCM
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Abstract

The invention discloses an allylamine compound shown in a formula I, wherein: r is R 1 Is substituted or unsubstituted C 6 ～C 10 Aromatic ring group, substituted or unsubstituted C 6 ～C 10 A heteroaromatic ring group; r is R 2 Is H, substituted or unsubstituted C 6 ～C 10 Aromatic ring group, substituted or unsubstituted C 6 ～C 10 A heteroaromatic ring group; r is R 3 Is H, substituted orUnsubstituted aromatic ring group, substituted or unsubstituted heteroaromatic ring group; x is methylene, O, N; n=0 to 1; wherein the substitution is halogen, nitro, ester, methoxy, trifluoromethyl, amino, C 1 ‑C 3 Alkyl or C 3 ～C 8 Cycloalkyl groups. The invention also discloses application of the allylamine compound or pharmaceutically acceptable salt thereof and a medicinal composition thereof in preparing antitumor and heart protecting difunctional medicaments.
Figure DDA0002783888290000011

Description

Allylamine bifunctional compound and application thereof
Technical Field
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to medical application of allylamine difunctional compounds.
Background
Patients with tumors are susceptible to serious cardiotoxicity related disorders during the course of treatment with antitumor drugs taken for medium and long periods of time, such as: fatal cardiovascular diseases (Cardiovascular disease, CVD) such as cardiac injury, myocardial infarction and heart failure, which lead to the development of tumor-associated cardiotoxic disorders, have become the second leading cause of morbidity and mortality in Cancer survivors (Cancer survivors). However, in the face of the critical clinical problem to be solved, there are currently few reports on the development of targeted new drugs. Although the pathological manifestations of the tumor combined cardiotoxic symptoms are complex and changeable, the pathogenesis is clear and can be categorized into two aspects: cardiotoxicity related disorders caused by intrinsic defects in antitumor drug targets, such as: angiogenesis related targets ErbB2, VEGFR and the like participate in the growth of myocardial cells by regulating intracellular phosphorylation, and when antitumor drugs inhibit the targets in heart tissues, normal myocardial cell apoptosis and necrosis can be caused; the pan-target activity of antitumor drug structures induces cardiotoxicity related disorders such as: in the anti-tumor process, the chemotherapeutic drugs such as doxorubicin and the like simultaneously influence various signal paths in myocardial cells, continuously activate intracellular oxidative stress and free radical enrichment, and cause myocardial injury and heart function decline. These two causes of disease cause that single functional therapeutic drugs (cardioprotective drugs or antitumor drugs) cannot fully treat the tumor complicated with cardiotoxic diseases, and the simple multi-drug combination brings the problems. Obviously, the research and development of high-efficiency low-toxicity single-molecule difunctional therapeutic drugs is a potential way for breaking through the dilemma, and the core of the drugs is anti-tumor, and the key point is difunctional drug effect (anti-tumor and cardiotoxicity related disease treatment). Specifically, the single drug molecule not only has high-efficiency and low-toxicity anti-tumor effect, but also has the treatment function of cardiotoxicity related diseases, can be singly used for playing the dual-function drug effect, and can effectively relieve the cardiotoxicity related diseases induced by other anti-tumor drugs during cooperative treatment. The key points for developing the single-molecule difunctional drugs are as follows: firstly, a safer and efficient novel anti-tumor target/mechanism is discovered, and the risk of cardiotoxicity related symptoms caused by the intrinsic defects of the target is reduced; then find out good candidate new medicine to this target/mechanism, make it not merely cause the relevant disease of cardiotoxicity in the course of tumor treatment, but possess good heart to protect the pharmacodynamic effect. Unfortunately, there is no report of such a bifunctional pharmacodynamic small molecule with anti-tumor and cardioprotection at present.
Neddylation modification is performed by transferring ubiquitin-like protein Nedd8 (Neuronal precursor cell-expressed developmentally down-regulated protein 8) to a conjugated enzyme E2 (UBE 2M or UBE 2F) under the catalysis of an activating enzyme E1 (NAE) in the presence of ATP, and performing a Neddylation modification on a related substrate under the catalysis of a main ligase E3 (Rbx 1 or Rbx 2). Among them, the family of the proteins of the Cullin (the main subunits are Cullin1, 2, 3, 4a/b, 5, 7) is not only the main regulatory substrate of the nedzylation modification pathway, but also one of the important backbone proteins of the ubiquitin ligase family of the CRL (Cullin-RING ligases). CRLs can specifically regulate degradation of intracellular 20% of ubiquitin-related protein substrates, and dysfunction can lead to development of various tumors. Meanwhile, the neddylation modification is mainly overactivated in tumor (including various solid tumors) tissues, and the related modification substrates are only more than ten (mainly the proteins of the cullin family), so that the novel tumor targeting modified substrate has natural tumor targeting selectivity. Earlier studies of the subject group and other groups have proved that the inactivation of neddylation can block the modification of the cullin family, further regulate and control the accumulation of various oncoproteins, can specifically induce the apoptosis, cycle retardation and aging of various tumor cells, achieves the aim of killing tumors in multiple ways and high efficiency, is a tumor treatment target with great potential and complicated with cardiotoxicity, and is also a main action mechanism of the drug effect of the compound.
In the invention, thousands of old drugs on the market are screened by utilizing a self-built screening platform of the netdylation inhibitor in the early stage, so that the original antihypertensive drug is found, and the beta-receptor blocker carvedilol shows good netdylation pathway inhibition activity and in-vivo and in-vitro antitumor activity. Notably, the cardioprotective activity of the beta-receptor blocker carvedilol is also clinically practiced, which provides a reliable opportunity for the us to find a class of small molecule drugs with both anti-tumor and cardioprotection functions on the basis of the optimized modification of the carvedilol lead structure. In conclusion, the invention develops the related antitumor small molecular compound through targeting the nedzylation pathway, skillfully designs the related antitumor small molecular compound to ensure that the compound not only has antitumor activity, but also has the heart injury protection and treatment functions, plays the single-molecule double-function pharmacodynamic activity, and has creativity and novelty.
Disclosure of Invention
The invention aims to provide an allylamine compound shown in a formula I, and provides a difunctional medical application of the allylamine compound or pharmaceutically acceptable salt thereof and a medicinal composition thereof in preventing, delaying or treating tumor combined cardiotoxicity.
To achieve the above object, the present invention provides a compound having the formula I:
Figure GDA0004214566460000031
in formula I:
R 1 is substituted or unsubstituted C 6 ～C 10 Aromatic ring group, substituted or unsubstituted C 6 ～C 10 A heteroaromatic ring group;
R 2 is H, substituted or unsubstituted C 3 ～C 8 Cycloalkyl, substituted or unsubstituted C 6 ～C 10 Aromatic ring group, substituted or unsubstituted C 6 ～C 10 A heteroaromatic ring group;
R 3 is H, a substituted or unsubstituted aromatic ring group, a substituted or unsubstituted heteroaromatic ring group;
x is methylene, O or N;
n＝0～1；
wherein the substitution is halogen, nitro, ester, methoxy, trifluoromethyl, amino, C 1 -C 3 Alkyl or C 3 ～C 8 Cycloalkyl groups.
In the allylamine compound of the present invention, R 1 Preferably substituted phenyl, R 2 Preferably substituted phenyl, R 3 Preferably substituted phenyl, and X is preferably N or absent.
In the allylamine compound, the allylamine compound is preferably (+ -) -1- (9H-4-carbazolyloxy) -3- (2-methoxyanilino) -2-propanol; (E) -1- (((9H-carbazol-2-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-1-yloxy) propan-2-ol, (E) -1- (((9H-carbazol-1-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-2-yloxy) propan-2-ol, (E) -1- (((1H-indol-4-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-24); (E) -5- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propan-2H) -3, 4-dihydroquinolin-2 (1H) ) -a ketone; (E) -1- (((1H-indol-5-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3-phenoxypropan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-6-acyloxy) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (3- (phenylamino) phenoxy) propan-2-ol, (E) -1- ([ [1,1' -biphenyl ] -4-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) acetamide, and (E) -1- (((3- (2-methoxyphenyl) amino) propan-2-ol) Allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol; (E) -1- ([ [1,1' -biphenyl ] -3-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol; (E) -1- ([ [1,1' -biphenyl ] -2-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol; (E) -N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) benzamide; (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-7-yloxy) propan-2-ol, (E) -1- (3- (dimethylamino) phenoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (4-cyclohexylphenoxy) -3- ((3- (2- (methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (furan-2-ylmethoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -6- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) -3, 4-dihydroquinolin-2 (1H) -one, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (4-propylphenoxy) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) Group) allyl) amino) -3- (pyridin-4-yloxy) propan-2-ol; (E) Preparation of (E) -1- (((3- (4-chlorophenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol, or (E) -1- (((3- (4-chlorophenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol.
According to an embodiment, the preparation method of the allylamine compound with the structure of the general formula I provided by the invention comprises the following steps:
Figure GDA0004214566460000041
the ethylene oxide is reacted withDerivative I A Dissolving in tetrahydrofuran, stirring for a while, slowly dripping allylamine intermediate I B Tetrahydrofuran solution of (a); after the addition, the reaction is carried out under reflux for 4 hours, and the TLC plate tracks the reaction progress; evaporating the solvent under reduced pressure, adding water, extracting with ethyl acetate for three times, drying with anhydrous magnesium sulfate, filtering, concentrating, and purifying by column chromatography to obtain allylamine compound I.
According to an embodiment, the present invention further provides the use of an allylamine compound, or a pharmaceutically acceptable salt thereof, preferably hydrochloride, phosphate, sulfate, acetate, trichloroacetate, lactate or citrate, or a pharmaceutical composition thereof, preferably an anthracycline antitumor drug, a nucleoside antitumor drug, a kinase inhibitor, a platinum antitumor drug, or an antitumor drug capable of inducing cardiac injury, which has been reported so far, in the preparation of an antitumor and cardioprotection dual-function drug.
In the medical application of the allylamine compound, or the pharmaceutically acceptable salt and the pharmaceutical composition thereof, the tumor is lung cancer, liver cancer, gastric cancer, breast cancer, intestinal cancer or a tumor or a disease with highly activated modification by nedzylation; the heart injury is a cardiovascular disease or a heart injury related condition caused by taking other antitumor drugs, and the heart injury related treatment condition is myocardial injury, heart failure or myocardial infarction.
In the medical application of the allylamine compound, or the pharmaceutically acceptable salt and the medicinal composition thereof, the compound shown in the formula I plays an anti-tumor role by blocking a ubiquitination Neddylation pathway; the beta-adrenergic receptor blocking activity and anti-inflammatory and antioxidant activity of the compound shown in the formula I play a heart protection function; the external manifestations of the anti-tumor function and the heart protection function are obvious anti-tumor activity and heart protection activity respectively.
Compared with the prior art, the compound has allylamine chemical micromolecules with brand new structures, and the design idea is to take the original antihypertensive drug beta-receptor blocker carvedilol as a lead compound to carry out structural transformation and optimization, so as to obtain the difunctional pharmacodynamic molecule with both anti-tumor activity and heart protection activity. The allylamine chemical small molecules are evaluated through proliferation inhibition activity experiments of various tumor cells in vitro; in vitro multiple myocardial cell injury repair evaluation; evaluating cell level neddylation inhibitory activity; evaluating in vivo anti-tumor activity by a mouse transplantation tumor experiment; after the therapeutic activity of the mice with myocardial injury induced by doxorubicin is evaluated, the remarkable difunctional activity of the molecules is fully proved.
Drawings
FIG. 1 shows that both I-15 and I-17 exhibit significant TNF- α inhibitory activity, comparable to the positive drug carvedilol.
FIG. 2 shows that both I-15 and I-17 exhibit significant myocardial cell injury protective activity.
FIG. 3 shows that both I-15 and I-17 exhibit significant TNF- α inhibitory activity, comparable to the positive drug lenalidomide.
Figure 4 shows that I-15 exhibits significant in vivo anti-tumor activity.
Figure 5 shows that I-15 exhibits significant myocardial injury protective activity in vivo.
Detailed Description
The invention is further illustrated in the following, in conjunction with the accompanying drawings and detailed embodiments. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Preparation of (+ -) -1- (9H-4-carbazolyloxy) -3- (2-methoxyphenylacrylamide) -2-propanol (I-01):
Figure GDA0004214566460000061
226mg of 9H-4-carbazolylmethylethylene oxide were dissolved in5 ml of tetrahydrofuran, and 162mg of 2-methoxyphenylpropene dissolved in tetrahydrofuran was added with stirringAmine was refluxed for 4 hours, and the reaction progress was followed by TLC plates; the solvent was distilled off under reduced pressure, water was added thereto, extraction was performed three times with ethyl acetate, drying over anhydrous magnesium sulfate, filtration and concentration, and purification by column chromatography gave the pale yellow target compound in 57% yield. Further dissolving 0.01 mol of the compound in 10 ml of acetone, stirring at normal temperature for dissolution, and adding a small amount of THF for dissolution assistance until the compound is completely dissolved; slowly introducing hydrogen chloride gas, separating out solid from the reaction liquid, filtering, and air drying to obtain white solid powder. 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.21(d,1H),7.43(d,2H),7.30-7.19(m,3H),7.05(m,2H),6.95(d,2H),6.87(t,1H),6.79(d,1H),6.67(d,1H),6.31(m,1H),5.15(s,1H),4.25(m,3H),3.77(s,3H),3.43(d,2H),2.84(m,2H).HRMS(EI)m/zcalcd C 25 H 26 N 2 O 4 [M] + 403.2022,found 403.2021.
Example 2
(E) Preparation of 1- (((9H-carbazol-2-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-02):
Figure GDA0004214566460000071
except for changing 9H-4-carbazolyl methyl ether ethylene oxide into 9H-2-carbazolyl methyl ether ethylene oxide, the other required raw materials, reagents and preparation methods were the same as in example 1, and the yield was 53%. The compound was a white solid. 1 H NMR(400MHz,Chloroform-d)δ9.40(s,1H),8.13–8.07(m,1H),7.89(d,J＝8.4Hz,1H),7.52(dd,J＝7.4,2.1Hz,1H),7.45(ddd,J＝7.7,1.5,0.7Hz,1H),7.34(td,J＝7.4,1.2Hz,1H),7.25(dtd,J＝17.3,7.7,1.7Hz,2H),7.08(d,J＝2.4Hz,1H),7.01(td,J＝7.6,1.2Hz,1H),6.93(dd,J＝8.0,1.2Hz,1H),6.89–6.82(m,2H),6.08(dt,J＝15.2,4.0Hz,1H),4.10–4.04(m,1H),3.90(t,J＝5.2Hz,2H),3.87(s,2H),3.55(d,J＝5.7Hz,1H),3.47(ddd,J＝5.1,3.9,1.0Hz,2H),3.32(tt,J＝6.7,5.3Hz,1H),2.96–2.82(m,2H).HRMS(EI)m/z calcd C 25 H 26 N 2 O 3 [M] + 403.2022,found403.2023.
Example 3
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-1-yloxy) propan-2-ol (I-03):
Figure GDA0004214566460000072
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 1-naphthylmethylethylethylene oxide, and the yield was 81%. The compound was a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.19(dd,J＝7.7,1.3Hz,1H),7.77(dt,J＝8.0,1.5Hz,1H),7.59–7.50(m,2H),7.48–7.39(m,2H),7.36(t,J＝7.8Hz,1H),7.27(td,J＝7.9,1.5Hz,1H),7.01(td,J＝7.6,1.2Hz,1H),6.96–6.79(m,3H),6.08(dt,J＝15.2,4.0Hz,1H),4.09(s,1H),4.09–3.98(m,3H),3.87(s,2H),3.55(d,J＝5.7Hz,1H),3.47(ddd,J＝5.1,4.0,1.0Hz,2H),3.32(tt,J＝6.7,5.3Hz,1H),2.96–2.82(m,2H).HRMS(EI)m/z calcd C 23 H 25 NO 3 [M] + 364.1913,found364.1914.
Example 4
(E) Preparation of 1- (((9H-carbazol-1-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-04):
Figure GDA0004214566460000081
the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 9H-1-carbazolylmethylethylene oxide, and the yield was 41%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.20(d,J＝7.8Hz,1H),7.47–7.41(m,2H),7.34–7.26(m,2H),7.22(s,1H),7.06(dd,J＝8.0,6.5Hz,2H),6.98(d,J＝8.2Hz,1H),6.89(t,J＝7.5Hz,1H),6.79(d,J＝16.1Hz,1H),6.69(d,J＝7.9Hz,1H),6.30(dt,J＝16.0,6.1Hz,1H),5.17(s,1H),4.18(dt,J＝13.8,6.2Hz,3H),3.77(s,3H),3.43–3.39(m,2H),2.92(dd,J＝11.9,4.2Hz,1H),2.80(dd,J＝12.0,6.5Hz,1H).HRMS(EI)m/z calcd C 25 H 26 N 2 O 3 [M] + 403.2022,found403.2023.
Example 5
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-2-yloxy) propan-2-ol (I-05):
Figure GDA0004214566460000082
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 2-naphthylmethylethylethylene oxide, and the yield was 65%. The compound was a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.82–7.72(m,2H),7.71–7.61(m,1H),7.54–7.42(m,3H),7.27(td,J＝7.9,1.5Hz,1H),7.06–6.97(m,2H),6.96–6.90(m,2H),6.86(dq,J＝15.2,0.9Hz,1H),6.08(dt,J＝15.2,4.0Hz,1H),4.06(dq,J＝5.7,5.0Hz,1H),3.92(t,J＝4.8Hz,2H),3.87(s,3H),3.55(d,J＝5.7Hz,1H),3.47(ddd,J＝5.1,4.0,1.0Hz,2H),3.32(tt,J＝6.7,5.3Hz,1H),2.96–2.82(m,2H).HRMS(EI)m/z calcd C 23 H 25 NO 3 [M] + 364.1913,found 364.1914.
Example 6
(E) Preparation of 1- (((1H-indol-4-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-06):
Figure GDA0004214566460000091
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the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 3-indolylmethylethylene oxide, and the yield was 64%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),7.45(d,J＝7.1Hz,1H),7.21(dd,J＝17.2,9.8Hz,2H),6.94(dt,J＝28.6,6.6Hz,4H),6.80(d,J＝16.1Hz,1H),6.55–6.38(m,2H),6.29(dt,J＝15.9,6.1Hz,1H),5.11(s,1H),4.03(s,3H),3.41(d,J＝6.1Hz,4H),3.17(s,1H),2.83(d,J＝10.6Hz,1H),2.76–2.68(m,1H).HRMS(EI)m/z calcd C 21 H 24 N 2 O 3 [M] + 353.1865,found 353.1866.
Example 7
(E) Preparation of 5- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) -3, 4-dihydroquinolin-2-one (I-07):
Figure GDA0004214566460000092
the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 5- (3, 4-dihydroquinolin-2 (1H) -one) ylmethylethylene oxide, and the yield was 44%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ10.12–10.02(m,1H),8.04(ddd,J＝77.0,5.9,3.3Hz,1H),7.50(dd,J＝7.7,1.7Hz,1H),7.34–7.24(m,1H),7.13(td,J＝8.1,3.9Hz,1H),7.07–7.01(m,1H),6.97(t,J＝7.6Hz,1H),6.93–6.82(m,1H),6.65(d,J＝8.2Hz,1H),6.33(dt,J＝16.1,6.3Hz,1H),5.23(d,J＝42.1Hz,1H),4.00(qt,J＝9.6,5.3Hz,4H),3.84(d,J＝6.6Hz,3H),2.93–2.72(m,5H),2.50–2.30(m,3H).HRMS(EI)m/z calcd C 22 H 26 N 2 O 4 [M] + 383.1971,found 383.1972.
Example 8
(E) Preparation of 1- (((1H-indol-4-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-08):
Figure GDA0004214566460000101
the required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 3-indolylmethylethylene oxide, and the yield was 53%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H),7.44(td,J＝7.0,6.3,1.6Hz,1H),7.30–7.18(m,3H),7.08–6.96(m,2H),6.90(t,J＝7.4Hz,1H),6.80–6.65(m,2H),6.35–6.22(m,2H),4.96(s,1H),4.02–3.84(m,3H),3.79(d,J＝2.4Hz,3H),3.36(d,J＝7.5Hz,2H),2.73(dd,J＝11.8,4.3Hz,1H),2.62(dd,J＝11.8,6.4Hz,1H).HRMS(EI)m/z calcd C 21 H 24 NO 3 [M] + 353.1865,found353.1867.
Example 9
(E) Preparation of-1- (((3- (2-methoxyphenyl) allyl) amino) -3-phenoxypropan-2-ol (I-09):
Figure GDA0004214566460000102
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to anisoylethylene oxide, and the yield was 82%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(dd,J＝7.7,1.7Hz,1H),7.25(dtd,J＝20.5,7.2,2.0Hz,3H),6.99(d,J＝8.2Hz,1H),6.95–6.85(m,4H),6.77(d,J＝16.1Hz,1H),6.27(dt,J＝16.1,6.2Hz,1H),5.06(s,1H),4.01–3.84(m,3H),3.79(s,3H),3.38–3.35(m,2H),2.74(dd,J＝11.9,4.4Hz,1H),2.64(dd,J＝11.9,6.3Hz,1H).HRMS(EI)m/z calcd C 19 H 23 NO 3 [M] + 314.1756,found 314.1757.
Example 10
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-6-yloxy) propan-2-ol (I-10):
Figure GDA0004214566460000111
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 5-quinolinylmethylethylene oxide, and the yield was 53%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ8.73(dd,J＝4.2,1.7Hz,1H),8.23(dd,J＝8.4,1.7Hz,1H),7.91(d,J＝8.9Hz,1H),7.50–7.43(m,2H),7.42–7.37(m,2H),7.22(s,1H),7.03–6.94(m,1H),6.90(t,J＝7.5Hz,1H),6.77(d,J＝16.1Hz,1H),6.28(dt,J＝16.1,6.2Hz,1H),5.11(s,1H),4.17–4.13(m,1H),4.05(d,J＝6.2Hz,1H),4.02–3.99(m,1H),3.78(s,3H),3.36(d,J＝1.4Hz,2H),2.85–2.72(m,1H),2.68(dd,J＝11.8,6.2Hz,1H).HRMS(EI)m/z calcd C 22 H 24 N 2 O 3 [M] + 365.1865,found 365.1866.
Example 11
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (3- (anilino) phenoxy) propan-2-ol (I-11):
Figure GDA0004214566460000112
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 3-anilinophenylmethylethylethylene oxide, and the yield was 49%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ8.15(s,1H),7.45(dd,J＝7.6,1.8Hz,1H),7.27–7.19(m,3H),7.15–7.04(m,3H),6.99(dt,J＝8.1,1.5Hz,1H),6.91(td,J＝7.5,1.1Hz,1H),6.83(d,J＝1.3Hz,2H),6.67–6.57(m,2H),6.40(dd,J＝7.8,2.4Hz,1H),6.33–6.14(m,1H),5.19(s,1H),3.98–3.88(m,2H),3.85(d,J＝3.6Hz,1H),3.78(d,J＝3.9Hz,3H),3.43(d,J＝6.3Hz,2H),2.83–2.75(m,1H),2.74–2.64(m,1H).HRMS(EI)m/z calcd C 25 H 28 N 2 O 3 [M] + 405.2178,found 405.2177.
Example 12
(E) Preparation of-1- ([ [1,1' -biphenyl ] -4-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-12):
Figure GDA0004214566460000121
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 1,1' -biphenylmethylethylethylene oxide, and the yield was 61%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.64–7.55(m,4H),7.48–7.37(m,3H),7.34–7.26(m,1H),7.22(td,J＝7.8,1.7Hz,1H),7.07–6.95(m,3H),6.91(q,J＝8.1,7.4Hz,1H),6.77(d,J＝16.2Hz,1H),6.28(dt,J＝16.0,6.2Hz,1H),5.06(s,1H),4.09–3.88(m,3H),3.79(s,3H),3.37(s,2H),2.71(d,J＝4.2Hz,1H),2.68–2.59(m,1H).HRMS(EI)m/z calcd C 25 H 27 NO 3 [M] + 390.2069,found 390.2070.
Example 13
(E) Preparation of N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) acetamide (I-13):
Figure GDA0004214566460000122
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 3-acetamidophenylmethylethylethylene oxide, and the yield was 48%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),7.45(dd,J＝7.7,1.7Hz,2H),7.31(t,J＝2.2Hz,1H),7.26–7.13(m,2H),7.07(dd,J＝7.6,1.8Hz,1H),6.98(dd,J＝8.3,1.1Hz,1H),6.90(td,J＝7.5,1.1Hz,1H),6.76(dd,J＝16.0,1.6Hz,1H),6.60(dd,J＝7.9,2.5Hz,1H),6.27(dt,J＝16.1,6.2Hz,1H),4.99(d,J＝46.4Hz,1H),3.97–3.87(m,2H),3.79(s,3H),3.36(s,2H),2.71(dd,J＝12.1,4.7Hz,1H),2.63(dd,J＝11.8,6.4Hz,1H),2.01(d,J＝13.7Hz,3H).HRMS(EI)m/z calcd C 21 H 26 N 2 O 4 [M] + 371.1971,found 371.1970.
Example 14
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol (I-14):
Figure GDA0004214566460000131
the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 3-anilinophenylmethylethylethylene oxide, and the yield was 54%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.81(s,1H),7.45(dd,J＝7.7,1.7Hz,1H),7.25–7.19(m,1H),7.15(t,J＝7.8Hz,2H),7.05–6.95(m,3H),6.94–6.83(m,5H),6.70(t,J＝7.3Hz,1H),6.27(dt,J＝16.0,6.1Hz,1H),4.97(s,1H),3.88(d,J＝23.5Hz,3H),3.79(s,3H),3.17(d,J＝3.9Hz,2H),2.70(dd,J＝12.0,4.4Hz,1H),2.61(dd,J＝11.9,6.2Hz,1H).HRMS(EI)m/z calcd C 25 H 28 N 2 O 3 [M] + 405.2178,found 405.2177.
Example 15
(E) Preparation of-1- ([ [1,1' -biphenyl ] -3-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-15):
Figure GDA0004214566460000132
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 3-biphenylmethylethylethylene oxide, and the yield was 56%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.71–7.60(m,2H),7.51–7.41(m,3H),7.41–7.34(m,2H),7.29–7.15(m,3H),7.04–6.88(m,3H),6.81(d,J＝16.0Hz,1H),6.28(dt,J＝16.0,6.3Hz,1H),5.76(s,1H),5.23(s,1H),4.07(q,J＝7.1Hz,1H),3.99(q,J＝5.4Hz,2H),3.79(s,3H),3.47–3.41(m,2H),2.82(dd,J＝12.1,3.9Hz,1H),2.72(dd,J＝12.1,6.4Hz,1H).HRMS(EI)m/z calcd C 25 H 27 NO 3 [M] + 390.2069,found 390.2070.
Example 16
(E) Preparation of-1- ([ [1,1' -biphenyl ] -2-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-16):
Figure GDA0004214566460000141
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 2-biphenylmethylethylethylene oxide, and the yield was 53%. The compound was a white solid. 1 H NMR(600MHz,DMSO-d 6 )δ7.55–7.50(m,2H),7.46–7.37(m,1H),7.36(s,2H),7.32–7.28(m,2H),7.27–7.19(m,2H),7.12(d,J＝8.2Hz,1H),7.02(td,J＝7.4,1.1Hz,1H),7.00–6.97(m,1H),6.94–6.88(m,1H),6.74(d,J＝16.0Hz,1H),6.24(dt,J＝16.1,6.2Hz,1H),4.99–4.86(m,1H),3.96(dd,J＝5.3,2.3Hz,2H),3.85(d,J＝7.2Hz,1H),3.79(s,3H),3.29(dt,J＝6.4,1.9Hz,2H),2.65(dd,J＝11.9,4.8Hz,1H),2.57(dd,J＝11.8,6.9Hz,1H).HRMS(EI)m/z calcd C 25 H 27 NO 3 [M] + 390.2069,found 390.2070.
Example 17
(E) Preparation of N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) benzamide (I-17):
Figure GDA0004214566460000142
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolyl methyl ether ethylene oxide was changed to 3-phenylacetylaminophenyl methyl ether ethylene oxide, and the yield was 42%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ10.21(s,1H),7.95(dd,J＝7.1,1.8Hz,2H),7.67–7.48(m,4H),7.45(dd,J＝7.7,1.7Hz,1H),7.37(dd,J＝8.0,1.9Hz,1H),7.28–7.17(m,2H),6.98(d,J＝8.1Hz,1H),6.90(t,J＝7.4Hz,1H),6.76(d,J＝16.1Hz,1H),6.69(dd,J＝8.2,2.5Hz,1H),6.28(dt,J＝16.1,6.2Hz,1H),5.04(s,1H),4.08–3.84(m,3H),3.79(s,3H),3.36(s,1H),3.18(s,1H),2.72(dd,J＝11.8,4.6Hz,1H),2.64(dd,J＝11.9,6.1Hz,1H).HRMS(EI)m/z calcd C 26 H 28 N 2 O 4 [M] + 433.2127,found 433.2128.
Example 18
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-7-yloxy) propan-2-ol (I-18):
Figure GDA0004214566460000151
the required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 6-quinolinylmethylethylene oxide, and the yield was 44%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ9.02–8.82(m,2H),8.34(d,J＝8.5Hz,1H),7.93(d,J＝9.1Hz,1H),7.61–7.39(m,3H),7.37–7.20(m,2H),7.10–6.94(m,2H),5.98(s,1H),5.76(s,1H),5.33(s,1H),4.28(d,J＝7.6Hz,1H),4.22–4.08(m,2H),3.81(d,J＝11.8Hz,3H),3.59(d,J＝18.0Hz,1H),3.08(d,J＝10.2Hz,1H),2.67(d,J＝2.2Hz,1H),2.33(t,J＝1.9Hz,1H).HRMS(EI)m/zcalcd C 22 H 24 N 2 O 3 [M] + 365.1865,found 365.1866.
Example 19
(E) Preparation of 1- (3- (dimethylamino) phenoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-19):
Figure GDA0004214566460000152
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to N, N-dimethylaminophenylmethylethylethylene oxide, and the yield was 55%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(dd,J＝7.6,1.7Hz,1H),7.22(d,J＝1.3Hz,0H),7.05(t,J＝8.1Hz,1H),6.91(d,J＝1.1Hz,0H),6.77(d,J＝16.1Hz,1H),6.34–6.15(m,4H),3.95–3.74(m,5H),3.41–3.35(m,1H),2.86(s,7H),2.78–2.68(m,1H),2.62(dd,J＝11.8,6.5Hz,1H).HRMS(EI)m/z calcd C 21 H 28 N 2 O 3 [M] + 357.2178,found 357.2179.
Example 20
(E) Preparation of 1- (4-cyclohexylphenoxy) -3- ((3- (2- (methoxyphenyl) allyl) amino) propan-2-ol (I-20):
Figure GDA0004214566460000161
the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 4-cyclohexylphenylmethylethylethylene oxide, and the yield was 46%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(d,J＝7.6Hz,1H),7.22(t,J＝7.6Hz,1H),7.10(d,J＝8.2Hz,2H),6.98(d,J＝8.3Hz,1H),6.90(t,J＝7.5Hz,1H),6.83(d,J＝8.3Hz,2H),6.75(d,J＝16.2Hz,1H),6.26(dt,J＝16.3,6.2Hz,1H),5.76(s,1H),4.99(s,1H),3.88(dt,J＝19.6,8.3Hz,3H),3.79(s,3H),3.32(s,1H),2.67(s,1H),2.62(d,J＝6.2Hz,1H),2.41(s,2H),1.77–1.65(m,6H),1.34(t,J＝10.1Hz,4H).HRMS(EI)m/z calcd C 25 H 33 NO 3 [M] + 396.2539,found 396.2538.
Example 21
(E) Preparation of 1- (furan-2-ylmethoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-21):
Figure GDA0004214566460000162
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to furanylmethylethylene oxide, and the yield was 45%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.62(d,J＝1.4Hz,1H),7.44(dd,J＝7.7,1.7Hz,1H),7.29–7.16(m,1H),6.98(d,J＝8.2Hz,1H),6.91(t,J＝7.4Hz,1H),6.74(d,J＝16.1Hz,1H),6.41(d,J＝1.9Hz,2H),6.25(dt,J＝16.0,6.1Hz,1H),4.78(s,1H),4.41(s,2H),3.81–3.72(m,3H),3.65(d,J＝29.5Hz,2H),3.39–3.34(m,3H),3.32(s,1H),2.73–2.52(m,1H).HRMS(EI)m/z calcd C 18 H 23 NO 4 [M] + 318.1705,found 318.1706.
Example 22
(E) Preparation of 6- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) -3, 4-dihydroquinolin-2 (1H) -one (I-22):
Figure GDA0004214566460000171
the other required raw materials, reagents and preparation methods were the same as in example 1, except that 9H-4-carbazolylmethylethylene oxide was changed to 6- (3, 4-dihydroquinolin-2 (1H) -one) ylmethylethylene oxide, and the yield was 49%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ10.12–10.02(m,1H),8.04(ddd,J＝77.0,5.9,3.3Hz,1H),7.50(dd,J＝7.7,1.7Hz,1H),7.34–7.24(m,1H),7.13(td,J＝8.1,3.9Hz,1H),7.07–7.01(m,1H),6.97(t,J＝7.6Hz,1H),6.93–6.82(m,1H),6.65(d,J＝8.2Hz,1H),6.33(dt,J＝16.1,6.3Hz,1H),5.23(d,J＝42.1Hz,1H),4.00(qt,J＝9.6,5.3Hz,4H),3.84(d,J＝6.6Hz,3H),2.93–2.72(m,5H),2.50–2.30(m,3H).HRMS(EI)m/z calcd C 22 H 26 N 2 O 4 [M] + 383.1971,found 383.1972.
Example 23
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (4-propylphenoxy) propan-2-ol (I-23):
Figure GDA0004214566460000172
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 4-n-propylphenylmethylethylethylene oxide, and the yield was 57%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.44(dd,J＝7.6,1.7Hz,1H),7.27–7.17(m,1H),7.10–7.04(m,2H),6.98(dd,J＝8.3,1.0Hz,1H),6.90(td,J＝7.5,1.1Hz,1H),6.86–6.79(m,2H),6.75(d,J＝15.9Hz,1H),6.27(dt,J＝16.1,6.2Hz,1H),4.98(s,1H),3.97–3.80(m,3H),3.79(s,3H),3.33(s,2H),2.69(dd,J＝11.9,4.5Hz,1H),2.61(dd,J＝11.9,6.2Hz,1H),1.54(h,J＝7.4Hz,2H),0.86(t,J＝7.3Hz,3H).HRMS(EI)m/z calcd C 22 H 29 NO 3 [M] + 356.2226,found 356.2228.
Example 24
(E) Preparation of 1- (((3- (2-methoxyphenyl) allyl) amino) -3- (pyridin-4-yloxy) propan-2-ol (I-24):
Figure GDA0004214566460000181
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 4-pyridylmethylethylene oxide, and the yield was 61%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.61–7.55(m,2H),7.45(dd,J＝7.7,1.7Hz,1H),7.27–7.18(m,1H),7.02–6.87(m,2H),6.75(d,J＝16.1Hz,1H),6.27(dt,J＝16.0,6.2Hz,1H),6.05(dd,J＝6.3,4.4Hz,2H),5.16(s,1H),3.97(dd,J＝13.1,2.5Hz,1H),3.84–3.69(m,4H),3.35–3.29(m,3H),3.17(s,1H),2.50(s,1H).HRMS(EI)m/z calcd C 18 H 22 N 2 O 3 [M] + 315.1709,found 315.1708.
Example 25
(E) Preparation of 1-butoxy-3- (((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-25):
Figure GDA0004214566460000182
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to n-butylmethylethylethylene oxide, and the yield was 44%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.45(d,J＝7.6Hz,1H),7.23(t,J＝7.5Hz,1H),7.02–6.80(m,2H),6.72(d,J＝16.1Hz,1H),6.30–6.20(m,1H),4.53(d,J＝12.9Hz,1H),3.85–3.67(m,2H),3.35(t,J＝6.9Hz,2H),3.26(dd,J＝10.4,5.4Hz,2H),2.51(d,J＝2.0Hz,1H),2.37(d,J＝31.4Hz,2H),1.49–1.38(m,2H),1.28(tt,J＝14.4,7.3Hz,2H),0.85(td,J＝7.3,5.2Hz,3H).HRMS(EI)m/z calcd C 17 H 27 NO 4 [M] + 294.2069,found 294.2068.
Example 26
(E) Preparation of 1- (4-benzylphenoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol (I-26):
Figure GDA0004214566460000191
the raw materials, reagents and preparation methods were the same as in example 1 except that 9H-4-carbazolylmethylethylene oxide was changed to 4-xylylmethylethylethylene oxide, and the yield was 53%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.39(ddd,J＝7.1,5.0,1.7Hz,1H),7.31–7.22(m,5H),7.06(ddd,J＝8.6,6.1,2.8Hz,4H),6.77(ddd,J＝10.4,8.7,2.2Hz,5H),6.34–6.12(m,1H),5.76(s,2H),4.92–4.80(m,2H),3.98–3.87(m,3H),3.83–3.75(m,3H),3.31(s,2H),2.68(dd,J＝13.0,5.9Hz,1H),2.63–2.51(m,1H).HRMS(EI)m/z calcd C 26 H 29 NO 4 [M] + 404.2226,found 404.2227.
Example 27
(E) Preparation of 1- (((3- (4-chlorophenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol (I-27):
Figure GDA0004214566460000192
the raw materials, reagents and preparation method were the same as in example 1 except that 2-methoxyphenylacrylamide was changed to 4-chloroacrylamide, and the yield was 55%. The compound was a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.83(s,1H),7.45(dd,J＝7.7,1.7Hz,1H),7.25–7.19(m,2H),7.16(t,J＝7.8Hz,2H),7.05–6.95(m,2H),6.94–6.83(m,5H),6.70(t,J＝7.3Hz,1H),6.27(dt,J＝16.0,6.1Hz,1H),4.97(s,1H),3.88(d,J＝23.5Hz,3H),3.19(d,J＝3.9Hz,2H),2.69(dd,J＝12.0,4.4Hz,1H),2.61(dd,J＝11.9,6.2Hz,1H).HRMS(EI)m/z calcd C 25 H 28 N 2 O 3 [M] + 405.2178,found 405.2177.
Example 28
The preparation method of the hydrochloride salt comprises the following steps: dissolving 0.01 molar mass of compounds I-01 to I-27 in 10 ml of acetone, stirring and dissolving at normal temperature, and adding a small amount of THF to assist dissolution until the compounds are completely dissolved; slowly introducing hydrogen chloride gas, separating out yellow, light yellow or white solid from the reaction solution, filtering and airing to obtain the hydrochloride salt of I-01-I-27.
The preparation method of sulfate, phosphate, acetate and trichloroacetate salt comprises the following steps: dissolving 0.01 molar mass of compounds I-01 to I-27 in 10 ml of diethyl ether, stirring and dissolving at normal temperature, and adding a small amount of THF to assist dissolution until the compounds are completely dissolved; respectively dissolving the same equivalent of sulfuric acid, phosphoric acid, acetic acid and trichloroacetic acid in methanol, slowly dripping the solution into diethyl ether solution, separating out yellow, light yellow or white solid from the reaction solution, filtering and airing to obtain sulfate, phosphate, acetate and trichloroacetate salts of I-01-I-27.
The preparation method of lactate and citrate salt comprises the following steps: dissolving 0.01 molar mass of compounds I-01 to I-27 in 10 ml of diethyl ether, stirring and dissolving at normal temperature, and adding a small amount of THF to assist dissolution until the compounds are completely dissolved; respectively dissolving the same equivalent of lactic acid and lemon in ethyl acetate, slowly dripping the solution into diethyl ether solution, separating out yellow, light yellow or white solid from the reaction solution, filtering, and airing to obtain lactate and citrate salt forms of I-01 to I-27.
Example 29 Compounds I-01 to I-27 inhibit the in vitro anti-tumor Activity of the neddylation pathway.
1. In vitro tumor cell proliferation experiments.
The candidate compounds I-01 to I-27 were evaluated for their proliferative activity on human tumor cells using CCK 8.
(1) Experimental materials: human lung cancer cell A549 and human lung cancer cell H1299. 10% bovine serum culture medium, PBS solution, trypsin (sigma), x 10CCK8 (sigma).
(2) The experimental method comprises the following steps:
(i) Resuscitation and passaging of a549 cells: the cell cryopreservation solution containing A549 was removed from the-80℃refrigerator and centrifuged (1200 rmp,3 min), the supernatant removed, 2ml of 10% bovine serum culture medium was added to resuspend and transferred to a 10cm dish and incubated in a 37℃incubator for 24 hours. Selecting cells with better growth, sucking culture solution, washing with PBS and digesting with pancreatin, centrifuging (1200 rmp,3 min), removing supernatant, and adding 2ml of 10% bovine serum culture medium for resuspension; (ii) seeding cells: counting the cells, evenly distributing 3000-5000 cells per well into each 96-well plate, and incubating overnight in a 37 ℃ incubator; (iii) Different concentrations of test compound were added and incubated for 24 hours; (iv) Sucking the supernatant, adding 100 mu L of 10% CCK8 culture solution into each hole, and incubating for 1 hour;
(v) The microplate reader detects the change in absorbance at 450nm for each well and calculates the IC50 value.
2. Intracellular ligation blocking assay based on western blotting.
(1) Experimental materials: humanized lung cancer cells A549, 10% bovine serum culture medium, PBS solution, trypsin (sigma), primary antibody (anti-cube 1-rubbi, anti-cube 2-rubbi, anti-cube 3-rubbi, anti-cube 4-a-rubbi, anti-cube 5-rubbi, anti-Nedd 8-rubbi, anti-cube 1-rubbi, anti-p 27-rubbi, abcam Co., 2000:1 dilution), secondary antibody (IgG-rubbi), protein lysate, ×4SDS-loading.
(2) The experimental method comprises the following steps:
(i) Resuscitation and passaging of a549 cells: the cell cryopreservation solution containing A549 was removed from the-80℃refrigerator and centrifuged (1200 rmp,3 min), the supernatant removed, 2ml of 10% bovine serum culture medium was added to resuspend and transferred to a 10cm dish and incubated in a 37℃incubator for 24 hours. Selecting cells with better growth, sucking culture solution, washing with PBS and digesting with pancreatin, centrifuging (1200 rmp,3 min), removing supernatant, and adding 2ml of 10% bovine serum culture medium for resuspension; (ii) seeding cells: counting the cells, evenly distributing 30 ten thousand cells per dish into each culture dish, and incubating overnight in a 37 ℃ incubator; (iii) adding the test compound and incubating for 6 hours; (iv) after incubation, protein quantification; (iv) 10% SDS-PAGE gel and electrophoresis experiments were performed; (v) After 1 hour of transfer, 20% milk is blocked for 1 hour, and a primary antibody is added for incubation overnight; (vi) washing the membrane and adding a secondary antibody for incubation for 1 hour.
The activity data are shown in Table 1 below, with A representing a compound having a netdylation inhibitory activity greater than 50% @ 5. Mu.M; the surface activity of the B-generation compound is more than 50% @10 mu M; c represents a compound having a netdylation inhibitory activity greater than 50% @ 20. Mu.M; d represents a tumor cell proliferation inhibition activity of the compound of more than 50% @2.5 mu M; e represents a tumor cell proliferation inhibitory activity of the compound of more than 50% @ 5. Mu.M; f represents a tumor cell proliferation inhibitory activity of the compound of more than 50% @ 10. Mu.M. From the results, the above compounds all showed good neddylation pathway inhibitory activity and in vitro antitumor activity.
TABLE 1
Figure GDA0004214566460000221
Example 30-cardiac injury protective Activity of Compounds I-01 to I-27.
1. Doxorubicin-induced cardiomyocyte injury protection experiments.
After 7 generations of myocardial cells are transferred, the viability of the myocardial cells is kept stable, normal sugar-containing culture medium is added for re-suspension, the myocardial cells are respectively filled into 96-well plates, 1 multiplied by 104 cells/well, and the myocardial cells are incubated overnight in a 37 ℃ incubator; doxorubicin (final concentration 2 μm) was added and incubation continued for 6 hours; after the incubation, the supernatant was aspirated and washed with PBS, the test compound (final concentration 10. Mu.M) and carvedilol (final concentration 10. Mu.M) as positive drugs were added, the incubation was continued for 12 hours, and Cell Counting Kit-8 (CCK 8 method) was used to test the survival rate of cardiomyocytes and calculate the protection rate of the compound against cardiomyocytes.
2. Hypoxia/reoxygenation induced cardiomyocyte injury protection experiments.
The same pretreatment and adherence overnight; removing supernatant, cleaning with PBS, adding normal sugar-containing culture medium, placing into an anoxic small chamber, and filling nitrogen to create an anoxic environment; after 6 hours incubation, reoxygenation was performed, and test compound (final concentration 10. Mu.M) and positive drug nicorandil (final concentration 100. Mu.M) were added, followed by co-incubation for 6 hours, removal of supernatant, washing with PBS, testing of survival of cardiomyocytes by Cell Counting Kit-8 (CCK 8 method) and calculation of protection of cardiomyocytes by the compound.
The activity data are shown in Table 2 below, with A representing compounds with a cardiomyocyte viability of greater than 60% @ 10. Mu.M, B representing compounds with a cardiomyocyte viability of greater than 50% @ 10. Mu.M, and C representing compounds with a cardiomyocyte viability of greater than 40% @ 10. Mu.M. From the results, it was found that the above compounds all showed good in vitro myocardial protective activity, and the activity was no worse than that of carvedilol, a positive drug, and that the other nedzyation inhibitor MLN4924 had no cardioprotective activity.
Table 2.
Figure GDA0004214566460000231
Figure GDA0004214566460000241
Example 31-proliferation-inhibiting Activity of preferred Compounds I-15, I-13, I-16 and I-17 against various tumor cells beta adrenergic blocking Activity.
1. The proliferation inhibition activity test method and procedure were the same as in example 29, and the highly activated tumor cell lines such as human hepatoma cells HepG2, huh7, gastric carcinoma cells MKN45, MGC803, breast cancer cells T-47D, MCF-7 and MB231, colon cancer cells SW480, etc. were selected respectively. The activity data are shown in table 3 below: i-15, I-13, I-16 and I-17 not only have proliferation inhibition activity on various tumor cells, but also have no worse effect than that of the positive medicine MLN4924.
2. Beta adrenergic blocking activity assay.
The experiments were set up as blank, epinephrine and different concentrations of drug, with three replicates per group. Then RAW264.7 macrophages are inoculated into a 6-hole plate, the 6-hole plate is placed into an incubator for culture, andrographolide with different concentrations is respectively added into the 6-hole plate after cells are attached, the incubator is pretreated for 1h, epinephrine (100 ng-1 ug/mL) is added into the incubator, the incubator is stimulated for 1h, cell supernatant is collected, and the content of TNF-alpha in the cell supernatant is detected by using an elisa kit according to the steps of the specification. As shown in FIG. 1, both I-15 and I-17 exhibited significant TNF- α inhibitory activity, comparable to the positive drug carvedilol.
TABLE 3 Table 3
Figure GDA0004214566460000242
Example 32- -in vitro anti-inflammatory antioxidant Activity of preferred Compounds I-15 and I-17.
1. 6-hydroxydopamine (6-OHDA) induced cardiomyocyte injury experiments.
The compound concentration of 10. Mu.M was 1X 10 4 Pretreatment for 4 hours in 96-well plates of individual/well cardiomyocytes; adding 6-OHDA with a certain concentration, and after co-incubation for 6 hours, respectively testing the survival rate of the cells; meanwhile, 12-well plates were used as parallel experiments to test intracellular LDH content using a commercial lactate dehydrogenase kit. As shown in FIG. 2, both I-15 and I-17 exhibited significant myocardial cell injury protective activity.
2. The test method and procedure for the intracellular TNF- α inhibitory activity assay were the same as in example 29, with the assay being set up as a blank, LPS group and drug group of different concentration, each set up in triplicate. Then RAW264.7 macrophages are inoculated into a 6-hole plate, the 6-hole plate is placed into an incubator for culture, andrographolide with different concentrations is respectively added into the 6-hole plate after cells are attached, the incubator is pretreated for 1h, LPS (100 ng-1 ug/mL) is then added into the incubator, the incubator is stimulated for 24h, cell supernatant is collected, and the content of TNF-alpha in the cell supernatant is detected by using an elisa kit according to the steps of the specification. As shown in FIG. 3, both I-15 and I-17 exhibited significant TNF- α inhibitory activity, comparable to that of the positive drug lenalidomide.
Example 33-in vivo anti-tumor Activity test of preferred Compound I-15.
BALB/c-Nude mice of 6 weeks old were taken and randomly grouped according to 6-8 mice/group, each mouse was subcutaneously injected with 100. Mu.L, 2-10X 106 tumor cells (the number is determined by the growth state of different types of test cells), after the tumor was planted, the tumor volume was observed to be 80-200 mm3 (V= (length. Times. Width. 2)/2) and administration was started. The administration doses were 15mg/Kg, 30mg/Kg (administration frequency was once a day, and the administration was stopped for 2 days after 5 days of continuous administration as a treatment course), and two positive groups of carvedilol group (30 mg/Kg) and doxorubicin (1 mg/Kg) were respectively set, the weight and the tumor volume were weighed and measured every other day, the tumor volume of the mice in the blank group was as long as 1000mm3 as the clinical endpoint, and the tumor weight was measured and compared by photographing after the neck breaking sacrifice. As shown in fig. 4, I-15 exhibited significant in vivo antitumor activity.
Example 34-in vivo cardiac injury protection Activity test of preferred Compound I-15.
C57BL/6 mice are randomly grouped according to 13 mice/group, the molding module is used for injecting 1mg/Kg of doxorubicin into the abdominal cavity, the administration frequency is twice a week, and the blank group is used for injecting physiological saline into the abdominal cavity; after 6-8 weeks, observing the behavior state of the model group mice, randomly taking 3 test related indexes from each group, judging whether the model is successful and the damage degree is low, and if the damage degree is low, prolonging the administration period for 2 weeks; continuously administering doxorubicin after successful molding, wherein 2 groups of test drugs of 1mg/Kg and 10mg/Kg are simultaneously administered, the administration frequency and the period are the same as those of doxorubicin, and continuously administering for 6-8 weeks, and simultaneously, 2 groups of carvedilol positive drug group comparison (1 mg/Kg and 10 mg/Kg) are additionally arranged; during the administration period, observing the behavior state, feeding, activity and weight of the mice; after the administration is finished, the mice are anesthetized by gas (isoflurane), blood is taken, and the serum is obtained by centrifugation, and biochemical indexes related to cardiac muscle are detected, including Lactate Dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB) and the like; after heart perfusion, heart test cardiac body ratio (HW/BW), fixation, paraffin embedding, slicing, and detection of cardiomyocyte morphology and fibrosis area by HE staining and Masson staining.
Observation results: compared with a blank group, the doxorubicin manufacturing module has the advantages of certain weight reduction, inappetence, dark hair color and no preference for walking; the feeding frequency, hair color and mobility agility of the mice of the administration group are obviously better than those of the doxorubicin molding. The slicing result is obvious, and the administration group has full cell morphology and neat and compact structure, and is used for the module preparation of the vs doxorubicin: the cells shrink irregularly and the whole structure is loose. The relevant index is shown in figure 5, and I-15 shows remarkable myocardial injury protection activity in vivo.
In conclusion, the compound of the invention shows excellent anti-tumor and heart protection activities in vitro or in vivo, provides a novel medication mode for developing medicaments for treating tumor-associated heart toxicity diseases, has no report on similar therapeutic compounds at present, and has remarkable novelty, originality and practicability.

Claims (7)

1. Application of allylamine compounds, or pharmaceutically acceptable salts thereof, in preparing antitumor and heart protecting difunctional drugs, wherein the allylamine compounds are (+ -) -1- (9H-4-carbazolyloxy) -3- (2-methoxyanilino) -2-propanol; (E) -1- (((9H-carbazol-2-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-1-yloxy) propan-2-ol, (E) -1- (((9H-carbazol-1-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (naphthalen-2-yloxy) propan-2-ol, (E) -1- (((1H-indol-4-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -5- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) -3, 4-dihydroquinolin-2 (1H) -one ) -1- (((1H-indol-5-yl) oxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol; (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3-phenoxypropan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-6-yloxy) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (3- (phenylamino) phenoxy) propan-2-ol, (E) -1- ([ [1,1 '-biphenyl ] -4-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) acetamide, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol, and (E) -1- ([ [1,1' -biphenyl ] -3-yloxy) -3-ol) - ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol; (E) -1- ([ [1,1' -biphenyl ] -2-yloxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol; (E) -N- (3- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) phenyl) benzamide; (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (quinolin-7-yloxy) propan-2-ol, (E) -1- (3- (dimethylamino) phenoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (4-cyclohexylphenoxy) -3- ((3- (2- (methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (furan-2-ylmethoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -6- (2-hydroxy-3- ((3- (2-methoxyphenyl) allyl) amino) propoxy) -3, 4-dihydroquinolin-2 (1H) -one, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) -3- (4-propylphenoxy) propan-2-ol, (E) -1- (((3- (2-methoxyphenyl) allyl) amino) Group) allyl) amino) -3- (pyridin-4-yloxy) propan-2-ol; (E) -1-butoxy-3- (((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, (E) -1- (4-benzylphenoxy) -3- ((3- (2-methoxyphenyl) allyl) amino) propan-2-ol, or (E) -1- (((3- (4-chlorophenyl) allyl) amino) -3- (4- (phenylamino) phenoxy) propan-2-ol.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the allylamine is a hydrochloride, phosphate, sulfate, acetate, trichloroacetate, lactate or citrate salt.
3. The use according to claim 1, wherein the tumor is lung cancer, liver cancer, gastric cancer, breast cancer, intestinal cancer, or a neodylation modified highly activated tumor.
4. The use according to claim 1, wherein the heart injury is a cardiovascular disease or a heart injury related condition caused by administration of other antineoplastic agents.
5. The use according to claim 4, wherein the condition associated with cardiac injury is myocardial injury, heart failure or myocardial infarction.
6. The use according to any one of claims 1 to 5, wherein the allylamine compound exerts an anti-tumour function by blocking the ubiquitinated Neddylination pathway; the beta-adrenergic receptor blocking activity and anti-inflammatory and antioxidant activity of the allylamine compound play a role in heart protection.
7. The use according to claim 6, wherein the external manifestations of antitumor and cardioprotective functions are marked antitumor and cardioprotective activities, respectively.
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