CN114763356B - Pyrrolo-benzodiazepine compound, and preparation method and application thereof - Google Patents
Pyrrolo-benzodiazepine compound, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and relates to pyrrolobenzodiazepine
The compounds and their preparation process and application in preparing medicine for treating fibrosis, tumor metastasis and tumor growth. The compound and pharmaceutically acceptable salt thereof are shown as a general formula I or II, wherein R 1 、R 2 、R 3 、R 4 And m, n and p are as defined in the claims and the specification. The compound and the pharmaceutically acceptable salt thereof can be prepared into pharmaceutical compositions with pharmaceutically acceptable carriers or excipients. The compounds of the present invention and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof can be prepared into tablets, capsules, solutions or ampoules for injection, suppositories, patches, inhalable powder formulations, suspensions, emulsions and ointments for anti-fibrosis, anti-tumor metastasis, anti-tumor growth.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to pyrrolobenzodiazepine
The compounds and their preparation process and application in preparing medicine for treating fibrosis, tumor metastasis and tumor growth.
Background
1. Histone deacetylase 6 inhibitors
Histone Deacetylases (HDACs) are enzymes that play an important role in epigenetic regulation, and regulate the level of acetylation of a variety of proteins, such as histones, transcription factors, chaperones, and signaling molecules. HDACs are often associated with concentration of chromatin and silencing of a variety of transcribed genes. Therefore, HDAC inhibitors (HDACi) are useful in the treatment of various diseases such as cancer, inflammation, neurodegenerative diseases and metabolic disorders. Whereas typical HDACi are non-selective or partially selective inhibitors, they often cause a number of side effects such as fatigue, taste impairment, nausea, vomiting, diarrhea, bone marrow suppression, cardiotoxicity, etc. These toxic effects may be associated with inhibitors acting on multiple isoforms or lack of selectivity for isoform members. HDAC6 selective inhibitors may exhibit lower toxicity by avoiding multiple histone acetylation-induced changes in whole gene expression. Therefore, HDAC6 inhibitors have good research prospects.
2. Anti-fibrosis
Fibrosis (fibrosis) is a medical concept, and fibrosis can occur in various organs (liver, kidney, lung, heart, etc.), and the main pathological change is that fibrous connective tissue in organ tissues is increased, parenchymal cells are reduced, and continuous progress can lead to structural damage and hypofunction of organs, even failure, and serious threat to human health and life. Any cause can cause tissue cell damage, can cause tissue cells to generate denaturation, necrosis and inflammatory reaction, if the damage is small, normal parenchymal cells around the damaged cells can generate proliferation repair, and the repair can completely restore normal structure and function. However, if the injury is large or repeated beyond the regenerative capacity of parenchymal cells surrounding the injury, the interstitial fibrous connective tissue (extracellular matrix) will proliferate in large amounts to repair the defective tissue, i.e., a pathological change in fibrosis occurs. Fibrosis is thus essentially a repair reaction of tissue after it has been damaged to preserve the relative integrity of the tissue organ. The proliferated fibrous connective tissue, although repairing the defect, does not possess the structure and function of the original organ parenchymal cells. If this repair is excessive, too strong and uncontrolled, it can cause fibrosis and lead to reduced function of the organ.
TGF-beta is an important cytokine which regulates a variety of biological processes including embryogenesis, cell differentiation, organogenesis, immune response, etc., has received a great deal of attention in the fields of fibrosis and tumor metastasis, and is currently recognized as the most potent cytokine for fibrosis. TGF-beta is available from a number of sources, macrophages, activated alveolar epithelial cells, endothelial cells and fibroblasts. TGF-beta has 3 subtypes, which have similar biological activities, but differ in expression pattern, TGF-beta 1 being a subtype that is differentially expressed in advanced lung fibrotic epithelial cells. Under physiological conditions, TGF- β1 is essential for lung morphogenesis and homeostasis, while aberrant TGF- β1 signaling has been demonstrated to be central to the progression of pulmonary fibrosis. Under stimulation of TGF- β1, extracellular matrix (Extracellular Matrix, ECM) is produced and deposited in large amounts. TGF-. Beta.1 has been found to induce a variety of pathways leading to pulmonary fibrosis, including induction of Epithelial-mesenchymal transition (EMT), direct effects on fibroblasts, and stimulation of macrophages to secrete other pro-fibrotic factors, among others. In vitro experiments prove that after the TGF-beta 1 is used for inducing and stimulating the fibroblasts, the expression of histone deacetylase 6 (HADC 6) and heat shock protein 90 (HSP 90) proteins can be up-regulated, and after an HDAC6 specific inhibitor is used, the expression of HDAC6 and HSP90 is reduced, the TGF-beta 1/Smad pathway is inhibited, and the myofibroblast differentiation can be blocked. This suggests that HDAC6 inhibitors may inhibit myofibroblast differentiation and collagen deposition, which may be a potential targeting agent for the treatment of fibrosis.
3. Anti-tumor metastasis
Tumor metastasis is a biological property of malignant tumors and is also a major cause of poor prognosis, recurrence of cancer, and even exacerbation of disease. Tumor metastasis mostly includes the following four stages: a. tumor cells at the primary part of the organism proliferate in a large quantity and start to fall off from the primary disease focus; b. the detached tumor cells penetrate through the basal lamina of the epithelium to infiltrate into the interstitium, and then are transferred into the vascular and lymphatic system and other parts; c. part of tumor cells survive in the transfer process through self-specific adhesion and immune escape and are transferred to other organs of the body along with blood flow or lymph flow; d. the transferred tumor cells are adsorbed to the vascular wall of the organ of the organism and permeate outwards to puncture the blood vessel, so that smaller tumor focus is generated firstly, secondary tumors are generated gradually along with the unlimited proliferation of the tumor cells, and the tumor cells can be transferred to other organs of the organism again. With the development of modern technology, the development of anti-tumor metastasis drugs mainly aims at a plurality of links of metastasis stage, and breaks through to different degrees in the research fields of clinic and the like. Studies have shown that histone deacetylase (histone deacetylases, HDACs) activity and expression are abnormal in many tumor cells and tissues, and are important anti-tumor targets. Expression levels of HDAC6 are abnormally up-regulated in a variety of tumor cells and tissues, for example: malignant tumors such as breast cancer, ovarian cancer, colorectal cancer, lung cancer and the like, and the high expression is closely related to invasion and metastasis processes of the tumors and even clinical pathological characteristics of patients. HDAC6 loses normal regulation of cell growth in promoting malignant transformation of tumors resulting in abnormal proliferation, and allows the transformed cells to undergo anchored independent growth to avoid the phenomenon of apoptosis. The motor capacity of cells is of great importance for metastasis of body tumors, whereas HDAC6 can be involved in regulating invasion and metastasis of tumor cells by modulating non-histone substrates. Abnormal upregulation of HDAC6 expression levels imbalances the body's acetylation level, and decreased acetylation of α -tubulin leads to increased microtubule dynamics, thereby accelerating cell motility; in contrast, inhibition of HDAC6 activity or expression causes excessive acetylation of α -tubulin in the body, and focal adhesion is effective in inhibiting cell motility due to accumulation of large amounts. HDAC6 can affect the migratory capacity of cells not only by modulating α -tubulin, but also by modulating the acetylation levels of cortical actin and Hsp90 to exert its biological functions. HDAC6 can specifically regulate and control non-histone substrates such as alpha-tubulin, hsp90 and the like, so that the non-histone substrates can participate in the life process of cells through various ways, and inhibiting HDAC6 can inhibit the development of tumors from various aspects. Although HDACi can obtain a good tumor inhibition effect, a broad-spectrum HDACi has the major problems of nausea, vomiting, bone marrow suppression and other toxic and side effects, so that the clinical application range of the HDACi is greatly limited. Compared with the broad-spectrum inhibitor of HDACs, the selective inhibitor has the advantages that the HDAC6 specific inhibitor has almost no cytotoxicity to normal cells, the defects of poor selectivity, large toxic and side effects and the like of the broad-spectrum HDACi are possibly eliminated, and the advantages lead the research and development of the specific HDAC6 inhibitor to become a research hot spot.
4. Anti-tumor growth
Cancer is a dangerous factor seriously affecting resident health, cancer burden is in a continuously growing situation in the global scope of the last ten years, and tumor death accounts for 1/4 of the total death cause in China, and is the first place of death. Cancer not only places a heavy burden on the patient's home and society, but also affects public safety and social stability. The cancer onset in China is in an ascending situation in the last ten years, the annual increase is about 4%, and the annual increase is about 2% after the age factors are regulated. The main factors of the high incidence of cancer in China are aging population, and other cancerogenic factors also comprise air environmental pollution, unhealthy diet, insufficient physical activity, obesity/overweight, smoking and the like. Along with the aggravation of the aging trend of the population and the wide existence of bad life style, the incidence and death rate of cancer in China are continuously increased. HDAC6 can specifically regulate and control non-histone substrates such as alpha-tubulin, hsp90 and the like, so that the non-histone substrates can participate in the life process of cells through various ways, and the development of tumors can be inhibited in various ways through inhibiting the HDAC 6.
The invention designs and synthesizes a series of novel pyrrolobenzodiazepines
The derivatives have good activity and dose dependency after being tested for anti-fibrosis, anti-tumor metastasis and anti-tumor growth activities.
Disclosure of Invention
The invention aims to provide a series of novel substituted pyrrolobenzodiazepines
The compounds have the functions of resisting fibrosis, tumor metastasis and tumor growth.
Another object of the invention isTo provide a process for preparing substituted pyrrolobenzodiazepines
Methods of class of compounds.
In order to accomplish the purpose of the present invention, the following technical scheme may be adopted:
the present invention provides pyrrolobenzodiazepines having the formula I or II
A class of compounds or optically active forms thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 each of which may be any one of (1) a H atom, (2) a hydroxyl group, (3) a halogen atom (4) a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C18 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 acyloxy group, a phenyl group, a benzyloxy group, a pyridyl group, a thienyl group, a pyrazolyl group, a pyrrolyl group, a pyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a thiazolyl group, an isothiazolyl group, an indolyl group, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylsulfonylamino group, a benzyloxycarbonyl group, a C1-C18 alkoxycarbonyl group, a C1-C18 alkylsulfonyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, a cyano group, a nitro group and an amino group.
n＝3-9；p＝1-3；m＝0-3
The pyrrole ring contains a chiral center;
further, the present invention preferably provides the following pyrrolobenzodiazepines
A class of compounds or optically active bodies thereof.
Wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 each of which may be any one of (1) a H atom, (2) a hydroxyl group, (3) a halogen atom (4) a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C18 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 acyloxy group, a phenyl group, a benzyloxy group, a pyridyl group, a thienyl group, a pyrazolyl group, a pyrrolyl group, a pyrimidinyl group, a quinolinyl group, an isoquinolinyl group, a thiazolyl group, an isothiazolyl group, an indolyl group, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylsulfonylamino group, a benzyloxycarbonyl group, a C1-C18 alkoxycarbonyl group, a C1-C18 alkylsulfonyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, a cyano group, a nitro group and an amino group.
n＝3-9；p＝1-3；m＝0-3
The pyrrole ring contains a chiral center;
further, the present invention preferably provides the following pyrrolobenzodiazepines
A compound or an optically active substance thereof, a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 、R 2 、R 3 、R 4 can be any one of (1) H atom, (2) hydroxy, (3) halogen atom (4) C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxy, each of which is optionally substituted by one or more substituents selected from the group consisting of H atom, halogen atom, hydroxy, cyano, nitro and amino, (5) phenyl, benzyloxy, pyridyl, thienyl, pyrazolyl,Pyrrolyl, pyrimidinyl, quinolinyl, isoquinolinyl, thiazolyl, isothiazolyl, indolyl, each of which is optionally substituted with one or more substituents selected from H, halogen, C1-C6 alkyl, C1-C6 alkylamino, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfonylamino, benzyloxycarbonyl, C1-C18 alkoxycarbonyl, C1-C18 alkoxysulfonyl, halo C1-C6 alkyl, hydroxy, cyano, nitro and amino.
n＝3-9；p＝1-3；m＝0-3
The pyrrole ring contains a chiral center;
further, the present invention preferably provides the following pyrrolobenzodiazepines
A compound or an optically active substance thereof, a pharmaceutically acceptable salt thereof:
R 1 、R 2 、R 3 、R 4 the independent method is as follows:
(1) an H atom, (2) a hydroxyl group, (3) a halogen atom (4) a C1-C6 alkyl group, a C1-C6 alkoxy group, a phenyl group, a benzyloxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of an H atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group and an amino group, and each of which is optionally substituted with one or more substituents selected from the group consisting of an H, a halogen, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylsulfonylamino group, a benzyloxycarbonyl group, a C1-C18 alkoxycarbonyl group, a C1-C18 alkylsulfonyl group, a halogenated C1-C6 alkyl group, a hydroxyl group, a cyano group, a nitro group and an amino group.
n＝5-9；p＝1-2；m＝0-1；
The invention preferably provides the following pyrrolobenzodiazepines
A class of compounds or optically active forms thereof:
R 1 、R 2 、R 3 、R 4 the independent method is as follows: h atom, bromine atom, chlorine atom, methoxy group, 2-methyl-phenyl group.
Wherein the pyrrole ring contains a chiral center;
the invention provides the following extractionSubstituted pyrrolobenzodiazepines
A class of compounds or optically active bodies thereof.
The invention also provides pyrrolobenzodiazepines of the general formula (I) or (II)
The synthetic route of the derivative and the optical active body is as follows:
the method comprises the steps of carrying out substitution reaction on substituted o-nitrobenzyl bromide and L or D-type pyroglutamic acid methyl ester in the presence of NaH to obtain an intermediate A-1, carrying out ferrite reduction reaction cyclization on the intermediate A-1 to obtain an intermediate A-2, carrying out substitution reaction on the intermediate A-2 in a system of NaH and DMF to obtain an intermediate A-3 or B-3, and carrying out ammonolysis reaction to synthesize a compound shown in a general formula I or II.
Wherein R is 1 、R 2 、R 3 、R 4 And m, p and n are as described above.
Drawings
FIG. 1 is a western blot experiment result of compounds A3-A9;
a: effect of compounds A3-A9 on HDAC6 action substrate expression in breast cancer cells; b: effect of compound A7 on HDAC6 action substrate expression in breast cancer cells at different concentrations. * : p <0.05,: p <0.01,: p <0.001 (as compared to blank).
FIG. 2 is the effect of compounds on breast cancer cell HDAC6 activity;
a: effect of compounds A3-A9 on HDAC6 activity in breast cancer cells; b: effect of compound A7 on normal cellular activity; c: effect of compound A7 on HDAC6 activity in breast cancer cells at different concentrations. * : p <0.05,: p <0.01,: p <0.001 (as compared to blank).
FIG. 3 shows the effect of scratch and Transswell tests on the in vitro migration and invasion of breast cancer cells by Compound A7;
a: effect of compound A7 on breast cancer cell migration at different concentrations; b: quantitative relationship of compound A7 effect on breast cancer cell migration at different concentrations; c: effect of compound A7 on breast cancer cell invasion at different concentrations; d: quantitative relationship of compound A7 effect on breast cancer cell invasion at different concentrations. * : p <0.05,: p <0.01,: p <0.001 (as compared to blank).
FIG. 4 is a graph showing the effect of A7 on changes in lung tissue and liver histopathology in nude mice during metastasis of breast cancer in vivo, and changes in the expression level of the tumor marker Ki67 in the lung tissue and liver tissue;
a: HE staining detects tumor cell lung metastasis; b: HE staining to detect liver metastasis of tumor cells; c: effect of compound A7 on Ki67 levels in nude mouse lung tissue; d: effect of compound A7 on Ki67 levels in liver tissue of nude mice. * P <0.001 (compared to blank); # p <0.01, # p <0.001 (as compared to model group).
FIG. 5 is a graph showing the effect of A7 on changes in HDAC6 activity in lung and liver tissues during metastasis of breast cancer in vivo and on changes in the amount of the substrate for the effect of HDAC6, acetylate- α -tubulin;
a: effect of A7 on HDAC6 activity in lung tissue of nude mice at different concentrations; b: effect of A7 on HDAC6 activity in liver tissue of nude mice at different concentrations; c: pulmonary HDAC6 substrate acetylation level change and quantitative relationship; d: liver tissue HDAC6 substrate acetylation level change and quantitative relationship. * p <0.05 (compared to blank); # p <0.01, # p <0.001 (as compared to model group).
FIG. 6 is an in vivo anti-pulmonary fibrosis effect of A7.
The specific embodiment is as follows:
the compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended to illustrate, but not limit the scope of the invention
Example 1 (S) -10- (N-hydroxy-p-methylbenzamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A1)
O-nitrobenzyl bromide is dripped into DMF, naH is added in batches under ice water bath, after one hour of reaction, L-pyroglutamic acid methyl ester is added, and the reaction is continued for two hours at room temperature. And (5) post-treatment. The solid powder was dissolved in acetic acid, and reduced iron powder was added thereto, and the temperature was raised to reflux for 2 hours. The solution was then concentrated in vacuo, the resulting black viscous material was diluted with ethyl acetate and most of the insoluble material was removed by filtration. The filtrate was purified by flash chromatography on silica gel using ethyl acetate-petroleum ether (10:1 v/v) to give an off-white solid. Anhydrous DMF was added to the solid, sodium hydride was added in portions, and after half an hour of stirring, methyl p-bromomethylbenzoate was added. The mixture was stirred at room temperature for a further 1h. 40mL of water was then added and stirred for 5 minutes, and the solution was extracted with ethyl acetate (50 mL. Times.3). The ethyl acetate layer was concentrated in vacuo to give a yellow oil. After that, the oil was dissolved in anhydrous methanol, hydroxylamine hydrochloride (0.56 g,8 mmol) and potassium hydroxide (0.90 g,16 mmol) were added at 0℃and stirred for 3h at room temperature. The resulting mixture was extracted and filtered, and the filtrate was concentrated and dried in vacuo to give a yellow viscous solid. Then 30mL of water was added, the aqueous layer was acidified to pH 4-5 with dilute hydrochloric acid (1M) and extracted with dichloromethane (50 mL. Times.3). The dichloromethane layer was concentrated, dried in vacuo and the residue purified by flash chromatography on silica gel using ethyl acetate-methanol (10:1 v/v) to give compound 1 in 21.1% yield. mp 178.3-179.6 ℃.
1 H NMR(600MHz,DMSO)δ11.17(s,1H),9.00(s,1H),7.64(d,J＝8.0Hz,2H),7.50(d,J＝7.9Hz,1H),7.44(t,J＝7.5Hz,1H),7.40(d,J＝7.3Hz,1H),7.28(d,J＝8.0Hz,2H),7.25(t,J＝7.4Hz,1H),5.38(d,J＝15.4Hz,1H),4.97(d,J＝15.4Hz,1H),4.63(d,J＝13.7Hz,1H),4.06(t,J＝7.0Hz,1H),3.75(d,J＝13.6Hz,1H),2.49–2.43(m,1H),2.32(t,J＝8.1Hz,2H),1.93(td,J＝12.8,7.8Hz,1H).
Example 2 (S) -10- (N-hydroxy-p-methylphenylacetamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A2)
The compound of example 2 was prepared in the same manner as in example 1 except that methyl p-bromomethylbenzoate was used in the third step instead of methyl p-bromomethylbenzoate. A white solid powder was obtained in 25.9% yield. mp 180.1-182.6 deg.c.
1 H NMR(600MHz,DMSO)δ10.61(s,1H),8.79(s,1H),7.52(d,J＝8.0Hz,1H),7.46–7.42(m,1H),7.39(d,J＝7.4Hz,1H),7.24(t,J＝7.3Hz,1H),7.16–7.10(m,4H),5.36(d,J＝15.2Hz,1H),4.85(d,J＝15.1Hz,1H),4.61(d,J＝13.6Hz,1H),4.03(t,J＝7.0Hz,1H),3.69(d,J＝13.5Hz,1H),3.20(s,2H),2.49–2.42(m,1H),2.34–2.28(m,2H),1.95–1.88(m,1H).
Example 3 (S) -10- (N-hydroxybutyramide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A3)
The compound of example 3 was prepared in the same manner as in example 1 except that methyl 4-bromobutyrate was used in the third step instead of methyl p-bromomethylbenzoate. A white solid powder was obtained in 25.9% yield. mp 180.1-182.6 deg.c. The yield thereof was found to be 21.1%. mp 178.3-179.6 ℃.
1 H NMR(600MHz,DMSO)δ10.34(s,1H),8.66(s,1H),7.48(d,J＝9.9Hz,3H),7.31(s,1H),4.70(d,J＝13.7Hz,1H),4.26–4.15(m,1H),3.93(d,J＝11.4Hz,2H),3.66–3.56(m,1H),2.41(s,1H),2.29(d,J＝7.4Hz,2H),1.91(d,J＝6.8Hz,2H),1.87(d,J＝7.3Hz,1H),1.18(t,J＝6.8Hz,2H).
Example 4 (S) -10- (N-hydroxypentanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A4)
The compound of example 4 was prepared in the same manner as in example 1 except that methyl-4-bromopentanoate was used in the third step in place of methyl-p-bromomethylbenzoate. A white solid powder was obtained in 23.9% yield. mp 173.7-174.6 ℃.
1 H NMR(600MHz,DMSO)δ10.32(s,1H),8.66(s,1H),7.53–7.48(m,2H),7.47(d,J＝7.2Hz,1H),7.33–7.29(m,1H),4.71(d,J＝13.7Hz,1H),4.26–4.19(m,1H),3.91(dd,J＝9.2,5.0Hz,2H),3.62–3.57(m,1H),2.41(dddd,J＝12.5,10.6,8.4,6.6Hz,1H),2.33–2.26(m,2H),1.95–1.88(m,2H),1.86(ddd,J＝12.8,8.3,5.0Hz,1H),1.45–1.37(m,4H).
Example 5 (S) -10- (N-hydroxyhexanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A5)
The compound of example 5 was prepared in the same manner as in example 1 except that methyl 4-bromohexanoate was used in the third step instead of methyl p-bromomethylbenzoate. A white solid powder was obtained in 21.2% yield. mp.163.2-165.3 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.66(s,1H),7.51(ddd,J＝8.8,7.5,1.4Hz,2H),7.47(d,J＝6.8Hz,1H),7.31(td,J＝7.5,1.7Hz,1H),4.71(d,J＝13.7Hz,1H),4.21(ddd,J＝13.8,9.2,6.6Hz,1H),3.91(dd,J＝14.7,8.2Hz,2H),3.58(ddd,J＝14.0,9.1,5.3Hz,1H),2.42(dddd,J＝12.5,10.5,8.4,6.6Hz,1H),2.32–2.26(m,2H),1.92–1.82(m,3H),1.49–1.38(m,4H),1.17(td,J＝7.4,3.9Hz,2H).
Example 6 (S) -10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A6)
The compound of example 6 was prepared in the same manner as in example 1 except that methyl 4-bromoheptanoate was used in the third step instead of methyl p-bromomethylbenzoate. A white solid powder was obtained in 38.6% yield. mp 150.2-152.0 ℃.
1 H NMR(600MHz,DMSO)δ7.50(dt,J＝7.0,3.9Hz,2H),7.47(d,J＝6.9Hz,1H),7.30(td,J＝7.5,1.7Hz,1H),4.70(d,J＝13.7Hz,1H),4.21(ddd,J＝13.8,9.2,6.6Hz,1H),3.93–3.87(m,2H),3.58(ddd,J＝14.1,9.1,5.4Hz,1H),2.44–2.38(m,1H),2.32–2.26(m,2H),2.11(t,J＝7.4Hz,2H),1.46–1.38(m,4H),1.25–1.18(m,6H).
Example 7 (S) -10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A7)
The compound of example 7 was prepared in the same manner as in example 1 except that methyl 4-bromooctoate was used in the third step instead of methyl p-bromomethylbenzoate to give a white solid powder in 25.3% yield. mp 183.6-184.9 ℃.
1 H NMR(600MHz,DMSO)δ10.30(s,1H),8.64(d,J＝1.4Hz,1H),7.50(t,J＝7.8Hz,2H),7.47(d,J＝7.4Hz,1H),7.33–7.29(m,1H),4.70(d,J＝13.7Hz,1H),4.22(ddd,J＝13.9,9.0,6.7Hz,1H),3.92(t,J＝7.0Hz,1H),3.88(d,J＝13.7Hz,1H),3.58(ddd,J＝14.0,9.0,5.4Hz,1H),2.41(dddd,J＝12.6,10.6,8.4,6.6Hz,1H),2.32–2.27(m,2H),1.89(t,J＝7.5Hz,2H),1.88–1.83(m,1H),1.47–1.39(m,4H),1.21–1.12(m,6H).
Example 8 (S) -10- (N-hydroxynonanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A8)
The compound of example 8 was prepared in the same manner as in example 1 except that methyl 4-bromononanoate was used in the third step instead of methyl p-bromomethylbenzoate, to give a white solid powder in a yield of 26.1%. mp 213.4-214.9 ℃.
1 H NMR(600MHz,DMSO)δ10.32(s,1H),8.66(s,1H),7.50(t,J＝8.0Hz,2H),7.47(d,J＝7.1Hz,1H),7.34–7.27(m,1H),4.71(d,J＝13.7Hz,1H),4.23(ddd,J＝13.8,9.0,6.7Hz,1H),3.95–3.90(m,1H),3.89(d,J＝13.8Hz,1H),3.58(ddd,J＝14.0,8.9,5.4Hz,1H),2.42(dddd,J＝12.6,10.5,8.4,6.5Hz,1H),2.35–2.25(m,2H),1.91(t,J＝7.3Hz,2H),1.89–1.82(m,1H),1.51–1.35(m,4H),1.17(d,J＝3.5Hz,8H).
Example 9 (S) -10- (N-hydroxydecanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A9)
The compound of example 9 was prepared in the same manner as in example 1 except that methyl 4-bromodecanoate was used in the third step instead of methyl p-bromomethylbenzoate to obtain a white solid powder in 18.4% yield. mp 187.3-188.9 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(d,J＝1.2Hz,1H),7.50(dt,J＝7.7,3.9Hz,2H),7.48–7.46(m,1H),7.30(td,J＝7.6,1.9Hz,1H),4.70(d,J＝13.7Hz,1H),4.23(ddd,J＝13.8,9.0,6.7Hz,1H),3.92(dd,J＝7.4,6.6Hz,1H),3.89(d,J＝13.7Hz,1H),3.58(ddd,J＝13.9,8.9,5.4Hz,1H),2.44–2.38(m,1H),2.32–2.26(m,2H),1.91(t,J＝7.4Hz,2H),1.89–1.83(m,1H),1.43(dd,J＝14.0,7.1Hz,4H),1.17(s,10H).
Example 10 (S) -7-bromo-10- (N-hydroxycaproamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A10)
The compound of example 10 was prepared in the same manner as in example 5 except that 2-bromomethyl-4-bromonitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to give a pale yellow solid powder in 29.6% yield. mp 255.7-257.6 ℃. 1 H NMR(600MHz,DMSO)δ10.30(s,1H),8.63(s,1H),7.75(d,J＝2.3Hz,1H),7.67(dd,J＝8.6,2.3Hz,1H),7.47(d,J＝8.7Hz,1H),4.74(d,J＝13.8Hz,1H),4.19(ddd,J＝14.0,9.0,6.8Hz,1H),3.97–3.93(m,1H),3.86(d,J＝13.8Hz,1H),3.54(ddd,J＝14.0,8.9,5.4Hz,1H),2.40(dddd,J＝12.5,10.6,8.2,6.6Hz,1H),2.33–2.26(m,2H),1.92–1.82(m,3H),1.43(pd,J＝13.6,7.8Hz,4H),1.16(dt,J＝14.9,7.4Hz,2H).
Example 11 (S) -7-bromo-10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A11)
The compound of example 11 was prepared in the same manner as in example 6 except that 2-bromomethyl-4-bromonitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to give a pale yellow solid powder in 29.6% yield. mp 255.7-257.6 ℃. 1 H NMR(600MHz,DMSO)δ10.30(s,1H),8.63(d,J＝0.9Hz,1H),7.75(d,J＝2.3Hz,1H),7.67(dd,J＝8.6,2.3Hz,1H),7.47(d,J＝8.7Hz,1H),4.74(d,J＝13.8Hz,1H),4.19(ddd,J＝13.9,9.1,6.7Hz,1H),3.99–3.92(m,1H),3.85(d,J＝13.7Hz,1H),3.54(ddd,J＝14.0,8.9,5.4Hz,1H),2.40(dddd,J＝12.5,10.5,8.2,6.4Hz,1H),2.34–2.24(m,2H),1.86(ddd,J＝12.6,11.5,6.2Hz,3H),1.41(dd,J＝14.1,6.9Hz,4H),1.18(d,J＝3.0Hz,4H).
Example 12 (S) -7-bromo-10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A12)
The compound of example 12 was prepared in the same manner as in example 7 except that 2-bromomethyl-4-bromonitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to give a white solid powder in 28.4% yield. mp 256.7-258.1 ℃. 1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.75(d,J＝2.1Hz,1H),7.67(dd,J＝8.6,2.0Hz,1H),7.47(d,J＝8.6Hz,1H),4.74(d,J＝13.8Hz,1H),4.20(ddd,J＝14.1,8.9,6.9Hz,1H),3.96(t,J＝6.9Hz,1H),3.85(d,J＝13.7Hz,1H),3.55(ddd,J＝14.0,8.7,5.5Hz,1H),2.45–2.36(m,1H),2.35–2.24(m,2H),1.95–1.83(m,3H),1.43(dd,J＝14.0,7.0Hz,4H),1.19(d,J＝20.3Hz,6H).
Example 13 (S) -7-chloro-10- (N-hydroxycaproamide) -1,5,10,11 a-tetralinhydrogen-3H-benzo [ e ]]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A13)
The compound of example 13 was produced in the same manner as in example 5 except that 2-bromomethyl-4-chloronitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene, to obtain a white solid powder in a yield of 31.2%. mp 252.1-253.5 ℃. 1 H NMR(600MHz,DMSO)δ10.33(s,1H),8.65(s,1H),7.63(s,1H),7.54(d,J＝1.0Hz,2H),4.74(d,J＝13.8Hz,1H),4.19(ddd,J＝14.1,9.0,6.8Hz,1H),3.95(t,J＝7.0Hz,1H),3.86(d,J＝13.7Hz,1H),3.55(ddd,J＝14.0,8.9,5.4Hz,1H),2.44–2.37(m,1H),2.33–2.26(m,2H),1.87(ddd,J＝12.6,11.5,6.2Hz,3H),1.48–1.39(m,4H),1.19–1.13(m,2H).
Example 14 (S) -7-chloro-10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A14)
The compound of example 14 was prepared in the same manner as in example 6 except that 2-bromomethyl-4-chloronitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to give a white solid powder in 33.1% yield. mp 252.1-253.5 ℃. 1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.63(s,1H),7.63(s,1H),7.56–7.52(m,2H),4.74(d,J＝13.8Hz,1H),4.20(ddd,J＝13.9,9.1,6.8Hz,1H),3.95(dd,J＝7.4,6.6Hz,1H),3.85(d,J＝13.7Hz,1H),3.55(ddd,J＝14.0,8.9,5.4Hz,1H),2.41(dddd,J＝12.5,10.5,8.2,6.5Hz,1H),2.33–2.27(m,2H),1.92–1.83(m,3H),1.45–1.37(m,4H),1.18(d,J＝2.9Hz,4H).
Example 15 (S) -7-chloro-10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A15)
The compound of example 15 was prepared in the same manner as in example 7 except that 2-bromomethyl-4-chloronitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to obtain a white solid powder in 31.2% yield. MP 253.4-255.6℃。 1 H NMR(600MHz,DMSO)δ10.30(s,1H),8.64(s,1H),7.62(s,1H),7.53(s,2H),4.74(d,J＝13.8Hz,1H),4.20(ddd,J＝14.0,8.9,6.8Hz,1H),3.95(t,J＝7.0Hz,1H),3.85(d,J＝13.7Hz,1H),3.54(ddd,J＝14.1,8.9,5.5Hz,1H),2.44–2.37(m,1H),2.32–2.25(m,2H),1.95–1.82(m,3H),1.43(dd,J＝13.9,6.9Hz,4H),1.21–1.11(m,6H).
EXAMPLE 16 (S) -7-methoxy-10- (N-hydroxycaproamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A16)
The compound of example 16 was prepared in the same manner as in example 5 except that 2-bromomethyl-4-methoxynitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene, to give a white solid powder in 24.4% yield. mp 224.2-225.4 ℃.
1 H NMR(600MHz,DMSO)δ10.30(s,1H),8.64(s,1H),7.42(d,J＝8.9Hz,1H),7.08(d,J＝2.9Hz,1H),7.03(dd,J＝8.8,2.9Hz,1H),4.68(d,J＝13.7Hz,1H),4.19(ddd,J＝13.8,9.1,6.7Hz,1H),3.93(t,J＝7.1Hz,1H),3.86(d,J＝13.6Hz,1H),3.79(s,3H),3.48(ddd,J＝13.9,9.1,5.2Hz,1H),2.40(dddd,J＝12.5,10.6,8.3,6.6Hz,1H),2.34–2.25(m,2H),1.92–1.81(m,3H),1.48–1.36(m,4H),1.16(dt,J＝14.3,7.3Hz,2H).
Example 17 (S) -7-methoxy-10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A17)
The compound of example 17 was prepared in the same manner as in example 6 except that 2-bromomethyl-4-methoxynitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene, to give a white solid powder in 24.4% yield. mp 224.2-225.4 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.64(s,1H),7.41(d,J＝8.8Hz,1H),7.08(d,J＝2.9Hz,1H),7.03(dd,J＝8.8,2.9Hz,1H),4.68(d,J＝13.7Hz,1H),4.20(ddd,J＝13.7,9.2,6.7Hz,1H),3.93(dd,J＝7.3,6.8Hz,1H),3.85(d,J＝13.6Hz,1H),3.79(s,3H),3.51–3.45(m,1H),2.40(dddd,J＝12.5,10.6,8.3,6.6Hz,1H),2.33–2.25(m,2H),1.94–1.82(m,3H),1.44–1.35(m,4H),1.18(d,J＝3.1Hz,4H).
Example 18 (S) -7-methoxy-10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A18)
The compound of example 18 was prepared in the same manner as in example 7 except that 2-bromomethyl-4-methoxynitrobenzene was used in the first step in place of o-bromomethyl nitrobenzene to give a white solid powder in 25.5% yield. mp.212.4-214.3 ℃. 1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.41(d,J＝8.8Hz,1H),7.08(d,J＝2.9Hz,1H),7.03(dd,J＝8.8,2.9Hz,1H),4.69(d,J＝13.7Hz,1H),4.21(ddd,J＝13.7,9.0,6.7Hz,1H),3.94–3.91(m,1H),3.85(d,J＝13.6Hz,1H),3.79(s,3H),3.49(ddd,J＝13.9,9.0,5.3Hz,1H),2.41(dddd,J＝12.5,10.6,8.3,6.6Hz,1H),2.34–2.24(m,2H),1.94–1.80(m,3H),1.46–1.35(m,4H),1.21–1.12(m,6H).
Example 19 (S) -7-O-methylbenzene-10- (N-hydroxyhexanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A19)
The compound of example 19 was prepared in the same manner as in example 5 except that 2-methyl-3 '-bromomethyl-4' -nitrobiphenyl was used in the first step instead of o-bromomethyl nitrobenzene, to obtain a white solid powder in a yield of 28.6%. mp 255.4-257.6 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.64(d,J＝1.4Hz,1H),7.56(d,J＝9.0Hz,1H),7.47(s,1H),7.45(d,J＝2.1Hz,1H),7.32–7.23(m,4H),4.77(d,J＝13.8Hz,1H),4.20(ddd,J＝13.8,9.3,6.5Hz,1H),4.03(dd,J＝7.6,6.3Hz,1H),3.95(d,J＝13.7Hz,1H),3.64(ddd,J＝14.1,9.1,5.2Hz,1H),2.45(dddd,J＝12.7,10.5,8.1,6.2Hz,1H),2.36–2.28(m,2H),2.27(s,3H),1.90(t,J＝7.2Hz,3H),1.46(qd,J＝13.6,7.4Hz,4H),1.21(dd,J＝15.5,7.8Hz,2H).
Examples20 (S) -7-O-methylbenzene-10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e ]]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A20)
The compound of example 20 was prepared in the same manner as in example 6 except that 2-methyl-3 '-bromomethyl-4' -nitrobiphenyl was used in the first step instead of o-bromomethyl nitrobenzene, to obtain a white solid powder in 29.6% yield. mp 255.4-257.6 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.63(s,1H),7.56(d,J＝8.9Hz,1H),7.47(s,1H),7.46–7.44(m,1H),7.28(dqd,J＝12.8,9.0,1.8Hz,4H),4.76(d,J＝13.8Hz,1H),4.21(ddd,J＝13.8,9.2,6.6Hz,1H),4.03(dd,J＝7.6,6.2Hz,1H),3.94(d,J＝13.7Hz,1H),3.67–3.60(m,1H),2.48–2.41(m,1H),2.35–2.28(m,2H),2.26(s,3H),1.94–1.86(m,3H),1.46(ddt,J＝28.8,14.3,6.9Hz,4H),1.22(s,4H).
Example 21 (S) -7-O-methylbenzene-10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A21)
The compound of example 21 was prepared in the same manner as in example 7 except that 2-methyl-3 '-bromomethyl-4' -nitrobiphenyl was used in the first step in place of o-bromomethyl nitrobenzene, in a yield of 31.2%. mp 253.4-259.6 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.55(d,J＝8.8Hz,1H),7.46(d,J＝5.6Hz,2H),7.32–7.21(m,4H),4.77(d,J＝13.8Hz,1H),4.25–4.19(m,1H),4.04–4.00(m,1H),3.94(d,J＝13.7Hz,1H),3.67–3.60(m,1H),2.48–2.41(m,1H),2.34–2.28(m,2H),2.26(s,3H),1.89(dt,J＝15.6,7.6Hz,3H),1.52–1.41(m,4H),1.20(dd,J＝15.9,8.7Hz,6H).
EXAMPLE 22 (R) -10- (N-hydroxycaproamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A22)
The compound of example 22 was prepared in the same manner as in example 5 except that methyl L-pyroglutamate was replaced with methyl D-pyroglutamate in the first step. A white solid powder was obtained in 25.6% yield. mp 161.2-163.6 ℃.
1 H NMR(600MHz,DMSO)δ10.32(s,1H),8.67(s,1H),7.48(dd,J＝17.5,7.6Hz,3H),7.31(t,J＝6.4Hz,1H),4.70(d,J＝13.7Hz,1H),4.26–4.16(m,1H),3.94–3.86(m,2H),3.61–3.54(m,1H),2.42(dt,J＝14.5,9.0Hz,1H),2.36–2.25(m,2H),1.88(dd,J＝17.5,10.2Hz,3H),1.48–1.36(m,4H),1.21–1.12(m,2H).
EXAMPLE 23 (R) -10- (N-hydroxyheptanamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A23)
The compound of example 23 was prepared in the same manner as in example 6 except that methyl L-pyroglutamate was replaced with methyl D-pyroglutamate in the first step. A white solid powder was obtained in 23.7% yield. mp 193.4-194.9 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.53–7.44(m,3H),7.33–7.28(m,1H),4.70(d,J＝13.7Hz,1H),4.22(ddd,J＝13.9,9.1,6.7Hz,1H),3.93–3.87(m,2H),3.58(ddd,J＝14.0,9.0,5.3Hz,1H),2.46–2.38(m,1H),2.35–2.25(m,2H),1.89(t,J＝7.5Hz,2H),1.42(dd,J＝14.5,7.2Hz,4H),1.18(s,4H).
EXAMPLE 24 (R) -10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A24)
The compound of example 24 was produced in the same manner as in example 7 except that methyl D-pyroglutamate was used in the first step in place of methyl L-pyroglutamate to obtain a white solid powder in a yield of 20.7%. mp 206.4-207.9 ℃. 1 HNMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.51–7.44(m,3H),7.31–7.27(m,1H),4.70(d,J＝13.7Hz,1H),4.22(ddd,J＝13.9,9.0,6.7Hz,1H),3.89(dd,J＝17.9,10.8Hz,2H),3.57(ddd,J＝14.0,8.9,5.4Hz,1H),2.45–2.38(m,1H),2.33–2.25(m,2H),1.94–1.82(m,3H),1.46–1.37(m,4H),1.17(t,J＝10.4Hz,6H).
EXAMPLE 25 (R) -7-chloro-10- (N-hydroxyoctanoamide) -1,5,10,11 a-tetrahydro-3H-benzo [ e]Pyrrolo [1,2 ]][1,4]Diaza-type
-3,11 (2H) -dione (A25)
The compound of example 25 was produced in the same manner as in example 15 except that methyl D-pyroglutamate was used in the first step in place of methyl L-pyroglutamate, to obtain a white solid powder in a yield of 31.2%. mp 253.4-255.6 ℃.
1 H NMR(600MHz,DMSO)δ10.31(s,1H),8.65(s,1H),7.63(s,1H),7.56–7.52(m,2H),4.75(d,J＝13.8Hz,1H),4.21(ddd,J＝13.9,9.0,6.8Hz,1H),3.96(dd,J＝7.3,6.6Hz,1H),3.85(d,J＝13.7Hz,1H),3.55(ddd,J＝14.0,8.9,5.5Hz,1H),2.41(dddd,J＝12.5,10.5,8.2,6.4Hz,1H),2.35–2.26(m,2H),1.94–1.83(m,3H),1.47–1.37(m,4H),1.21–1.12(m,6H).
Pharmacological investigation of the products of the invention
Pharmacological tests prove that the compound of the embodiment of the invention has the activities of resisting fibrosis, tumor metastasis and tumor growth.
1. Substrate-enzyme binding assay
Using a substrate-enzyme binding assay, various concentrations of the example compounds were incubated with HDAC6 substrate and enzyme, and inhibition of HDAC6 activity by the example compounds was measured by the resulting fluorescence intensity.
The Ac-Lys (Ac) -AMC fluorogenic substrate was diluted to 80. Mu.M for use with buffer and the HDAC6 enzyme was diluted to 1. Mu.g/mL for use. Subsequently, a black ELISA plate was used, and HDAC6 enzyme having a volume of 10. Mu.L, 20. Mu.L of the fluorogenic substrate and 20. Mu.L of the gradient-diluted example compound were added to the wells and mixed uniformly, and incubated in a constant temperature incubator at 37℃for 2 hours. Then 50. Mu.L of stop solution was added to each well and incubated again at 37℃for 15min to terminate the reaction. Fluorescence intensity (excitation wavelength 380nm, emission wavelength 460 nm) was then detected using a multifunctional microplate reader. The results are shown in Table 1.
Table 1 substrate-enzyme binding experiments to investigate the effect of compounds on HDAC6 activity
| Compd. | IC 50 (nM) | Compd. | IC 50 (nM) |
| A1 | 38.799 | A14 | 27.081 |
| A2 | 147.002 | A15 | 137.774 |
| A3 | 789.663 | A16 | 45.456 |
| A4 | 654.913 | A17 | 153.468 |
| A5 | 24.138 | A18 | 352.143 |
| A6 | 32.22 | A19 | 34.79 |
| A7 | 21.419 | A20 | 52.436 |
| A8 | 22.383 | A21 | 22.653 |
| A9 | 94.731 | A22 | 32.540 |
| A10 | 23.797 | A23 | 44.234 |
| A11 | 25.146 | A24 | 24.878 |
| A12 | 86.581 | A25 | 168.144 |
| A13 | 21.655 |
* IC of Compounds with HDAC6 inhibitory Activity 50 Values, data are expressed as mean ± standard deviation of three independent experiments.
Experimental results show that the compound of the invention can inhibit the activity of HDAC6 to different degrees, wherein the lead compound A7 has the strongest inhibition effect on the activity of HDAC6, and IC thereof 50 The value was 21.419nM.
2. MTT assay for inhibition of proliferation of cells by Compounds of examples
Taking MDA-MB-231 cells, pancreatic cancer cells (PANC-1) and lung cancer cells (A549) grown in logarithmic phase, digesting with 0.25% trypsin, preparing into single cell suspension with corresponding culture medium containing no serum or 10% FBS, and mixing with culture medium of 6×10 4 The cells were seeded at a density of 100. Mu.L per well in 96-well plates at 37℃in 5% CO 2 Or no CO 2 Culturing in a saturated humidity incubator for 12h to adhere cells. The culture medium in the wells was pipetted off, 100. Mu.L of culture medium containing different concentrations of the compound of example A series was added to each well, and incubated in an incubator for the corresponding time. After the incubation, the culture broth was aspirated, and a culture broth containing 10%5mg/mL MTT was added and placed in an incubator for incubation for 4 hours. Removing supernatant, adding 150 μl DMSO into each well, shaking 96-well plate on an oscillator for 10min to dissolve crystals, measuring OD value at 492nm, calculating proliferation inhibition rate of drug on cells, and calculating half Inhibition Concentration (IC) using SPSS data processing software 50 ). The results are shown in Table 2.
TABLE 2 MTT assay for growth inhibition of A-series Compounds on different tumor cells and Normal cells
Data are expressed as mean ± standard deviation of three independent experiments.
Experimental data show that the compounds A3-A9 have strong proliferation inhibition effect on MDA-MB-231 cells. To investigate whether compounds A3-A9 selectively inhibited proliferation of tumor cells, we selected both C2C12 and HELF normal cells for validation. The results show that (Table 3-5), except A8 and A9, the other compounds have no obvious cytotoxicity to normal cells, and can selectively inhibit proliferation of tumor cells.
3. Western blot experiment:
(1) total cell protein extraction
Taking a proper amount of RIPA lysate according to the weight ratio of 100:1, adding PMSF according to the proportion to prepare a cell lysate, discarding the culture solution of the cells to be extracted, adding a small amount of PBS to wash the cells, sucking the residual PBS, adding the cell lysate according to 100 mu L of each culture dish, and lysing for 15min at 4 ℃. The obtained lysate was centrifuged in a 1.5ml EP tube at 12000rpm for 15min at 4deg.C, and the supernatant was the desired protein extract.
(2) Protein concentration determination using BCA kit
Detecting and drawing an absorbance-protein concentration curve, obtaining a protein concentration calculation formula by linear regression, and carrying the absorbance value obtained by detecting each protein extracting solution into the formula to obtain the protein concentration of the sample.
(3) Polyacrylamide gel electrophoresis protein sample preparation
Adding the protein extract in the step (1) into a clean centrifuge tube, adding a 5X sample loading buffer solution according to the ratio of 1:4, placing the centrifuge tube into boiling water, boiling for 10min, cooling at room temperature, and storing at low temperature for standby, so as to avoid repeated freezing and thawing.
(4) SDS-PAGE gel electrophoresis
Glue making
Sequentially adding corresponding reagents into a clean centrifuge tube according to the formulas of the glue with different concentrations, quickly adding the reagents into a pre-installed glass glue plate after the preparation is completed, and adding isopropanol to carry out liquid sealing on a glue plane and flattening the glue plane. After gelation, the isopropanol was discarded; the upper glue layer is configured by adopting the same method, and the comb is quickly vertically inserted into the middle of the glass plate while being added into the glass glue plate so as to ensure that no bubbles are generated. After gelation, the gel was transferred to an electrophoresis apparatus, and after adding the prepared electrophoresis liquid (1×), the comb was pulled out vertically slowly and with uniform force to ensure that the gel was not deformed.
Electrophoresis
The wet transfer method is adopted for electric transfer, and the electric transfer is carried out on a clamp for electric transfer according to the sequence of sponge-filter paper-gel-PVDF film-filter paper-sponge, so that bubbles are avoided in the whole process. And (3) placing the fixed clamp and the matched ice bag into an electrotransfer instrument, switching on a power supply after filling electrotransfer liquid, setting the electrotransfer instrument to 100V, performing electrotransfer at a low temperature of 4 ℃, and adjusting the transfer time according to the molecular weight of the target protein.
Electric rotating device
The wet transfer method is adopted for electric transfer, and the electric transfer is carried out on a clamp for electric transfer according to the sequence of sponge-filter paper-gel-PVDF film-filter paper-sponge, so that bubbles are avoided in the whole process. And (3) placing the fixed clamp and the matched ice bag into an electrotransfer instrument, switching on a power supply after filling electrotransfer liquid, setting the electrotransfer instrument to 100V, performing electrotransfer at a low temperature of 4 ℃, and adjusting the transfer time according to the molecular weight of the target protein.
Antibody incubation
The strips were transferred to PVDF membrane and placed in the prepared sealing solution and the shaker was sealed for 1h at room temperature. After washing with TBST, incubation was carried out overnight at 4℃with diluted primary antibody. The next day the membranes were washed and incubated with diluted secondary antibodies for 1h at room temperature.
Development process
Protein development was performed using chemiluminescent reagent ECL and image acquisition was performed using a gel imaging system. The results are shown in FIG. 1.
Experimental results indicate that compounds A3-A9, tubacin and SAHA all induce up-regulation of Ac- α -tubulin expression levels to varying degrees, but only a broad spectrum of HDACi SAHA induces hyperacetylation of history H3. From the quantitative results, it can be seen that A7 has the strongest acetylation promotion effect on alpha-tubulin; and A7 can induce the increase of Ac-alpha-tubulin expression level in a dose-dependent manner without obvious influence on the expression of Ac-history H3. The above results indicate that compounds A3-A9 can specifically act on non-histone substrates of HDAC6 and are specific inhibitors of HDAC 6.
4. Intracellular HDAC6 activity assay
HDAC6 activity in cells was detected using the BioVision HDAC6 activity assay kit. Cells treated with the compound of example A series were seeded into 6-well plates (2X 10) 4 Individual/well) for 48h. After washing with cold PBS, cells per well (2×10 6 ) Mu.l of HDAC6 was added to the mixture to be gently cleaved, and incubated on ice for 5 minutes. The cytoplasmic fraction was prepared by centrifugation at 16000r for 10min at 4 ℃. The supernatant was transferred to a pre-chilled 0.5mL EP tube and quantified using BCA protein quantification kit. Mu.l of diluted protein was added to 40. Mu.l of pre-chilled HDAC6 assay buffer followed by 50. Mu.l of HDAC6 substrate per well and incubated at 37℃for 30 min in the absence of light. Finally, 10 μl of developer was added to each well and incubated again for 10 minutes at 37 ℃ to generate fluorescence. Fluorescence intensity was measured using a multifunctional microplate reader (excitation wavelength 380nm, emission wavelength 490 nm). The results are shown in FIG. 2.
Experimental results show that the compounds A3-A9 can inhibit the activity of HDAC6 in MDA-MB-231 cells to different degrees, wherein the inhibition effect of A7 is strongest; and A7 can significantly inhibit the activity of HDAC6 in MDA-MB-231 cells in a dose dependent manner without significant cytotoxic concentrations.
5. Migration experiment
Human breast cancer MDA-MB-231 cells were seeded onto 6-well plates for wound healing assays. When the cells reached 100% confluence, a10 μl tip was used to form a scratch on the cell monolayer and the cells were washed to remove debris. Cells were incubated in fresh medium with or without A7 or HDAC6 inhibitor (Tubacin) for 48h, cell migration images were taken with an inverted microscope at 0h and 48h, and migration results were quantified with Image J software. The results are shown in FIG. 3A and FIG. 3B.
Experimental results show that MDA-MB-231 cells are treated for 48h by using the A7 with the non-cytotoxic concentration, and Tubacin (5 mu M) is used as a positive control, and the experimental results show that the A7 remarkably inhibits the migration capacity of the MDA-MB-231 cells in a dose-dependent manner.
6. Invasion experiment
Transwell experiments were performed using a 24-well matrigel invasion chamber (BD Biosciences). After trypsinization of the cells, the density of the cells was adjusted to 3×10 5 And each ml. Cell suspensions with or without A7 or HDAC6 inhibitors (Tubacin) were inoculated into the upper Transwell chamber, 500 μl of 10% serum-containing culture medium was added to the lower chamber, and after incubation for 24 hours, the cells on the upper surface of the chamber were wiped and fixed with 4% paraformaldehyde on the lower surface, followed by staining with crystal violet. The results are shown in FIG. 3C and FIG. 3D.
Experimental results show that the influence of A7 on the invasive capacity of MDA-MB-231 cells is studied using a Transwell laboratory experiment. MDA-MB-231 cells were treated with a cytotoxic concentration of A7 for 24h and Tubacin (5. Mu.M) was used as a positive control, and the data showed that A7 significantly inhibited the invasive capacity of MDA-MB-231 cells in a dose-dependent manner. In summary, the novel HDAC6 inhibitor A7 designed by the subject significantly inhibits migration and invasion ability of MDA-MB-231 cells by specifically inhibiting the activity of HDAC 6.
7. In vivo nude mouse tumor metastasis experiment
The effect of A7 on breast cancer metastasis in nude mice was observed by tail vein injection MDA-MB-231 cell modeling and continuous administration for 8 weeks. The results are shown in FIGS. 4 and 5.
Detecting the index: HE staining, immunohistochemistry (Ki 67 malignant tumor proliferation)
Detecting tissue: lung, liver and kidney
The pathological changes of the lung tissue and the liver tissue of the nude mice of each experimental group are detected by adopting an HE staining method, and the HE staining result of the lung tissue shows that the pulmonary alveolus morphological structure of the lung tissue of the control group is regular and the cells are arranged normally; the structure of the alveoli of the mice in the model group is damaged, the alveoli become smaller, disordered and even collapse, the cells are in different shapes and sizes in disordered arrangement, the cytoplasm is rich, the cell nucleus is enlarged, and the dyeing is deepened; the A7 administration group obviously reduces the alveolar injury of the lung tissue of the nude mice caused by breast cancer metastasis, the alveolar morphological structure of the administration group mice is clearer, and the alveolar cavity collapse and disorder phenomenon are obviously reduced. The HE staining result of the liver tissue shows that the normal liver tissue cells of the nude mice are arranged normally; the liver tissue cells of the model group are irregularly arranged, have disordered structures, are unobvious in hepatic chordae, have small liver blood sinuses, have large cell nuclei and are deeply stained, and are accompanied by inflammatory cell infiltration; and the arrangement of the liver tissue structure of the A7 administration group is regular, so that the liver injury caused by breast cancer metastasis is obviously inhibited.
Ki67 is a malignant tumor cell proliferation marker whose expression level is abnormally up-regulated in tumor tissues, and a large number of proliferating tumor cells are often present in tumor metastasis tissues, so Ki67 is also often used as a marker of tumor metastasis. The subject adopts an immunohistochemical method to detect the variation of Ki67 and Ac-alpha-tubulin expression levels in the lung tissue and liver tissue of each group of nude mice, and as shown in the figure, ki67 expression in normal lung and liver tissue is less or even not; a large number of brown particles can be observed in both lung and liver tissues of the model group, which positively stained for Ki67, and a large number of positive expression of Ki67 marks the formation of tumor metastasis; while a small amount of Ki67 positive staining exists in lung and liver tissues of the A7 administration group, but the expression level is remarkably reduced compared with the model group, and the increase of Ki67 expression caused by breast cancer metastasis can be inhibited by the A7 in a dose-dependent manner, which shows that the A7 can effectively inhibit the metastasis of the breast cancer in the nude mice.
The variation of the expression quantity of Ac-alpha-tubulin in each group of nude mice tissues is opposite to Ki67, and the positive staining of Ac-alpha-tubulin in the lung and liver tissues of the model group is obviously reduced compared with that of the control group; a7 significantly increased the expression level of Ac- α -tubulin in lung and liver tissues, and showed a dose-dependent relationship, indicating that A7 induced an increase in the Ac- α -tubulin expression level by acting on HDAC6 in nude mice.
Research shows that the metastasis site of breast cancer is common in lung and liver metastasis, and in the experiment, A7 remarkably increases the expression of Ac-alpha-tubulin by specifically inhibiting the activity of HDAC6 in lung and liver tissues of nude mice; and the A7 can obviously reduce the damage of lung tissues and liver tissues of mice caused by breast cancer metastasis, reduce the formation of breast cancer metastasis focus and obviously inhibit the metastasis of breast cancer in nude mice. From the above experimental results, A7 effectively inhibits metastasis of breast cancer in vivo and in vitro by specifically inhibiting the activity of HDAC 6.
8. C57BL/6J mouse pulmonary fibrosis experiment
The effect of A7 on pulmonary fibrosis in C57BL/6J mice was observed by tracheal injection of Bleomycin (BLM) molding and continuous dosing for 21 days. The results are shown in FIG. 6.
Detecting the index: masson staining, HE staining
Detecting tissue: lung (lung)
The pathological changes of the lung tissues of the C57BL/6J mice in each experimental group are detected by adopting a Masson staining method and an HE staining method, and the HE staining result of the lung tissues shows that the pulmonary alveolus morphological structure of the lung tissues in the control group is regular and the cells are arranged normally; the alveolar structure of the mice in the model group is damaged, the alveoli are smaller and collapse, the cell size and morphology are different, obvious fibrotic tissues are generated, and the staining is deepened; the A7 administration group obviously reduces the injury of the lung tissue of the C57BL/6J mice caused by fibrosis, the morphological structure of the alveoli of the administration group mice is clearer, and the alveolar collapse and fibrosis phenomena are obviously reduced.
In summary, a number of pharmacological experiments indicate that the structural compound has the inhibitory activity of HDAC6 and has the activities of anti-fibrosis, anti-tumor metastasis and anti-tumor growth in the aspect of indications.
Claims (9)
1. A pyrrolobenzodiazepine compound or pharmaceutically acceptable salt of the structure:
n=3-9；p=1-3；m=0-3。
2. the pyrrolobenzodiazepine compound or pharmaceutically acceptable salt of claim 1,
wherein n=5-9; p=1-2; m=0-1.
3. The pyrrolobenzodiazepine compound or pharmaceutically acceptable salt of claim 1 or 2,
wherein R is 1 、R 2 、R 3 、R 4 The independent method is as follows: h atom, bromine atom, chlorine atom, methoxy group, 2-methyl-phenyl group.
4. A pyrrolobenzodiazepine compound or pharmaceutically acceptable salt selected from the group consisting of:
5. a process for the preparation of a pyrrolobenzodiazepine compound or pharmaceutically acceptable salt as claimed in claim 1, wherein:
carrying out substitution reaction on substituted o-nitrobenzyl bromide and L or D-type pyroglutamic acid methyl ester in the presence of NaH to obtain an intermediate A-1, carrying out ferrite reduction reaction cyclization on the intermediate A-1 to obtain an intermediate A-2, carrying out substitution reaction on the intermediate A-2 in a system of NaH and DMF to obtain an intermediate A-3 or B-3, and synthesizing the compound of claim 1 through ammonolysis reaction;
wherein R is 1 、R 2 、R 3 、R 4 M, p, n are as defined in claim 1.
6. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1-4 and a pharmaceutically acceptable carrier.
7. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 for the preparation of a histone deacetylase 6 inhibitor.
8. Use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 for the manufacture of an anti-fibrotic medicament.
9. Use of a compound or a pharmaceutically acceptable salt according to any one of claims 1-4 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for anti-tumour growth or anti-tumour metastasis.
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