CN112142818B - Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof - Google Patents

Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof Download PDF

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CN112142818B
CN112142818B CN201910572404.0A CN201910572404A CN112142818B CN 112142818 B CN112142818 B CN 112142818B CN 201910572404 A CN201910572404 A CN 201910572404A CN 112142818 B CN112142818 B CN 112142818B
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oleanane
nmr
300mhz
esi
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CN112142818A (en
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孙宏斌
胡凯文
刘柳
程亚龙
秦鹿柘
李浩斌
戴量
柳军
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China Pharmaceutical University
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Abstract

The invention discloses derivatives of pentacyclic triterpene type AMPK agonists oleanolic acid and delta-oleanolic acid and medical application thereof, in particular to a compound shown in a formula I or a formula II, and pharmaceutically acceptable salt, ester or solvate thereof, which can be used for preparing an AMPK agonist with activity of enhancing AMPK phosphorylation level and preparing a medicament for preventing or treating AMPK mediated diseases. The novel pentacyclic triterpene compound has remarkable AMPK agonistic activity, the activity of the pentacyclic triterpene compound is remarkably superior to that of a recognized AMPK agonist AICAR, and the pentacyclic triterpene compound has better pharmacokinetic properties such as oral bioavailability and very good safety;

Description

Derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof
Technical Field
The invention relates to the field of biological medicine, relates to novel pentacyclic triterpene compounds with AMPK (AMPK) agonistic activity, in particular to derivatives of oleanolic acid and delta-oleanolic acid and medical application thereof, and further relates to application of the compounds in preparation of medicines for preventing or treating diseases mediated by AMPK and pharmaceutical compositions thereof.
Background
AMPK (adenylate activating protein kinase) is a key kinase regulating energy metabolism and inflammatory response in the body, and its phosphorylation activation can overcome insulin resistance, reduce blood sugar, reduce blood lipid (by inhibiting synthesis of fatty acids and cholesterol), resist inflammation, apoptosis, fibrosis, promote mitochondrial synthesis, enhance oxidative metabolism of mitochondria, resist aging, and tumor etc. (physiol. Rev.2009,89,1025). In recent years, the anti-inflammatory and anti-fibrotic effects of AMPK have been attracting attention (Nature 2013,493,346), a possible mechanism of which is that AMPK exerts anti-inflammatory and anti-fibrotic effects by enhancing the transcriptional function of estrogen-related receptor α (errα) (Immunity 2015,43,80).
There is growing evidence that AMPK dysfunction is closely related to the development and progression of a variety of diseases. AMPK mediated diseases include metabolic diseases and cardiovascular and cerebrovascular diseases, such as insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy, diabetic ulcers, etc.), non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, gout, stroke, cerebral infarction, etc.; AMPK mediated diseases also include inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neuro-damaging diseases or diseases secondary to pathogen infection, such as pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibropulmonary disease, allergic rhinitis, inflammatory bowel disease (such as crohn's disease and ulcerative colitis), polycystic kidney disease, polycystic ovary syndrome (PCOS), behcet's disease, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloids, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyodermatitis, parkinson's disease, alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, down's pain, 62-chorea, huntington's disease, or the like.
The literature reports that AMPK agonists can prevent and treat a variety of AMPK mediated diseases (J.Med.Chem., 2015,58 2;Nature 2013,493,346;Experimental Neurology 2017,298,31;Biochemical Pharmacology 2010,80,1708;Current Drug Targets,2016,17,908;Nat Rev Drug Discov,2019,DOI:10.1038/s 41573-019-0019-2). For example, the widely used hypoglycemic agent, metformin, is thought to exert a variety of clinical effects mainly by activating AMPK (j.clin. Invest.2001,108, 1167). Although AMPK agonists have broad clinical application prospects, to date, there has been no substantial progress in developing novel safe, effective AMPK agonists. There are few AMPK agonists under investigation that have entered the clinical stage of research for safety or efficacy reasons. For example, the broad-spectrum AMPK-beta subunit agonist MK-8722, while reducing blood glucose, was found to produce irreversible myocardial hypertrophy side effects in animal hearts in rat and monkey experiments (Science 2017,357,507). In addition, AICAR was one of the most commonly used AMPK agonists (Eur. J. Biochem.1995,229, 558) and was also terminated in clinical trials due to its large toxic side effects (J Clin Pharmacol 1991, 31:342-347).
In conclusion, there is a great need in clinic to develop novel AMPK agonists with high activity and low toxic side effects. On the other hand, oleanolic acid is a pentacyclic triterpene commonly found in medicinal plants, which has a broad range of biological activities (Nat Prod Rep 2011,28,543). While 3β -hydroxy-oleanane-13 (18) -en-28-oic acid (δ -oleanolic acid) is a very rare pentacyclic triterpenic acid (Phytochemistry 1999,51,83) in nature. To date, little literature reports on the bioactivity of delta-oleanolic acid.
Disclosure of Invention
The invention aims to: aiming at the problems existing in the prior art in the field of AMPK agonist research and development, the invention provides novel derivatives of oleanolic acid and delta-oleanolic acid; the novel oleanolic acid derivative or delta-oleanolic acid derivative provided by the invention is a novel AMPK agonist, so that the novel oleanolic acid derivative or delta-oleanolic acid derivative can be used for preparing medicaments for preventing or treating AMPK mediated diseases.
The present inventors have unexpectedly discovered a series of potent novel AMPK agonists when delta-oleanolic acid and oleanolic acid are structurally modified, and the AMPK agonistic activity thereof is significantly superior to that of the well-recognized AMPK agonist AICAR.
The technical scheme is as follows: in order to achieve the above object, a delta-oleanolic acid derivative or oleanolic acid derivative shown in the following formula I or formula II, a pharmaceutically acceptable salt or ester or solvate thereof, according to the present invention:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
r is H,Or R is a CO-；
R 1 Is H, C 1 -C 5 C substituted by alkyl or by substituent Y 1 -C 5 Alkyl, the substituent Y being OH, C (O) NH 2 、NH 2 、NHC(O)CH 3 Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonio or diethanolamino;
R a c being unsubstituted or substituted by substituents L 1 -C 5 Alkyl, said substituent L being one or two substituents independently selected from the group consisting of: OH, C (O) OH, NH 2 Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl or NHC (O) CH (CH) 3 )NHC(O)CH(CH 3 )NH；
R' is OR 2 、NR 3 R 4 Or (b)
R 2 Is C substituted by substituent Z 1 -C 5 Alkyl, said substituent Z being pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonium or diethanolamine;
R 3 is H or C 1 -C 3 An alkyl group;
R 4 is C substituted by substituent W 1 -C 5 Alkyl, the substituent W being pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonium, diethanolamine or acetylamino;
R 5 H, OH, F, NH attached to any carbon on the ring 2 、C 1 -C 3 Alkylamino, COOH, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, cycloalkyloxy or heterocycloalkyloxy;
q is CH 2 、O、NR 6 、S、SO 2 、CHR 7 Or a chemical bond;
R 6 is H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl acyl, C 1 -C 3 C substituted by alkylsulfonyl or by substituent P 1 -C 3 Alkyl, said substituent P being OH, COOH, NH 2 Or C 1 -C 3 An alkylamino group;
R 7 is OH, NH 2 、COOH、C 1 -C 3 Alkylamino, C 1 -C 3 Alkoxy, cycloalkyloxy or heterocycloalkyloxy;
n is 0, 1 or 2;
m is 0, 1 or 2.
In certain preferred embodiments, the compound of formula I or formula II, a pharmaceutically acceptable salt or ester or solvate thereof,
r is H,Or R is a CO-；
R 1 Is H, C 1 -C 5 C substituted by alkyl or by substituent Y 1 -C 5 Alkyl, the substituent Y being OH, C (O) NH 2 、NH 2 、NHC(O)CH 3 Pivot-pyridinePyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonio or diethanolamino;
R a c being unsubstituted or substituted by substituents L 1 -C 5 Alkyl, said substituent L being one or two substituents independently selected from the group consisting of: OH, C (O) OH, NH 2 Pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl or NHC (O) CH (CH) 3 )NHC(O)CH(CH 3 )NH；
R' is OR 2 、NR 3 R 4 Or (b)
R 2 Is C substituted by substituent Z 1 -C 5 Alkyl, said substituent Z being pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonium or diethanolamine; r is R 3 Is H;
R 4 is C substituted by substituent W 1 -C 5 Alkyl, the substituent W being pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-1, 1-dioxo-4-yl, N-dimethylamino, N-diethylamino, trimethylammonium, diethanolamine or acetylamino;
R 5 h, OH, F, NH attached to any carbon on the ring 2 、C 1 -C 3 Alkylamino or COOH;
q is CH 2 、O、NR 6 、S、SO 2 Or CHR (CHR) 7 ；
R 6 Is H, C 1 -C 3 Alkyl, C 1 -C 3 Alkyl acyl, C 1 -C 3 C substituted by alkylsulfonyl or by substituent P 1 -C 3 Alkyl, wherein the substituent P is OH,COOH、NH 2 Or C 1 -C 3 An alkylamino group;
R 7 is OH, NH 2 COOH or C 1 -C 3 An alkylamino group;
n is 0 or 1;
m is 0 or 1.
Still further, in the compounds of formula II, when the substituent Z is N, N-dimethylamino or trimethylammonio, R is not H; when the substituent W is acetylamino, R is not H.
In certain more preferred embodiments, the compound or pharmaceutically acceptable salt or ester or solvate thereof is selected from the following compounds:
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The compounds of the present invention may also be used as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactose diacid, D-glucuronic acid, glycerophosphate, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1, 5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharin acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, dichloroacetic acid, ethanesulfonic acid. On the other hand, the salt may also be a salt of the compound of the present invention with a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.), ammonium ion or choline. The compounds of the invention may also be formulated in the form of esters, prodrugs, N-oxides, or solvates thereof as pharmaceutical compositions.
Oleanolic acid can be purchased commercially. The synthesis of delta-oleanolic acid can be carried out by reference to the literature method (org. Biomol. Chem.,2016,14,11154), i.e. benzyl ester of delta-oleanolic acid is first prepared by reference to the literature method, and then the delta-oleanolic acid can be prepared by conventional catalytic hydrogenation debenzylation reaction. The synthesis of delta-oleanolic acid and oleanolic acid derivatives can be carried out by referring to the methods of the examples or modified methods.
The invention provides application of the compound shown in the formula I or the formula II, and pharmaceutically acceptable salt, ester or solvate thereof in preparing an AMPK agonist with activity of enhancing the phosphorylation level of AMPK. The compound has remarkable agonistic activity on AMPK, and can be used for preparing an AMPK agonist with activity of enhancing the phosphorylation level of the AMPK.
The invention also provides application of the compound shown in the formula I or the formula II, and pharmaceutically acceptable salt, ester or solvate thereof in preparing medicines for preventing or treating AMPK mediated diseases.
Wherein the AMPK mediated disease comprises metabolic disease, cardiovascular and cerebrovascular disease, inflammatory disease, autoimmune disease, organ fibrosis disease, neurodegenerative disease, secondary disease caused by pathogen infection, mitochondrial dysfunction or disorder disease or tumor.
The AMPK-mediated diseases, such as metabolic diseases and cardiovascular and cerebrovascular diseases, include: such as insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, retinopathy, neuropathy, diabetic ulcers, etc.), non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, gout, stroke, cerebral infarction, etc.
The AMPK-mediated diseases, such as inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve injury diseases or secondary diseases caused by pathogen infection, include: pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, allergic rhinitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), polycystic kidney disease, polycystic ovary syndrome (PCOS), behcet's disease, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloids, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyodermia gangrene, uveitis, parkinson's disease, alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, down's syndrome, hardon-Shi Pabing, huntington's chorea or Wilson's disease, and the like.
The AMPK-mediated diseases, such as mitochondrial dysfunction and disorder, include: muscle weakness, myoclonus, exercise intolerance, karsch-Sail syndrome, chronic fatigue syndrome, lishi syndrome, mitochondrial myopathy-encephalopathy-hyperlactinemia, stroke syndrome or stroke-like attacks. Likewise, the compounds of the invention may also be useful in the treatment of muscular dystrophy, e.g., duchenne muscular dystrophy, conchiolin muscular dystrophy or friedel-crafts ataxia.
The AMPK-mediated diseases, such as tumors, include: bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, hodgkin's lymphoma, non-hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningioma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, fibroneuroma, sarcoma, esophageal carcinoma, gastric carcinoma, pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, renal carcinoma, prostate carcinoma, lymphoma, testicular carcinoma, interstitial cell carcinoma, lung carcinoma, liver carcinoma, skin carcinoma, malignant melanoma, or basal cell carcinoma, and the like.
The invention relates to a pharmaceutical composition for preventing or treating AMPK mediated diseases, which contains a therapeutically effective amount of a compound of a formula I or a formula II or pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and pharmaceutically acceptable auxiliary materials. The optionally mixed adjuvants may be changed according to dosage form, administration form, etc. Examples of excipients include excipients, binders, disintegrants, lubricants, flavoring agents, coloring agents or sweeteners, and the like. The pharmaceutical composition can be in the form of conventional preparations such as capsules, powder, tablets, granules, pills, injection, syrup, oral liquid, inhalants, ointments, suppositories or patches.
If desired, the compounds of formula I or formula II of the present invention or pharmaceutically acceptable salts or esters or solvates thereof may be used in combination with one or more other types of agents for the prevention or treatment of AMPK mediated diseases, including but not limited to the following combinations.
The drug that may be optionally used in combination with the compounds of the present invention may be one or more antidiabetic drugs including metformin, sulfonylurea hypoglycemic agents (e.g., glibenclamide and glimepiride, etc.), glucosidase inhibitors (e.g., acarbose and miglitol, etc.), pparγ agonists (e.g., pioglitazone and rosiglitazone), pparα/γ dual agonists, dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, saxagliptin, alogliptin, and linagliptin, etc.), gliptin hypoglycemic agents (e.g., repagliptin and nateglinide, etc.), SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, enggliptin, eaglegliptin, lu Gelie net, tolgliptin, etc.), glucokinase agonists (e.g., HMS5552, etc.), insulin, glucagon-like peptide-1 (PTP-1) drugs (e.g., exenatide, liraglutide, dulcitaloide, and a glycogen-1, GPR-6, a phosphate agonist, a GPR-120, etc.
The drug which may be optionally used in combination with the compounds of the present invention may be one or more weight-reducing drugs including lorcaserin, orlistat and glucagon-like peptide-1 (GLP-1) type drugs (e.g., exenatide, liraglutide, lisinatide, dolraglutide, benraglutide, abilutide, etc.), and the like.
The drug which may be optionally used in combination with the compounds of the present invention may be one or more anti-nonalcoholic fatty liver disease drugs comprising: AMPK agonists (e.g., metformin), farnesoid X Receptor (FXR) agonists (e.g., obeticholic acid, GS-9674, EDP-305, LJN, etc.), acetyl-coa carboxylase (ACC) inhibitors (e.g., GS-0976, etc.), apoptosis-signaling kinase-1 (ASK 1) inhibitors (e.g., selonsertib, etc.), PPAR agonists (e.g., elafibranor, saroglitazar, IVA337 and MSDC-0602K, etc.), caspase (caspase), stearoyl-coa desaturase 1 (SCD 1) inhibitors (e.g., amamchol, etc.), long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglycol, etc.), apical sodium-dependent bile salt transporter (ASBT) inhibitors (e.g., volixibat, etc.), vascular adhesion protein 1 (VAP-1) inhibitors (e.g., BI 1467335, etc.), CCR5R blockers (e.g., ceririvic, etc.), and thyroid hormone β (e.g., MGL-3196, etc.
The drug which may be optionally used in combination with the compounds of the present invention may be one or more hypolipidemic drugs including niacin, statin drugs (e.g. lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin), cholesterol absorption inhibitors (e.g. ezetimibe etc.), fibrates (e.g. clofibrate, bezafibrate, fenofibrate etc.), PCSK9 inhibitors (e.g. Evolocumab and Alirocumab etc.), CETP inhibitors (e.g. anacetrapib etc.), AMPK agonists and ACC inhibitors (e.g. GS-0976 etc.), etc.
The amount of the compound of formula I or formula II of the present invention or a pharmaceutically acceptable salt or ester or solvate thereof may be appropriately changed according to the age, weight, symptoms, administration route, etc. of the patient. When administered to an adult (about 60 kg), the compound of formula I or formula II, or a pharmaceutically acceptable salt or ester or solvate thereof, is administered in an amount of 1mg to 1000mg per time, preferably 5mg to 500mg per time, more preferably 10mg to 60mg per time, 1 to 3 times per day. This dosage range may also vary depending on the degree of disease and the dosage form.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
(1) The novel derivatives of oleanolic acid and delta-oleanolic acid have potent AMPK agonistic activity, and the activity thereof is significantly superior to that of the acknowledged AMPK agonist AICAR.
(2) Compared with lead compounds delta-oleanolic acid and oleanolic acid, the novel pentacyclic triterpene compound has better oral bioavailability and other pharmacokinetic properties.
(3) Compared with the existing AMPK agonist AICAR (clinical test is terminated due to large toxic and side effects) and MK-8722 (irreversible myocardial hypertrophy side effects can be caused), the novel pentacyclic triterpene compound has very good safety.
(4) Compared with the existing AMPK agonist, the novel pentacyclic triterpene compound has the advantages of low cost, easy preparation, small potential side effect and the like, can be used independently, can be used in combination with one or more other types of drugs for preventing or treating AMPK mediated diseases, and is expected to become a novel drug for preventing or treating AMPK mediated diseases.
Drawings
FIG. 1 is a graph showing the effect of a fraction of compounds on the downstream signal pathway of AMPK from Huh-7 cells (Western Blot detection).
Detailed Description
The following is a detailed description of the present invention by way of examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention.
Example 1
(2- (trimethylammonio) ethyl) -3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amidebromide (Compound A-1)
Compound I-1 (1.27 g,5.0 mmol) was placed in a Schlenk tube, and a solution of trimethylamine in tetrahydrofuran (20 mL,40 mmol) was added thereto, and the mixture was heated at 55℃under argon atmosphere to react for 24 hours. After the reaction was completed, the mixture in the reaction tube was transferred to a eggplant-shaped bottle with methylene chloride, concentrated under reduced pressure, and the residue was suction-filtered, and the cake was washed with methylene chloride (5 ml×3) to give compound I-2 (white solid, 1.166g, yield 75%).
Compound I-2 (1.166 g,3.723 mmol) was suspended in a mixed solution of chloroform and ethanol (20 mL, v: v=7:3), and after cooling to 0deg.C, hydrazine hydrate (340 μL) was added thereto, and the mixture was heated under reflux at 50deg.C under argon atmosphere for 12 hours. After the reaction is finished, the reaction solution is filtered, a filter cake is washed by a mixed solvent of chloroform and ethanol (5 mL multiplied by 3, v: v=8.5:1.5), filtrate is concentrated and dried, and a crude product of the compound I-3 is obtained and is directly used for the next reaction.
The crude product of the compound I-3 obtained in the above step was dissolved in deionized water (2 mL), cooled to 0℃and aqueous hydrobromic acid (2 mL, 48%) was added thereto and stirred at 0℃for 1 hour. A mixed solvent of toluene and methanol (5 mL, v: v=4.5:0.5) was added to the reaction mixture, the mixture was concentrated under reduced pressure at 45℃to repeat the procedure twice, and a large amount of white solid was precipitated, suction-filtered, and the cake was washed with deionized water (1 mL. Times.2). The filtrate was further added with a mixed solvent of toluene and methanol (5 mL, v: v=4.5:0.5), concentrated at 45 ℃ under reduced pressure until most of the solvent was removed, slurried with acetonitrile (5 mL), suction filtered, the filter cake washed with a small amount of methanol (1 mL), and dried to give compound I-4 (white solid, 915mg, two-step yield 93%): 1 H NMR(300MHz,D 2 O)δ3.82–3.73(m,2H),3.66–3.57(m,2H),3.30(s,9H).
delta-Oleanolic acid (delta-OA, 100mg,0.219 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (122. Mu.L, 0.876 mmol) was added, 2- (7-benzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 108mg,0.284 mmol) was added with stirring at room temperature, and after 1 hour of reaction, compound I-4 (58 mg,0.219 mmol) was added and the reaction mixture was warmed to 50 ℃. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and deionized water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with deionized water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound I-5 (white solid, 41mg, yield 30%).
Compound I-5 (175 mg, 0.281mmol) was suspended in anhydrous dichloromethane (10 mL), and N, N' -dicyclohexylcarbodiimide (DCC, 232mg,1.124 mmol), 4-dimethylaminopyridine (DMAP, 34mg, 0.281mmol) and monobenzyl phthalate (86 mg,0.337 mmol) were added in this order and reacted under stirring at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with deionized water (5 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, purification by silica gel column chromatography (dichloromethane: methanol=30:1) gave compound I-6 (white solid, 100mg, yield 41%).
Compound I-6 (100 mg,0.116 mmol) was dissolved in tetrahydrofuran (8 mL), 10% palladium on carbon (10 mg) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of TLC detection reaction, celite was filtered, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound a-1 (white solid, 66mg, 73% yield): 1 H NMR(300MHz,DMSO-d 6 )δ13.18(s,1H),7.79–7.69(m,1H),7.69–7.57(m,3H),7.17–7.08(m,1H),4.74–4.60(m,1H),3.59–3.43(m,2H),3.12(s,9H),2.81(d,J＝14.1Hz,1H),2.49–2.37(m,1H),2.17(d,J＝13.2Hz,1H),1.18(s,3H),0.93(s,3H),0.91(s,9H),0.84(s,3H),0.74(s,3H).ESI-MS:m/z 689.6[M-Br] + 。
example 2
N- (2- (dimethylamino) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-3)
Delta-oleanolic acid (5 g, 0.0111 mol) was taken and dissolved in anhydrous pyridine (35 mL), acetic anhydride (4 mL) was slowly added dropwise with stirring, and the mixture was heated and refluxed for 1 hour after the addition. After completion of the TLC detection reaction, the reaction solution was cooled to room temperature, and was dropped into ice water (20 mL. Times.2), a large amount of white solid was precipitated, suction filtration was performed, the cake was washed with water (10 mL. Times.3), n-hexane (10 mL. Times.3), vacuum-dried, and ethanol recrystallized to give Compound II-1 (white solid, 4.52g, yield 83%).
Compound II-1 (150 mg,0.30 mmol) was dissolved in anhydrous dichloromethane (5 mL), and oxalyl chloride (130. Mu.L, 1.50 mmol) and N, N-dimethylformamide (1 drop) were slowly added dropwise with stirring and reacted at room temperature for 3 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure to give Compound II-2 (yellow solid, 155mg, yield 100%).
N, N-dimethylethylenediamine (66. Mu.L, 0.60 mmol) was dissolved in anhydrous dichloromethane (5 mL), and a solution of Compound II-2 (155 mg,0.30 mmol) in anhydrous dichloromethane (5 mL) and triethylamine (84. Mu.L, 0.60 mmol) were slowly added dropwise with stirring and reacted at room temperature for 5 hours. After completion of the TLC detection reaction, methylene chloride (10 mL) was added to dilute the reaction solution, which was washed with saturated sodium hydrogen carbonate solution (10 mL. Times.3), water (10 mL. Times.3) and saturated brine (10 mL. Times.3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methylene chloride: methanol=20:1) to give compound II-3 (white solid, 143mg, yield 84%).
Compound II-3 (141 mg,0.248 mmol) was suspended in methanol (10 mL), potassium hydroxide (140 mg,2.48 mmol) was added, and stirred overnight at room temperature. After completion of the TLC detection, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was treated with ethyl acetate (20 mL) and water (20 mL), the organic phase was washed successively with water (20 ml×3) and saturated brine (20 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound II-4 (white solid, 87mg, yield 67%).
Compound II-4 (87 mg,0.165 mmol) was dissolved in anhydrous pyridine (10 mL), phthalic anhydride (245 mg,1.65 mmol) and 4-dimethylaminopyridine (20 mg,0.165 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of the TLC detection reaction, dichloromethane (20 mL) was added to dilute the reaction solution, which was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound a-3 (white solid, 93mg, yield 84%): 1 H NMR(300MHz,CDCl 3 )δ7.84–7.63(m,1H),7.63–7.51(m,1H),7.51–7.30(m,2H),6.72–6.50(m,1H),4.82–4.59(m,1H),3.77–3.43(m,2H),3.07–2.83(m,2H),2.83–2.70(m,1H),2.63(s,6H),2.41(d,J＝13.7Hz,1H),2.36–2.18(m,1H),1.16(s,3H),0.98(s,3H),0.87(s,9H),0.83(s,3H),0.72(s,3H).ESI-MS:m/z 673.3[M-H] - 。
example 3
N- (2- (1-piperidinyl) ethyl) -3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-4)
Referring to the procedure of example 2, N-dimethylethylenediamine was replaced with 1- (2-aminoethyl) piperidine to give compound A-4: 1 H NMR(300MHz,CDCl 3 )δ7.74(d,J＝7.1Hz,1H),7.52(d,J＝6.9Hz,1H),7.47–7.29(m,2H),6.77–6.64(m,1H),4.78–4.59(m,1H),3.75–3.46(m,2H),3.08–2.67(m,7H),2.43(d,J＝13.6Hz,1H),2.31(d,J＝10.1Hz,1H),1.16(s,3H),0.98(s,3H),0.88(s,3H),0.86(s,6H),0.79(s,3H),0.72(s,3H).ESI-MS:m/z 715.5[M+H] + 。
example 4
N- (2- (4-morpholinyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-5)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 4- (2-aminoethyl) morpholine produced compound A-5: 1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝5.8Hz,1H),7.63(d,J＝5.8Hz,1H),7.52–7.41(m,2H),6.57–6.46(m,1H),4.76–4.67(m,1H),3.76(s,4H),3.57–3.38(m,2H),2.81(d,J＝13.8Hz,1H),2.63(s,6H),2.45(d,J＝13.5Hz,1H),2.42–2.33(m,1H),1.18(s,3H),0.95(s,3H),0.90(s,3H),0.89(s,3H),0.87(s,3H),0.84(s,3H),0.74(s,3H).ESI-MS:m/z 715.5[M-H] - 。
example 5
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-6)
With reference to the method of example 2, the following will be describedN, N-dimethyl ethylenediamine is replaced by 1- (2-aminoethyl) pyrrolidine to prepare a compound A-6: 1 H NMR(300MHz,CDCl 3 )δ7.73(d,J＝7.3Hz,1H),7.49(d,J＝7.1Hz,1H),7.37(dt,J＝19.0,7.3Hz,2H),4.78–4.65(m,1H),3.72–3.54(m,2H),3.26–3.08(m,4H),3.08–2.95(m,2H),2.77(d,J＝13.3Hz,1H),2.42(d,J＝13.5Hz,1H),2.31(d,J＝12.0Hz,1H),1.16(s,3H),1.02(s,3H),0.88(s,3H),0.86(s,6H),0.82(s,3H),0.72(s,3H).ESI-MS:m/z 699.3[M-H] - 。
example 6
N- (2- (4-methyl-1-piperazinyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-8)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 1- (2-aminoethyl) -4-methylpiperazine produced compound a-8: 1 H NMR(300MHz,CDCl 3 )δ7.75(d,J＝6.9Hz,1H),7.64(d,J＝7.0Hz,1H),7.53–7.35(m,2H),6.46–6.36(m,1H),4.80–4.69(m,1H),3.54–3.30(m,2H),3.04–2.80(m,4H),2.73(s,5H),2.57(s,5H),2.53–2.45(m,1H),2.46–2.38(m,1H),1.24(s,3H),1.00(s,3H),0.97(s,3H),0.93(s,9H),0.78(s,3H).ESI-MS:m/z 730.5[M+H] + 。
example 7
N- (2- (4-morpholinyl) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-12)
Oleanolic acid (OA, 20g,0.044 mol) was dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (6 g,0.044 mol) was added, benzyl bromide (8 mL,0.044 mol) was slowly added dropwise with stirring, and after the addition was completed, the reaction solution was warmed to 85℃and reacted for 10 hours. After the completion of the TLC detection reaction, the reaction was filtered with suction while it was hot, the cake was washed with hot N, N-dimethylformamide (10 mL. Times.3), the filtrate was cooled to room temperature and then dropped into ice water (100 mL. Times.2), a large amount of white solid was precipitated, the filter cake was filtered with suction, washed with water (50 mL. Times.3), washed with N-hexane (50 mL. Times.3), and dried in vacuo to give Compound III-1 (white solid, 22.02g, yield 92%).
Compound III-1 (22 g,0.040 mol) was dissolved in methylene chloride (200 mL), and protonated montmorillonite (44 g) was added thereto, and the reaction mixture was heated to 40℃and reacted for 8 hours. After completion of TLC detection, cooled to room temperature, suction filtered, the filter cake washed with dichloromethane (50 ml×3), the filtrate concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound III-2 (white solid, 16.52g, 75% yield).
Compound III-2 (1 g,1.829 mmol) was dissolved in anhydrous pyridine (10 mL), phthalic anhydride (2.708 g,18.29 mmol) and 4-dimethylaminopyridine (223 mg,1.829 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of TLC detection, dichloromethane (30 mL) was added to dilute the reaction, and the reaction was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound III-3 (white solid, 925mg, yield 73%).
Compound III-3 (150 mg,0.216 mmol) was dissolved in anhydrous dichloromethane (6 mL), and N, N' -dicyclohexylcarbodiimide (134 mg,0.647 mmol), 4-dimethylaminopyridine (27 mg,0.216 mmol) and N-acetylethanolamine (30. Mu.L, 0.324 mmol) were added in this order and reacted under stirring at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with water (5 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) gave compound III-4 (white solid, 159mg, yield 95%).
Compound III-4 (159 mg,0.204 mmol) was dissolved in tetrahydrofuran (10 mL), 10% palladium on carbon (16 mg) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of TLC detection, celite was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound III-5 (white solid, 90mg, yield 64%)
Compound III-5 (100 mg, 0.145)mmol) was dissolved in N, N-dimethylformamide (6 mL), triethylamine (40. Mu.L, 0.290 mmol) was added, 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (72 mg,0.188 mmol) was added with stirring at room temperature, N- (2-aminoethyl) morpholine (23. Mu.L, 0.174 mmol) was added after 1 hour of reaction, and the reaction mixture was warmed to 50 ℃. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound a-12 (white solid, 80mg, yield 69%): 1 H NMR(300MHz,CDCl 3 )δ7.81(d,J＝7.3Hz,1H),7.66(d,J＝7.0Hz,1H),7.63–7.50(m,2H),6.60–6.49(m,1H),6.49–6.36(m,1H),4.77–4.65(m,1H),4.44(t,J＝4.8Hz,2H),3.76–3.56(m,6H),3.47–3.25(m,2H),2.86(d,J＝15.4Hz,1H),2.53–2.33(m,8H),2.03(s,3H),1.21(s,3H),0.97(s,3H),0.96(s,6H),0.94(s,3H),0.89(s,3H),0.75(s,3H).ESI-MS:m/z 824.6[M+Na] + 。
example 8
N- (2- (4-methyl-1-piperazinyl) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-14)
Referring to the procedure of example 7, substituting 4- (2-aminoethyl) morpholine with 1- (2-aminoethyl) -4-methylpiperazine produced compound a-14: 1 H NMR(300MHz,CDCl 3 )δ7.81(d,J＝7.2Hz,1H),7.66(d,J＝7.0Hz,1H),7.62–7.48(m,2H),6.58–6.48(m,1H),6.45–6.36(m,1H),4.76–4.67(m,1H),4.44(t,J＝4.8Hz,2H),3.73–3.55(m,2H),3.43–3.21(m,2H),2.85(d,J＝15.3Hz,1H),2.71–2.51(m,6H),2.51–2.42(m,4H),2.42–2.38(m,1H),2.36(s,4H),2.03(s,3H),1.20(s,3H),0.97(s,3H),0.95(s,9H),0.90(s,3H),0.75(s,3H).ESI-MS:m/z 815.7[M+H] + 。
example 9
N- (2- (trimethylammonio) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-amide bromide (Compound A-15)
Compound III-5 (100 mg,0.145 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (80. Mu.L, 0.580 mmol) was added thereto, 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (72 mg,0.188 mmol) was added thereto with stirring at room temperature, compound I-4 (60 mg,0.174 mmol) (prepared in example 1) was added thereto after 1 hour of reaction, and the reaction mixture was warmed to 50 ℃. After completion of TLC detection, the reaction mixture was treated with dichloromethane (10 mL) and deionized water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with deionized water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound a-15 (white solid, 80mg, 65% yield): 1 H NMR(300MHz,DMSO-d 6 )δ8.09–7.98(m,1H),7.83–7.74(m,2H),7.74–7.64(m,2H),7.17–7.06(m,1H),4.74–4.61(m,1H),4.30–4.14(m,2H),3.59–3.45(m,2H),3.44–3.33(m,4H),3.13(s,9H),2.91–2.72(m,1H),2.48–2.39(m,1H),2.18(d,J＝12.1Hz,1H),1.84(s,3H),1.19(s,3H),0.92(s,12H),0.86(s,3H),0.75(s,3H).ESI-MS:m/z 774.6[M-Br] + 。
example 10
N- (3- (trimethylammonio) propyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-amide bromide (Compound A-16)
Reference implementationCompound I-4 'was prepared by substituting compound I-1 with I-1' in the manner of example 1. Referring again to the procedure of example 9, the substitution of compound I-4 for I-4' produced compound A-16: 1 H NMR(300MHz,DMSO-d 6 )δ8.08–7.96(m,1H),7.79–7.71(m,2H),7.67(d,J＝8.6Hz,2H),7.04–6.88(m,1H),4.71–4.60(m,1H),4.29–4.13(m,2H),3.41–3.29(m,2H),3.29–3.18(m,2H),3.18–3.08(m,2H),3.04(s,9H),2.79(d,J＝12.5Hz,1H),2.43(d,J＝14.3Hz,1H),2.17(d,J＝12.9Hz,1H),1.81(s,3H),1.16(s,3H),0.90(s,12H),0.83(s,3H),0.72(s,3H).ESI-MS:m/z 788.6[M-Br] + 。
example 11
N- (2- (trimethylammonio) ethyl) -3β - (2-methoxyacyl benzoyl) oxy-oleanane-13 (18) -en-28-amide bromide (Compound A-17)
Compound III-2 was obtained by the method described in example 7, and Compound III-2 (150 mg,0.274 mmol) was dissolved in anhydrous dichloromethane (6 mL), followed by addition of N, N' -dicyclohexylcarbodiimide (170 mg,0.823 mmol), 4-dimethylaminopyridine (34 mg,0.274 mmol) and monomethyl phthalate (54 mg,0.302 mmol) in this order, followed by stirring at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with water (5 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) gave compound IV-1 (white solid, 159mg, yield 82%).
Compound IV-1 (159 mg,0.224 mmol) was dissolved in tetrahydrofuran (10 mL), 10% palladium on carbon (20 mg) was added thereto, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After completion of TLC detection, celite was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound IV-2 (white solid, 118mg, yield 85%).
Compound IV-2 (150 mg,0.242 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (135. Mu.L, 0.970 mmol) was added, and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyl was added with stirring at room temperatureUrea hexafluorophosphate (120 mg,0.315 mmol) was added compound I-4 (128 mg, 0.480 mmol) after 1 hour of reaction, and the reaction was warmed to 50 ℃. After completion of TLC detection, the reaction mixture was treated with dichloromethane (10 mL) and deionized water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with deionized water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound a-17 (white solid, 77mg, 40% yield): 1 H NMR(300MHz,DMSO-d 6 )δ7.82–7.64(m,4H),7.18–7.06(m,1H),4.74–4.64(m,1H),3.83(s,3H),3.59–3.45(m,2H),3.39–3.34(m,2H),3.13(s,9H),2.83(d,J＝13.4Hz,1H),2.50–2.41(m,1H),2.24–2.11(m,1H),1.19(s,3H),0.93(s,6H),0.92(s,6H),0.86(s,3H),0.75(s,3H).ESI-MS:m/z 703.6[M-Br] + 。
example 12
N- (3- (trimethylammonio) propyl) -3β - (2-methoxyacyl benzoyl) oxy-oleanane-13 (18) -en-28-amide bromide (Compound A-18)
Referring to the procedure of example 11, substituting compound I-4 with I-4' produced compound A-18: 1 H NMR(300MHz,DMSO-d 6 )δ7.80–7.63(m,4H),7.02–6.89(m,1H),4.76–4.62(m,1H),3.82(s,3H),3.30–3.20(m,2H),3.20–3.10(m,2H),3.06(s,9H),2.81(d,J＝14.7Hz,1H),2.46(d,J＝14.8Hz,1H),2.20(d,J＝13.1Hz,1H),1.19(s,3H),0.93(s,12H),0.86(s,3H),0.74(s,3H).ESI-MS:m/z 717.7[M-Br] + 。
example 13
N- (3- (dimethylamino) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-19)
delta-Oleanolic acid (delta-OA, 100mg,0.219 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (122. Mu.L, 0.876 mmol) was added, 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (108 mg, 0.284 mmol) was added with stirring at room temperature, and after 1 hour of reaction, 3-dimethylaminopropylamine (55. Mu.L, 0.438 mmol) was added, and the reaction mixture was warmed to 50 ℃. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound V-1 (white solid, 113mg, yield 96%).
Compound V-1 (113 mg,0.209 mmol) was dissolved in anhydrous pyridine (8 mL), phthalic anhydride (309 mg,2.09 mmol) and 4-dimethylaminopyridine (26 mg,0.209 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of the TLC detection reaction, dichloromethane (20 mL) was added to dilute the reaction solution, which was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound a-19 (white solid, 121mg, yield 84%): 1 H NMR(300MHz,CDCl 3 )δ7.72(d,J＝7.2Hz,1H),7.55(d,J＝7.1Hz,1H),7.47–7.30(m,2H),6.36–6.27(m,1H),4.76–4.65(m,1H),3.46–3.18(m,2H),2.91–2.72(m,3H),2.62(s,6H),2.43(d,J＝14.2Hz,1H),2.39–2.30(m,1H),1.17(s,3H),0.98(s,3H),0.89(s,3H),0.87(s,6H),0.82(s,3H),0.72(s,3H).ESI-MS:m/z 689.6[M+H] + 。
example 14
N- (3- (4-morpholinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-20)
Referring to the procedure of example 13, substituting N- (3-aminopropyl) morpholine for 3-dimethylaminopropylamine produced compound A-20: 1 H NMR(300MHz,CDCl 3 )δ7.90–7.78(m,1H),7.72–7.59(m,1H),7.59–7.46(m,2H),6.40–6.25(m,1H),4.79–4.66(m,1H),4.13–3.93(m,4H),3.50–3.22(m,2H),3.21–3.04(m,2H),3.04–2.88(m,2H),2.81(d,J＝13.7Hz,1H),2.47(d,J＝13.8Hz,1H),2.35(d,J＝11.9Hz,1H),2.17–2.00(m,2H),1.19(s,3H),0.95(s,3H),0.89(s,6H),0.87(s,6H),0.73(s,3H).
example 15
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-yl) -morpholine (compound A-27)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with morpholine produced compound A-27: 1 H NMR(300MHz,DMSO)δ7.94–7.85(m,1H),7.78–7.68(m,1H),7.63–7.49(m,2H),4.84–4.74(m,1H),3.80(s,4H),3.63(s,4H),2.77(d,J＝14.5Hz,1H),2.46(d,J＝13.2Hz,2H),1.19(s,3H),0.97(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.87(s,3H),0.79(s,3H).ESI-MS:m/z 672.5[M-H] - 。
example 16
3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (4-morpholinyl) ethyl ester (Compound A-44)
Compound III-5 was obtained by the method described in example 7, and Compound III-5 (120 mg,0.174 mmol) was dissolved in N, N-dimethylformamide (10 mL), 4- (2-bromoethyl) morpholine hydrobromide (57 mg,0.208 mmol) and potassium carbonate (70 mg,0.522 mmol) were added and the mixture was stirred at room temperature. After completion of the TLC detection reaction, the reaction mixture was treated with ethyl acetate (20 mL) and (10 mL), the aqueous layer was extracted with ethyl acetate (10 mL), the organic phases were combined, washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound a-44 (white solid, 87mg, yield 62%): 1 H NMR(300MHz,CDCl 3 )δ7.86–7.78(m,1H),7.69–7.63(m,1H),7.63–7.49(m,2H),6.64–6.47(m,1H),4.77–4.67(m,1H),4.44(t,J＝4.8Hz,2H),4.30–4.13(m,2H),3.77–3.55(m,6H),2.75(d,J＝14.0Hz,1H),2.59(t,J＝5.7Hz,2H),2.54–2.46(m,4H),2.42(d,J＝14.1Hz,1H),2.18(d,J＝6.9Hz,1H),2.03(s,3H),1.17(s,3H),0.96(s,6H),0.94(s,3H),0.93(s,3H),0.92(s,3H),0.74(s,3H).ESI-MS:m/z 825.6[M+Na] + 。
example 17
N- (2- (trimethylammonio) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide bromide (Compound A-66)
Compound a-66 was prepared according to the procedure of example 1: 1 H NMR(300MHz,DMSO-d 6 )δ7.16–7.03(m,1H),4.31(d,J＝5.1Hz,1H),3.59–3.41(m,2H),3.08–2.92(m,2H),2.80(d,J＝12.4Hz,1H),2.45(d,J＝14.4Hz,1H),2.17(d,J＝13.4Hz,1H),1.15(s,3H),0.91(s,3H),0.90(s,6H),0.85(s,3H),0.73(s,3H),0.68(s,3H).ESI-MS:m/z541.5[M-Br] + 。
example 18
N- (3- (trimethylammonio) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide bromide (Compound A-67)
Referring to the procedure of example 1, substituting compound I-4 with I-4' produced compound A-67: 1 H NMR(300MHz,DMSO-d6)δ7.00–6.89(m,1H),4.31(d,J＝5.0Hz,1H),3.28–3.19(m,2H),3.19–3.09(m,2H),3.05(s,9H),2.79(d,J＝13.4Hz,1H),2.44(d,J＝13.9Hz,1H),2.18(d,J＝13.3Hz,1H),1.15(s,3H),0.90(s,9H),0.85(s,3H),0.72(s,3H),0.68(s,3H).ESI-MS:m/z 555.5[M-Br] + 。
example 19
N- (2- (dimethylamino) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-68)
Compound a-68 was prepared according to the procedure of example 2: 1 H NMR(300MHz,CDCl 3 )δ6.45(t,J＝4.7Hz,1H),3.45–3.31(m,2H),3.30–3.21(m,1H),2.93–2.80(m,1H),2.54–2.31(m,4H),2.23(s,6H),1.22(s,3H),1.03(s,3H),0.97(s,3H),0.94(s,3H),0.93(s,3H),0.81(s,3H),0.78(s,3H).ESI-MS:m/z 527.5[M+H] + 。
Example 20
N- (2- (1-piperidinyl) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-69)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 1- (2-aminoethyl) piperidine produced compound A-69: 1 H NMR(300MHz,CDCl 3 )δ6.71–6.26(m,1H),3.47–3.32(m,1H),3.32–3.16(m,2H),2.93–2.78(m,1H),2.55–2.22(m,8H),1.18(s,3H),0.99(s,3H),0.94(s,3H),0.90(s,3H),0.88(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 567.5[M+H] + 。
example 21
N- (2- (4-morpholinoalkyl) ethyl) -3 beta-hydroxy-oleanane-13 (18) -en-28-amide (Compound A-70)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 4- (2-aminoethyl) morpholine produced compound A-70: 1 H NMR(300MHz,CDCl 3 )δ6.50–6.40(m,1H),3.76–3.60(m,4H),3.45–3.29(m,2H),3.29–3.18(m,1H),2.90–2.79(m,1H),2.55–2.31(m,8H),1.19(s,3H),0.99(s,3H),0.94(s,3H),0.89(s,3H),0.87(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 569.5[M+H] + 。
example 22
N- (2- (4-methyl-1-piperazinyl) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-73)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 1- (2-aminoethyl) -4-methylpiperazine produced compound a-73: 1 H NMR(300MHz,CDCl 3 )δ6.53–6.44(m,1H),3.47–3.33(m,1H),3.34–3.18(m,2H),2.90–2.80(m,1H),2.64–2.33(m,12H),2.28(s,3H),1.19(s,3H),0.99(s,3H),0.94(s,3H),0.90(s,3H),0.89(s,3H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 582.5[M+H] + 。
example 23
N- (3- (dimethylamino) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-77)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 3-dimethylaminopropylamine produced compound A-77: 1 H NMR(300MHz,CDCl 3 )δ6.24(t,J＝5.1Hz,1H),3.46–3.32(m,1H),3.29–3.11(m,2H),2.87–2.73(m,1H),2.50–2.42(m,1H),2.41–2.35(m,1H),2.31(t,J＝7.1Hz,2H),2.22(s,6H),1.18(s,3H),0.99(s,3H),0.92(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 541.5[M+H] + 。
example 24
N- (3- (4-morpholinoalkyl) propyl) -3 beta-hydroxy-oleanane-13 (18) -en-28-amide (Compound A-78)
Referring to the method of example 2, N-dimethylSubstitution of ethylenediamine with N- (3-aminopropyl) morpholine produced compound a-78:1H NMR (300 MHz, CDCl) 3 )δ6.03(t,J＝5.7Hz,1H),3.71(d,J＝4.6Hz,4H),3.43–3.28(m,1H),3.28–3.14(m,2H),2.87–2.76(m,1H),2.53–2.30(m,8H),1.19(s,3H),0.99(s,3H),0.91(s,3H),0.90(s,3H),0.88(s,3H),0.78(s,3H),0.74(s,3H).ESI-MS:m/z 583.5[M+H] + 。
Example 25
N- (2- (acetamido) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-83)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with N-acetylethylenediamine produced compound A-83: 1 H NMR(300MHz,CDCl 3 )δ6.49–6.35(m,1H),6.34–6.17(m,1H),3.55–3.28(m,4H),3.27–3.14(m,1H),2.88–2.74(m,1H),2.55–2.42(m,1H),2.42–2.30(m,1H),1.96(s,3H),1.19(s,3H),0.99(s,3H),0.91(s,6H),0.88(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 539.4[M-H] - 。
example 26
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -morpholine (compound A-84)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with morpholine produced compound a-84: 1 H NMR(300MHz,CDCl 3 )δ4.01–3.69(m,4H),3.68–3.52(m,4H),3.27–3.17(m,1H),2.81–2.70(m,1H),2.54–2.38(m,2H),1.17(s,3H),0.99(s,3H),0.92(s,3H),0.87(s,3H),0.86(s,3H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z 548.4[M+Na] + 。
example 27
N- (3β -hydroxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide (compound A-85)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with morpholinothiomorpholine-1, 1-dioxide produced compound a-85: 1 H NMR(300MHz,CDCl 3 )δ4.38–4.12(m,4H),3.28–3.17(m,1H),3.07–2.93(m,4H),2.81–2.70(m,1H),2.53–2.44(m,1H),2.44–2.33(m,1H),1.19(s,3H),0.99(s,3H),0.92(s,3H),0.87(s,3H),0.86(s,3H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z 572.4[M-H] - 。
example 28
N- (3β -hydroxy-oleanane-13 (18) -en-28-yl) -4-methylpiperazine (Compound A-87)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with N-methylpiperazine produced compound a-87: 1 H NMR(300MHz,CDCl 3 )δ4.01–3.58(m,4H),3.28–3.19(m,1H),2.83–2.71(m,1H),2.54–2.40(m,2H),2.40–2.31(m,4H),2.29(s,3H),1.17(s,3H),0.99(s,3H),0.91(s,3H),0.89(s,3H),0.88(s,3H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z 539.5[M+H] + 。
example 29
N- (2- (dimethylamino) ethyl) -N-methyl-3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-102)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with N, N, N' -trimethylethylenediamine produced compound A-102: 1 H NMR(300MHz,CDCl 3 )δ3.66–3.53(m,1H),3.53–3.38(m,1H),3.32–3.24(m,1H),3.22(s,3H),2.83–2.71(m,1H),2.57–2.36(m,4H),2.32(s,6H),1.19(s,3H),1.01(s,3H),0.96(s,3H),0.93(s,3H),0.89(s,3H),0.81(s,3H),0.79(s,3H).ESI-MS:m/z 541.5[M+H] + 。
Example 30
N- (2- (diethylamino) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-103)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with N, N-diethylethylenediamine produced compound A-103: 1 H NMR(300MHz,CDCl 3 )δ6.54–6.29(m,1H),3.50–3.32(m,1H),3.31–3.06(m,2H),2.87–2.78(m,1H),2.60–2.32(m,8H),1.18(s,3H),0.99(s,3H),0.93(s,3H),0.90(s,3H),0.88(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 555.4[M+H] + 。
example 31
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -piperidine (Compound A-104)
Referring to the procedure of example 2, N-dimethylethylenediamine was substituted for piperidine to give compound A-104: 1 H NMR(300MHz,CDCl 3 )δ3.88–3.54(m,4H),3.31–3.22(m,1H),2.84–2.74(m,1H),2.54–2.37(m,2H),1.20(s,3H),1.02(s,3H),0.93(s,6H),0.91(s,3H),0.80(s,3H),0.80(s,3H).ESI-MS:m/z 546.4[M+Na] + 。
example 32
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -piperazine (Compound A-86)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with piperazine produced compound A-86: 1 H NMR(300MHz,CDCl 3 )δ3.87–3.64(m,3H),3.28–3.18(m,1H),2.88–2.78(m,3H),2.78–2.70(m,1H),2.45(d,J＝12.8Hz,2H),2.00–1.87(m,2H),1.17(s,3H),0.99(s,3H),0.91(s,3H),0.88(s,6H),0.77(s,6H).ESI-MS:m/z 525.6[M+H] + 。
example 33
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -tetrahydropyrrole (Compound A-88)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with tetrahydropyrrole produced compound a-88: 1 H NMR(300MHz,CDCl 3 )δ3.66–3.49(m,4H),3.21(dd,J＝10.6,5.6Hz,1H),2.84–2.69(m,1H),2.48–2.38(m,1H),2.38–2.30(m,1H),1.16(s,3H),0.98(s,3H),0.94(s,3H),0.89(s,3H),0.87(s,3H),0.77(s,3H),0.76(s,3H).ESI-MS:m/z 532.5[M+Na] + 。
example 34
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) - (3S) -hydroxy-tetrahydropyrrole (Compound A-91)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with (S) -3-pyrrolidinol produced compound A-91: 1 H NMR(300MHz,CDCl 3 )δ5.29(s,1H),4.49–4.36(m,1H),3.91–3.72(m,1H),3.73–3.54(m,3H),3.22(dd,J＝9.6,4.9Hz,1H),2.76(d,J＝14.9Hz,1H),2.50–2.39(m,1H),2.39–2.29(m,1H),2.22–2.09(m,1H),1.16(s,3H),0.98(s,3H),0.94(s,3H),0.90(s,3H),0.87(s,3H),0.77(s,3H),0.76(s,3H).ESI-MS:m/z 526.4[M+H] + 。
example 35
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) - (3R) -hydroxy-tetrahydropyrrole (Compound A-92)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with (R) -3-pyrrolidinol produced compound A-92: 1 H NMR(300MHz,CDCl 3 )δ4.50–4.34(m,1H),3.80–3.66(m,2H),3.68–3.60(m,2H),3.30–3.12(m,1H),2.75(d,J＝14.8Hz,1H),2.48–2.37(m,1H),2.38–2.26(m,2H),1.15(s,3H),0.97(s,3H),0.95(s,3H),0.89(s,3H),0.86(s,3H),0.77(s,3H),0.75(s,3H).ESI-MS:m/z 526.4[M+H] + 。
example 36
N- (3β -hydroxy-oleanane-13 (18) -en-28-yl) - (2R) -carboxy-tetrahydropyrrole (Compound A-93)
Referring to the procedure of example 2, N-dimethylethylenediamine was replaced with D-proline benzyl ester hydrochloride to give compound VI-1.
Compound VI-1 (120 mg,0.186 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and methanol (1 mL), and 2N sodium hydroxide solution (1 mL) was added thereto to react at 80℃for 2 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, the pH was adjusted to weakly acidic with a 1N hydrochloric acid solution, the organic phase was extracted with dichloromethane (5 mL. Times.2), washed with water (5 mL. Times.2), washed with saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was treated with a mixed solvent of dichloromethane and acetonitrile (5.5 mL, v: v=10:1) in ultrasound to precipitate a white solid, suction filtration, the filter cake was washed twice with a mixed solvent of dichloromethane and acetonitrile (5.5 mL, v: v=10:1), and dried under infrared to give compound A-93 (white solid, 88mg, yield 85%): 1 H NMR(300MHz,CDCl 3 )δ4.70(q,J＝3.8Hz,1H),3.94–3.79(m,1H),3.72–3.59(m,1H),3.25(dd,J＝10.8,5.4Hz,1H),2.79(dd,J＝15.5,4.0Hz,1H),2.53–2.40(m,1H),2.38–2.21(m,2H),1.19(s,3H),1.01(s,3H),0.94(s,6H),0.89(s,3H),0.81(s,3H),0.78(s,3H).ESI-MS:m/z 552.4[M-H] - 。
example 37
N- (3β -hydroxy-oleanane-13 (18) -en-28-yl) - (2S) -carboxy-tetrahydropyrrole (Compound A-94)
Referring to the procedure of example 36, substituting benzyl D-proline hydrochloride for benzyl L-proline hydrochloride produced compound a-94: 1 H NMR(300MHz,CDCl 3 )δ4.77–4.62(m,1H),3.90–3.75(m,1H),3.74–3.56(m,1H),3.34–3.18(m,1H),2.78(d,J＝17.1Hz,1H),2.53–2.43(m,1H),2.42–2.33(m,1H),2.28–2.16(m,1H),1.19(s,3H),1.00(s,3H),0.94(s,3H),0.92(s,3H),0.89(s,3H),0.80(s,3H),0.78(s,3H).ESI-MS:m/z 576.53[M+Na] + 。
example 38
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -azetidine (Compound A-95)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with silacyclobutane produced compound A-95: 1 H NMR(300MHz,CDCl 3 )δ4.48–3.89(m,4H),3.30–3.14(m,1H),2.81–2.66(m,1H),2.48–2.34(m,1H),2.26–2.07(m,3H),1.14(s,3H),0.97(s,3H),0.95(s,3H),0.91(s,3H),0.86(s,3H),0.75(s,3H),0.74(s,3H).ESI-MS:m/z518.5[M+Na] + 。
example 39
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide (compound A-28)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with thiomorpholine-1, 1-dioxide produced compound a-28: 1 H NMR(300MHz,CDCl 3 )δ7.96–7.86(m,1H),7.81–7.70(m,1H),7.65–7.52(m,2H),4.85–4.73(m,1H),4.37–4.12(m,4H),3.08–2.92(m,4H),2.77(d,J＝13.3Hz,1H),2.49(d,J＝13.2Hz,1H),2.44–2.32(m,1H),1.20(s,3H),0.97(s,3H),0.90(s,9H),0.86(s,3H),0.79(s,3H).ESI-MS:m/z 720.5[M-H] - 。
example 40
N- (2- (1, 1-dioxothiomorpholinyl) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-74)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide gives compound a-74: 1 H NMR(300MHz,CDCl 3 )δ6.27–6.11(m,1H),3.48–3.29(m,2H),3.29–3.16(m,1H),3.13–2.91(m,8H),2.82(d,J＝13.0Hz,1H),2.60(t,J＝5.7Hz,2H),2.47(d,J＝13.5Hz,1H),2.43–2.31(m,1H),1.20(s,3H),0.99(s,3H),0.92(s,3H),0.90(s,3H),0.87(s,3H),0.76(s,3H),0.74(s,3H).ESI-MS:m/z 615.5[M-H] - 。
example 41
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-81)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide gives compound a-81: 1 H NMR(300MHz,CDCl 3 )δ6.05–5.95(m,1H),3.38–3.17(m,3H),3.12–2.90(m,8H),2.81(d,J＝12.5Hz,1H),2.59–2.32(m,4H),1.19(s,3H),0.99(s,3H),0.90(s,6H),0.88(s,3H),0.77(s,3H),0.73(s,3H).ESI-MS:m/z 629.5[M-H] - 。
Example 42
N- (2- (1, 1-dioxothiomorpholinyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-9)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide gives compound a-9: 1 H NMR(300MHz,DMSO-d 6 )δ13.20(s,1H),7.79–7.69(m,1H),7.69–7.59(m,3H),6.63–6.52(m,1H),4.73–4.60(m,1H),3.29–3.15(m,2H),3.12–2.98(m,4H),2.98–2.87(m,4H),2.83(d,J＝15.0Hz,1H),2.62–2.53(m,2H),2.47(d,J＝14.2Hz,1H),1.24–1.17(m,3H),0.94(s,6H),0.92(s,6H),0.85(s,3H),0.74(s,3H).ESI-MS:m/z 763.6[M-H] - 。
example 43
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-23)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide gives compound a-23: 1 H NMR(300MHz,methanol-d 4 )δ7.82–7.74(m,1H),7.74–7.66(m,1H),7.66–7.57(m,2H),6.86–6.77(m,1H),4.80–4.67(m,1H),3.42–3.23(m,2H),3.18–3.07(m,4H),3.07–2.97(m,4H),2.97–2.86(m,1H),2.64–2.49(m,3H),2.31(d,J＝12.8Hz,1H),1.28(s,3H),1.03(s,6H),1.00(s,3H),0.95(s,3H),0.94(s,3H),0.81(s,3H).ESI-MS:m/z 777.6[M-H] - 。
example 44
N- (3- (1-tetrahydropyrrolyl) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-80)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 1- (3-aminopropyl) pyrrolidine produced compound A-80: 1 H NMR(300MHz,CDCl 3 )δ6.22–6.12(m,1H),3.50–3.34(m,1H),3.29–3.15(m,2H),2.87–2.75(m,1H),2.61–2.37(m,8H),1.21(s,3H),1.18(s,3H),0.99(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.73(s,3H).ESI-MS:m/z 567.5[M+H] + 。
example 45
N- (3- (4-methyl-1-piperazinyl) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-79)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 1- (3-aminopropyl) -4-methylpiperazine produced compound a-79: 1 H NMR(300MHz,CDCl 3 )δ6.09–5.96(m,1H),3.41–3.28(m,1H),3.27–3.12(m,2H),2.86–2.72(m,1H),2.65–2.31(m,10H),2.28(s,3H),2.02–1.79(m,2H),1.18(s,6H),0.98(s,3H),0.88(s,6H),0.76(s,3H),0.72(s,3H).ESI-MS:m/z 596.5[M+H] + 。
example 46
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide) tetrahydropyrrole (Compound A-31)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with tetrahydropyrrole produced compound a-31: 1 H NMR(300MHz,methanol-d 4 )δ7.81–7.65(m,2H),7.65–7.51(m,2H),4.80–4.70(m,1H),3.81–3.44(m,4H),2.86(d,J＝15.1Hz,1H),2.52(d,J＝13.4Hz,1H),2.37(d,J＝13.1Hz,1H),1.27(s,3H),1.03(s,3H),1.01(s,6H),0.95(s,6H),0.85(s,3H).ESI-MS:m/z 656.5[M-H] - 。
example 47
N- (2- (acetamido) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-64)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with N-acetylethylenediamine gives compound A-64: 1 H NMR(300MHz,CDCl 3 )δ7.93–7.77(m,1H),7.77–7.62(m,1H),7.60–7.46(m,2H),6.62–6.45(m,1H),6.38–6.21(m,1H),4.82–4.66(m,1H),3.57–3.20(m,4H),2.82(d,J＝15.1Hz,1H),2.46(d,J＝13.3Hz,1H),2.36(d,J＝11.6Hz,1H),1.97(s,3H),1.19(s,3H),0.95(s,3H),0.90(s,12H),0.74(s,3H).ESI-MS:m/z 687.5[M-H] - 。
example 48
N- (2- (acetamido) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-65)
Referring to the procedure of example 7, substituting N- (2-aminoethyl) morpholine for N-acetyl ethylenediamine produced compound A-65: 1 H NMR(300MHz,CDCl 3 )δ7.85–7.77(m,1H),7.70–7.63(m,1H),7.62–7.50(m,2H),6.60–6.47(m,1H),6.43–6.34(m,1H),6.33–6.23(m,1H),4.76–4.67(m,1H),4.45(t,J＝4.7Hz,2H),3.71–3.58(m,2H),3.49–3.26(m,4H),2.91–2.76(m,1H),2.48(d,J＝14.3Hz,1H),2.42–2.32(m,1H),2.03(s,3H),1.96(s,3H),1.21(s,3H),0.97(s,3H),0.96(s,6H),0.93(s,3H),0.91(s,3H),0.75(s,3H).ESI-MS:m/z 796.6[M+Na] + 。
example 49
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-71)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 1- (2-aminoethyl) pyrrolidine gave compound A-71: 1 H NMR(300MHz,CDCl 3 )δ6.59–6.45(m,1H),3.46–3.17(m,3H),2.89–2.74(m,1H),2.60–2.30(m,7H),1.18(s,6H),0.99(s,3H),0.93(s,3H),0.89(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 553.5[M+H] + 。
example 50
1-methyl-4- (3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide) piperazine (compound a-30)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with N-methylpiperazine produced compound a-30: 1 H NMR(300MHz,methanol-d 4 )δ7.79–7.72(m,1H),7.72–7.65(m,1H),7.65–7.54(m,2H),4.74(dd,J＝10.7,5.1Hz,1H),4.28–3.84(m,4H),3.28–3.12(m,4H),2.89(s,3H),2.84(d,J＝12.6Hz,1H),2.57(d,J＝13.3Hz,1H),2.38(d,J＝12.6Hz,1H),1.27(s,3H),1.00(s,3H),0.99(s,3H),0.97(s,3H),0.95(s,3H),0.93(s,3H),0.85(s,3H).ESI-MS:m/z 687.5[M+H] + 。
example 51
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) - (3S) -amino-tetrahydropyrrole (Compound A-89)
Referring to the procedure of example 2, N-dimethylethylenediamine was substituted with (S) -3-N-benzyloxycarbonyl-aminopyrrolidine to give compound VII-1.
Compound VII-1 (200 mg,0.303 mmol) was dissolved in tetrahydrofuran (10 mL), 10% palladium on carbon (20 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After completion of TLC detection, celite was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (IIMethyl chloride: methanol=10: 1) Purification gave compound a-89 (white solid, 135mg, 85% yield): 1 H NMR(300MHz,CDCl 3 )δ3.84–3.75(m,1H),3.74–3.66(m,1H),3.66–3.57(m,1H),3.51(p,J＝6.0Hz,1H),3.24(td,J＝10.6,5.9Hz,2H),2.82–2.69(m,1H),2.48–2.38(m,1H),2.39–2.29(m,1H),2.04(dt,J＝12.4,6.6Hz,1H),1.16(s,3H),0.98(s,3H),0.95(s,3H),0.90(s,3H),0.87(s,3H),0.77(s,3H),0.76(s,3H).ESI-MS:m/z 525.5[M+H] + 。
example 52
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -3-hydroxy-azetidine (Compound A-96)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with azetidin-3-ol produced compound a-96: 1 H NMR(300MHz,CDCl 3 )δ5.29–5.20(m,1H),3.90–3.72(m,1H),3.72–3.59(m,1H),3.58–3.40(m,2H),3.26–3.04(m,3H),2.13–1.99(m,2H),1.13(s,3H),0.98(s,3H),0.93(s,3H),0.89(s,6H),0.77(s,3H),0.71(s,3H).ESI-MS:m/z 510.5[M-H] - 。
example 53
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -3-methoxy-azetidine (Compound A-99)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 3-methoxyazetidine produced compound A-99: 1 H NMR(300MHz,CDCl 3 )δ4.56–4.17(m,2H),4.11(dt,J＝9.4,4.9Hz,1H),4.07–3.71(m,2H),3.29(s,3H),3.26–3.16(m,1H),2.80–2.68(m,1H),2.46–2.35(m,1H),2.17–2.08(m,1H),1.14(s,3H),0.98(s,3H),0.95(s,3H),0.91(s,3H),0.86(s,3H),0.76(s,3H),0.75(s,3H).ESI-MS:m/z 548.5[M+Na] + 。
example 55
N- (3 beta-hydroxy-oleanane-13 (18) -en-28-yl) -3-carboxy-azetidine (Compound A-100)
Compound VIII-1 (500 mg, 2.480 mmol) was dissolved in toluene (7.5 mL) and 1, 8-diazabicyclo undec-7-ene (576 mg, 3.428 mmol) and benzyl bromide (467 mg,2.73 mmol) were added sequentially and the reaction stirred at room temperature for 4 hours. After completion of TLC detection, quench with water (5 mL), extract with ethyl acetate (10 ml×2), combine the organic phases, wash with water (10 ml×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate=6:1) to give compound VIII-2 (colorless oily liquid, 296mg, 40% yield).
Compound VIII-2 (298 mg,1.016 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature. After completion of TLC detection, the solvent was distilled off under reduced pressure to give Compound VIII-3, which was used directly in the next step.
Referring to the procedure of example 36, substituting D-proline benzyl ester hydrochloride for compound VIII-3, compound A-100 is prepared: 1 H NMR(300MHz,CDCl 3 )δ4.65–4.01(m,4H),3.42–3.30(m,1H),3.24(dd,J＝10.3,5.5Hz,1H),2.85–2.65(m,1H),2.51–2.32(m,1H),2.26–2.04(m,1H),1.15(s,3H),0.98(s,3H),0.95(s,3H),0.92(s,3H),0.87(s,3H),0.76(s,3H),0.75(s,3H).ESI-MS:m/z 538.4[M-H] - 。
example 55
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-25)
Referring to the procedure of example 7, N- (2-aminoethyl) morpholine was replaced with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide to produceCompound a-25: 1 H NMR(300MHz,CDCl 3 )δ7.86–7.76(m,1H),7.70–7.63(m,1H),7.63–7.50(m,2H),6.58–6.46(m,1H),6.11–5.97(m,1H),4.77–4.66(m,1H),4.49–4.38(m,2H),3.69–3.59(m,2H),3.38–3.24(m,2H),3.18–2.94(m,6H),2.84(d,J＝15.3Hz,1H),2.68–2.53(m,2H),2.48(d,J＝12.8Hz,1H),2.43–2.34(m,1H),2.03(s,3H),1.21(s,3H),0.96(s,9H),0.93(s,3H),0.92(s,3H),0.75(s,3H).ESI-MS:m/z 862.5[M-H] - 。
example 56
N- (3- (1-tetrahydropyrrolyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-22)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 1- (3-aminopropyl) pyrrolidine gave compound a-22: 1 H NMR(300MHz,methanol-d 4 )δ7.78(d,J＝7.4Hz,1H),7.69–7.54(m,2H),7.54–7.44(m,1H),4.82–4.72(m,1H),3.46–3.39(m,2H),3.18(t,J＝7.2Hz,2H),2.95(d,J＝14.6Hz,1H),2.62(d,J＝13.8Hz,1H),2.36–2.26(m,1H),2.14(s,3H),1.30(s,3H),1.06(s,6H),1.05(s,3H),1.03(s,3H),0.99(s,3H),0.84(s,2H).ESI-MS:m/z 713.6[M-H] - 。
example 57
N- (3- (4-methyl-1-piperazinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-21)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 1- (3-aminopropyl) -4-methylpiperazine produced compound a-21: 1 H NMR(300MHz,methanol-d 4 )δ7.84–7.77(m,1H),7.74–7.68(m,1H),7.68–7.59(m,2H),4.78(dd,J＝11.0,4.2Hz,1H),3.82–3.43(m,8H),3.42–3.37(m,2H),3.20–3.09(m,2H),3.02(s,3H),2.95(d,J＝13.9Hz,1H),2.62(d,J＝13.7Hz,1H),2.32(d,J＝13.3Hz,1H),1.30(s,3H),1.05(s,3H),1.04(s,3H),1.02(s,3H),0.98(s,3H),0.95(s,3H),0.83(s,3H).ESI-MS:m/z 742.6[M-H] - 。
Example 58
N- (2- (1-piperazinyl) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-13)
Referring to the procedure of example 7, substituting N- (2-aminoethyl) morpholine for N-aminoethylpiperazine produced compound A-13: 1 H NMR(300MHz,CDCl 3 )δ7.81(d,J＝7.0Hz,1H),7.66(d,J＝7.0Hz,1H),7.62–7.51(m,2H),6.57–6.47(m,1H),6.19–6.11(m,1H),4.77–4.67(m,1H),4.49–4.41(m,2H),3.69–3.60(m,2H),3.49–3.28(m,2H),3.25–3.09(m,4H),2.90–2.71(m,5H),2.59–2.35(m,4H),2.03(s,3H),1.21(s,3H),0.97(s,3H),0.96(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.75(s,3H).ESI-MS:m/z801.6[M+H] + 。
example 59
3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2-dimethylaminoethyl ester (Compound A-35)
delta-Oleanolic acid (delta-OA, 2g,4.379 mmol) was dissolved in N, N-dimethylformamide (20 mL), 1, 2-dibromoethane (3.75 mL,43.79 mmol), potassium carbonate (605 mg,4.379 mmol) and acetonitrile (2 mL) were sequentially added, and the reaction solution was warmed to 50℃and stirred for 3 hours. After completion of the TLC detection reaction, the reaction solution was treated with ethyl acetate (30 mL) and water (10 mL), the aqueous layer was extracted with ethyl acetate (20 mL), the organic phases were combined, washed with water (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound IX-1 (white solid, 2.25g, yield 91%).
Compound IX-1 (150 mg,0.266 mmol) was dissolved in anhydrous N, N-dimethylformamide (8 mL), dimethylamine hydrochloride (33 mg,0.405 mmol) and potassium carbonate (56 mg,0.405 mmol) were added in this order, and the reaction mixture was warmed to 50℃and stirred for reaction. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic phases were combined, washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound IX-2 (white solid, 91mg, 65% yield).
Compound IX-2 (91 mg,0.172 mmol) was dissolved in anhydrous pyridine (8 mL), phthalic anhydride (255 mg,1.72 mmol) and 4-dimethylaminopyridine (21 mg,0.172 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of the TLC detection reaction, dichloromethane (10 mL) and water (10 mL) were added to treat the reaction solution, the aqueous layer was extracted with dichloromethane (10 mL), and the organic phases were combined, washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound a-35 (white solid, 83mg, yield 72%): 1 H NMR(300MHz,CDCl 3 )δ7.82(d,J＝7.2Hz,1H),7.58(d,J＝6.6Hz,1H),7.52–7.39(m,2H),4.83–4.74(m,1H),4.41(t,J＝5.5Hz,2H),3.11–2.95(m,2H),2.76(d,J＝14.6Hz,1H),2.61(s,6H),2.45(d,J＝13.7Hz,1H),2.17(d,J＝13.2Hz,1H),1.19(s,3H),1.02(s,3H),0.92(s,9H),0.89(s,3H),0.76(s,3H).ESI-MS:m/z 674.5[M-H] - 。
example 60
3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (4-morpholinyl) ethyl ester (Compound A-39)
Referring to the procedure of example 59, substituting dimethylamine hydrochloride for morpholine produced compound a-39: 1 H NMR(300MHz,CDCl 3 )δ7.92–7.81(m,1H),7.74–7.63(m,1H),7.58–7.46(m,2H),4.83–4.71(m,1H),4.28(t,J＝4.9Hz,2H),3.81–3.68(m,4H),2.81–2.66(m,3H),2.66–2.50(m,4H),2.42(d,J＝13.9Hz,1H),2.22–2.11(m,1H),1.17(s,3H),0.96(s,3H),0.90(s,12H),0.74(s,3H).ESI-MS:m/z 716.5[M-H] - 。
example 61
3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (1-tetrahydropyrrolyl) ethyl ester (Compound A-40)
Referring to the procedure of example 59, substituting dimethylamine hydrochloride with tetrahydropyrrole produced compound a-40: 1 H NMR(300MHz,CDCl 3 )δ7.79(d,J＝7.3Hz,1H),7.52(d,J＝6.6Hz,1H),7.47–7.34(m,2H),4.76(dd,J＝10.7,3.2Hz,1H),4.55–4.35(m,2H),3.31–3.05(m,6H),2.73(d,J＝12.0Hz,1H),2.42(d,J＝13.9Hz,1H),2.12(d,J＝13.1Hz,1H),2.08–1.96(m,4H),1.16(s,3H),1.02(s,3H),0.90(s,9H),0.86(s,3H),0.74(s,3H).ESI-MS:m/z 700.5[M-H] - 。
example 62
3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (1-piperidinyl) ethyl ester (Compound A-38)
Referring to the procedure of example 59, substituting dimethylamine hydrochloride for piperidine produced compound a-38: 1 H NMR(300MHz,methanol-d 4 )δ7.79(d,J＝7.3Hz,1H),7.67(d,J＝7.2Hz,1H),7.59(t,J＝7.0Hz,1H),7.49(t,J＝7.2Hz,1H),4.81–4.73(m,1H),4.45–4.21(m,3H),2.95–2.84(m,1H),2.80(t,J＝5.8Hz,2H),2.74–2.62(m,4H),2.56(d,J＝14.6Hz,1H),2.31–2.22(m,1H),1.31(s,3H),1.07(s,6H),1.06(s,6H),1.02(s,3H),0.86(s,3H).ESI-MS:m/z 714.5[M-H] - 。
example 63
3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 3- (1-tetrahydropyrrolyl) propyl ester (Compound A-42)
Referring to the procedure of example 59, substituting 1, 2-dibromoethane for 1, 3-dibromopropane and dimethylamine hydrochloride for tetrahydropyrrole produced compound a-42: 1 H NMR(300MHz,CDCl 3 )δ7.74(d,J＝7.3Hz,1H),7.55(d,J＝7.0Hz,1H),7.46–7.31(m,2H),4.78–4.69(m,1H),4.24–4.03(m,2H),3.19(s,4H),3.08–2.95(m,2H),2.74(d,J＝13.6Hz,1H),2.43(d,J＝14.1Hz,1H),2.26–2.01(m,7H),1.17(s,3H),0.99(s,3H),0.89(s,12H),0.74(s,3H).ESI-MS:m/z 714.5[M-H] - 。
example 64
3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 3-dimethylaminopropyl ester (Compound A-43)
Referring to the procedure of example 59, substituting 1, 2-dibromoethane for 1, 3-dibromopropane produced compound a-43: 1 H NMR(300MHz,methanol-d 4 )δ7.76(d,J＝7.5Hz,1H),7.64–7.53(m,2H),7.50–7.42(m,1H),4.81–4.69(m,1H),4.32–4.14(m,2H),3.18–3.08(m,2H),2.86(s,7H),2.55(d,J＝14.3Hz,1H),2.26–2.20(m,1H),2.20–2.08(m,2H),1.29(s,3H),1.04(s,6H),1.02(s,6H),0.98(s,3H),0.83(s,3H).ESI-MS:m/z 690.6[M+H] + 。
example 65
3 beta- (2- (2-Acetaminophen-yl) benzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (4-methyl-1-piperazinyl) ethyl ester (Compound A-48)
Compound III-5 was prepared according to the procedure of example 7. Compound III-5 (345 mg,0.500 mmol) was dissolved in anhydrous N, N-dimethylformamide (8 mL), 1, 2-dibromoethane (435. Mu.L, 5.00 mmol) and potassium carbonate (70 mg,0.500 mmol) were sequentially added, and the reaction solution was warmed to 50℃and stirred for 3 hours. After completion of the TLC detection reaction, the reaction solution was treated with ethyl acetate (10 mL) and water (10 mL), the aqueous layer was extracted with ethyl acetate (10 mL), the organic phases were combined, washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound X-1 (white solid, 348mg, yield 87%).
Compound X-1 (116 mg,0.145 mmol) was dissolved in anhydrous N, N-dimethylformamide (8 mL), N-methylpiperazine (33. Mu.L, 0.291 mmol) and triethylamine (41. Mu.L, 0.291 mmol) were added in this order, and the reaction mixture was heated to 50℃and stirred for reaction. After completion of the TLC detection reaction, the reaction mixture was treated with ethyl acetate (10 mL) and water (10 mL), the aqueous layer was extracted with ethyl acetate (10 mL), the organic phases were combined, washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound a-48 (white solid, 63mg, yield 53%): 1 H NMR(300MHz,CDCl 3 )δ7.86–7.78(m,1H),7.69–7.63(m,1H),7.63–7.49(m,2H),6.62–6.50(m,1H),4.77–4.67(m,1H),4.45(t,J＝4.8Hz,2H),4.28–4.14(m,2H),3.70–3.59(m,2H),2.75(d,J＝13.0Hz,1H),2.68–2.33(m,11H),2.29(s,3H),2.21–2.15(m,1H),2.03(s,3H),1.17(s,3H),0.96(s,6H),0.95(s,3H),0.93(s,3H),0.92(s,3H),0.74(s,3H).ESI-MS:m/z 816.7[M+H] + 。
example 66
3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (1-piperazinyl) ethyl ester (Compound A-47)
Referring to the procedure of example 65, substituting piperazine for N-methylpiperazine produced compound a-47: 1 H NMR(300MHz,CDCl 3 )δ7.84–7.79(m,1H),7.69–7.63(m,1H),7.62–7.50(m,2H),6.61–6.50(m,1H),4.77–4.67(m,1H),4.44(t,J＝5.0Hz,2H),4.26–4.12(m,2H),3.71–3.60(m,2H),3.25–3.13(m,4H),2.91–2.70(m,5H),2.66(t,J＝5.5Hz,2H),2.42(d,J＝14.1Hz,1H),2.21–2.11(m,1H),2.03(s,3H),1.18(s,3H),0.97(s,3H),0.96(s,3H),0.95(s,3H),0.91(s,6H),0.74(s,3H).ESI-MS:m/z 802.7[M+H] + 。
example 67
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-acyl) -azetidine (Compound A-106)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with silacyclobutane produced compound A-106: 1 H NMR(300MHz,CDCl 3 )δ8.00–7.36(m,4H),4.88–4.64(m,1H),4.34–3.93(m,4H),2.83–2.66(m,1H),2.48–2.33(m,1H),1.15(s,3H),0.93(s,9H),0.85(s,6H),0.77(s,3H).ESI-MS:m/z 642.5[M-H] - 。
example 68
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-yl) -3-methoxy-azetidine (Compound A-107)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 3-methoxyazetidine produced compound A-107: 1 H NMR(300MHz,DMSO-d 6 )δ13.24(s,1H),7.76–7.68(m,1H),7.66–7.57(m,3H),4.71–4.56(m,1H),4.50–3.58(m,5H),3.19(s,3H),2.79–2.63(m,1H),2.34(d,J＝13.5Hz,1H),2.10–1.97(m,1H),1.14(s,3H),0.91(s,3H),0.88(s,9H),0.82(s,3H),0.73(s,3H).ESI-MS:m/z 672.5[M-H] - 。
example 69
N- (2- (1-piperazinyl) ethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-72)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with N-aminoethylpiperazine produced compound A-72: 1 H NMR(300MHz,DMSO-d 6 )δ9.77–9.47(m,2H),7.71–7.58(m,1H),5.30–5.19(m,1H),3.97–3.58(m,4H),3.52–3.32(m,6H),3.14–2.95(m,3H),2.88–2.76(m,1H),1.09(s,3H),0.89(s,6H),0.87(s,3H),0.85(s,3H),0.67(s,3H),0.66(s,3H).ESI-MS:m/z 568.5[M+H] + 。
example 70
3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2-trimethylammonio ethyl bromide (Compound A-45)
Referring to the procedure of example 65, substituting trimethylamine for N-methylpiperazine produced compound A-45: 1 H NMR(300MHz,methanol-d 4 )δ7.78–7.71(m,2H),7.66–7.59(m,2H),4.76–4.67(m,2H),4.61–4.51(m,2H),4.36(t,J＝5.5Hz,2H),3.73(t,J＝5.0Hz,2H),3.53(t,J＝5.4Hz,2H),3.24(s,9H),2.81(d,J＝15.0Hz,1H),2.49(d,J＝13.9Hz,1H),2.19(d,J＝13.5Hz,1H),1.96(s,4H),1.24(s,3H),0.99(s,3H),0.97(s,3H),0.97(s,3H),0.94(s,3H),0.92(s,3H),0.79(s,3H).ESI-MS:m/z 775.6[M-Br] + 。
example 71
3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-13 (18) -en-28-oic acid 3-trimethylammoniopropyl bromide (Compound A-46)
With reference to the method of example 65, 1, 2-dibromoethane was replaced with 1, 3-dibromopropane and N-methylpiperazine was replaced withTrimethylamine to produce compound a-46: 1 H NMR(300MHz,methanol-d 4 )δ7.83–7.76(m,2H),7.71–7.64(m,2H),4.81–4.73(m,1H),4.41(t,J＝5.5Hz,2H),4.23(dd,J＝11.7,5.9Hz,2H),3.58(t,J＝5.5Hz,2H),3.48(dd,J＝10.2,6.5Hz,2H),3.23(s,9H),2.86(d,J＝14.4Hz,1H),2.56(d,J＝14.1Hz,1H),2.30–2.16(m,3H),2.01(s,4H),1.29(s,3H),1.04(s,3H),1.02(s,6H),0.98(s,3H),0.97(s,3H),0.83(s,3H).ESI-MS:m/z 789.6[M-Br] + 。
example 72
3β - (2-carboxybenzoyl) oxy-oleanane-13 (18) -en-28-oic acid 2- (4-methyl-1-piperazinyl) ethyl ester (Compound A-37)
Referring to the procedure of example 59, substituting dimethylamine hydrochloride with N-methylpiperazine produced compound A-37: 1 H NMR(300MHz,methanol-d 4 )δ7.84–7.76(m,1H),7.75–7.68(m,1H),7.68–7.60(m,2H),4.77(dd,J＝10.6,5.2Hz,1H),4.52–4.40(m,2H),3.80–3.25(m,10H),3.02(s,3H),2.85(d,J＝14.8Hz,1H),2.53(d,J＝14.2Hz,1H),2.30–2.22(m,1H),1.28(s,3H),1.03(s,3H),1.02(s,3H),1.01(s,3H),0.99(s,3H),0.95(s,3H),0.83(s,3H).ESI-MS:m/z 731.6[M+H] + 。
Example 73
N- (2- (dimethylamino) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-1)
Oleanolic acid (OA, 5g, 0.0111 mol) was dissolved in anhydrous pyridine (35 mL), acetic anhydride (4 mL) was slowly added dropwise with stirring, and the mixture was heated under reflux for 1 hour after the completion of the dropwise addition. After completion of the TLC detection, the reaction solution was cooled to room temperature, and was dropped into ice water (20 mL. Times.2), a large amount of white solid was precipitated, suction-filtered, the cake was washed with water (10 mL. Times.3), n-hexane (10 mL. Times.3), dried in vacuo, and recrystallized from ethanol to give compound XI-1 (white solid, 4.52g, yield 83%).
Compound XI-1 (150 mg,0.301 mmol) was dissolved in anhydrous dichloromethane (8 mL), oxalyl chloride (130. Mu.L, 1.504 mmol) and N, N-dimethylformamide (1 drop) were slowly added dropwise with stirring, and reacted at room temperature for 3 hours. After completion of the TLC detection, the solvent was distilled off under reduced pressure to give compound XI-2 (yellow solid, 155mg, yield 100%).
N, N-dimethylethylenediamine (66. Mu.L, 0.602 mmol) was dissolved in anhydrous dichloromethane (5 mL), and a solution of compound XI-2 (155 mg,0.301 mmol) in anhydrous dichloromethane (5 mL) and triethylamine (84. Mu.L, 0.602 mmol) were slowly added dropwise with stirring and reacted at room temperature for 5 hours. After completion of the TLC detection reaction, methylene chloride (10 mL) was added to dilute the reaction solution, which was washed with saturated sodium hydrogen carbonate solution (10 mL. Times.3), water (10 mL. Times.3) and saturated brine (10 mL. Times.3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methylene chloride: methanol=100:1 to 50:1) to give compound XI-3 (white solid, 156mg, yield 91%).
Compound XI-3 (156 mg,0.274 mmol) was suspended in methanol (10 mL), potassium hydroxide (154 mg,2.74 mmol) was added, and the reaction mixture was heated to 65℃and reacted for 5 hours. After completion of TLC detection, the reaction was cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was treated with ethyl acetate (20 mL) and water (20 mL), the organic phase was washed successively with water (20 ml×3) and saturated brine (20 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound B-1 (white solid, 123mg, yield 85%): 1 H NMR(300MHz,CDCl 3 )δ6.59–6.45(m,1H),5.35(t,J＝3.4Hz,1H),3.44–3.29(m,1H),3.27–3.07(m,2H),2.59–2.46(m,1H),2.37(t,J＝6.1Hz,2H),2.23(s,6H),1.16(s,3H),0.99(s,3H),0.91(s,9H),0.79(s,3H),0.78(s,3H).ESI-MS:m/z 527.5[M+H] + 。
example 74
N- (3 beta-hydroxy-oleanane-12-en-28-amide) -morpholine (compound B-2)
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Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with morpholine produced compound B-2: 1 H NMR(300MHz,CDCl 3 )δ5.33–5.21(m,1H),3.76–3.54(m,8H),3.28–3.15(m,1H),3.15–3.03(m,1H),1.16(s,3H),1.00(s,3H),0.95(s,3H),0.92(s,6H),0.80(s,3H),0.75(s,3H).ESI-MS:m/z 526.5[M+H] + 。
example 75
N- (2- (dimethylamino) ethyl) -N-methyl-3β -hydroxy-oleanane-12-en-28-amide (Compound B-3)
Referring to the procedure of example 73, N, N-dimethylethylenediamine was replaced with N, N, N' -trimethylethylenediamine to obtain compound B-3: 1 H NMR(300MHz,CDCl 3 )δ5.26(t,J＝3.3Hz,1H),3.43(t,J＝7.2Hz,2H),3.26–3.17(m,1H),3.16–3.12(m,1H),3.10(s,3H),2.54–2.31(m,3H),2.25(s,6H),1.14(s,3H),0.99(s,3H),0.93(s,3H),0.91(s,3H),0.89(s,3H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 541.6[M+H] + 。
example 76
N- (3- (dimethylamino) propyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-4)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 3-dimethylaminopropylamine produced compound B-4: 1 H NMR(300MHz,CDCl 3 )δ7.03–6.96(m,1H),5.33–5.28(m,1H),3.59–3.45(m,1H),3.27–3.15(m,1H),3.08–2.94(m,1H),2.60–2.47(m,1H),2.47–2.26(m,2H),2.23(s,6H),1.15(s,3H),0.99(s,3H),0.91(s,9H),0.78(s,3H),0.76(s,3H).ESI-MS:m/z 563.5[M+Na] + 。
Example 77
N- (2- (diethylamino) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-5)
Referring to the procedure of example 73, N-dimethylethylenediamine was replaced with N, N-diethylethylenediamine to obtain Compound B-5: 1 H NMR(300MHz,CDCl 3 )δ6.63–6.53(m,1H),5.38–5.33(m,1H),3.53–3.41(m,1H),3.28–3.17(m,1H),3.10–2.97(m,1H),2.65–2.39(m,7H),1.17(s,3H),1.04(t,J＝7.1Hz,6H),1.01(s,3H),0.92(s,9H),0.80(s,3H),0.78(s,3H).ESI-MS:m/z 577.5[M+Na] + 。
example 78
N- (2- (1-piperidinyl) ethyl) -3 beta-hydroxy-oleanane-12-en-28-amide (Compound B-6)
Referring to the procedure of example 73, N-dimethylethylenediamine was substituted for 1- (2-aminoethyl) piperidine to give compound B-6: 1 H NMR(300MHz,CDCl 3 )δ6.65–6.55(m,1H),5.43–5.28(m,1H),3.45–3.32(m,1H),3.27–3.08(m,2H),2.57–2.47(m,1H),2.47–2.24(m,6H),1.16(s,3H),0.99(s,3H),0.91(s,9H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z567.5[M+H] + 。
example 79
N- (2- (4-morpholinoalkyl) ethyl) -3 beta-hydroxy-oleanane-12-en-28-amide (Compound B-7)
Referring to the procedure of example 73, N-dimethylethylenediamine was replaced with N- (2)-aminoethyl) morpholine to produce compound B-7: 1 H NMR(300MHz,CDCl 3 )δ6.54–6.42(m,1H),5.42–5.30(m,1H),3.78–3.62(m,4H),3.50–3.33(m,1H),3.30–3.08(m,2H),2.58–2.49(m,1H),2.49–2.32(m,6H),1.16(s,3H),0.99(s,3H),0.91(s,6H),0.89(s,3H),0.78(s,3H),0.76(s,3H).ESI-MS:m/z 569.5[M+H] + 。
example 80
N- (3- (4-morpholinoalkyl) propyl) -3 beta-hydroxy-oleanane-12-en-28-amide (Compound B-8)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with N- (3-aminopropyl) morpholine produced compound B-8: 1 H NMR(300MHz,CDCl 3 )δ6.30–6.21(m,1H),5.40–5.31(m,1H),3.79–3.66(m,4H),3.51–3.36(m,1H),3.27–3.16(m,1H),3.13–2.98(m,1H),2.61–2.50(m,1H),2.50–2.31(m,6H),1.16(s,3H),0.99(s,3H),0.90(s,9H),0.78(s,3H),0.76(s,3H).ESI-MS:m/z 569.5[M+H] + 。
example 81
N- (3β -hydroxy-oleanane-12-en-28-yl) -thiomorpholine-1, 1-dioxide (compound B-9)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with thiomorpholine-1, 1-dioxide produced compound B-9: 1 H NMR(300MHz,CDCl 3 )δ5.32–5.23(m,1H),4.09(t,J＝5.2Hz,4H),3.26–3.14(m,1H),3.11–2.90(m,4H),2.29–2.10(m,1H),1.15(s,3H),0.99(s,3H),0.93(s,3H),0.91(s,3H),0.90(s,3H),0.78(s,3H),0.71(s,3H).ESI-MS:m/z 574.4[M+H] + 。
Example 82
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-10)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 1- (2-aminoethyl) pyrrolidine gave compound B-10: 1 H NMR(300MHz,CDCl 3 )δ6.64–6.52(m,1H),5.37–5.26(m,1H),3.50–3.34(m,1H),3.19(d,J＝4.7Hz,1H),2.63–2.44(m,4H),1.14(s,2H),0.97(s,2H),0.89(s,5H),0.76(s,3H).ESI-MS:m/z 553.5[M+H] + 。
example 83
N- (2- (1-piperazinyl) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-11)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with N-aminoethylpiperazine produced compound B-11: 1 H NMR(300MHz,DMSO-d 6 )δ9.77–9.47(m,2H),7.71–7.58(m,1H),5.30–5.19(m,1H),3.97–3.58(m,4H),3.52–3.32(m,6H),3.14–2.95(m,3H),2.88–2.76(m,1H),1.09(s,3H),0.89(s,6H),0.87(s,3H),0.85(s,3H),0.67(s,3H),0.66(s,3H).ESI-MS:m/z 568.5[M+H] + 。
example 84
N- (2- (4-methyl-1-piperazinyl) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-12)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 1- (2-aminoethyl) -4-methylpiperazine produced compound B-12: 1 H NMR(300MHz,CDCl 3 )δ6.55–6.44(m,1H),5.35(s,1H),4.30–4.14(m,1H),3.46–3.31(m,1H),3.28–3.05(m,2H),2.61–2.36(m,10H),2.29(s,3H),1.14(s,3H),0.96(s,3H),0.88(s,9H),0.75(s,3H),0.73(s,3H).ESI-MS:m/z 582.5[M+H] + 。
example 85
N- (2- (1, 1-dioxothiomorpholinyl) ethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-13)
Oleanolic acid (OA, 200mg,0.438 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (243. Mu.L, 1.752 mmol) was added, 2- (7-oxybenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (216 mg,0.569 mmol) was added with stirring at room temperature, and after 1 hour of reaction, the compound 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide (156 mg,0.875 mmol) was added, and the reaction mixture was warmed to 60 ℃. After completion of the TLC detection reaction, the reaction mixture was treated with ethyl acetate (10 mL) and water (5 mL), the aqueous layer was extracted with ethyl acetate (10 ml×2), the organic layers were combined, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=50:1) to give compound B-13 (white solid, 175mg, yield 65%): 1 H NMR(300MHz,CDCl 3 )δ6.22(s,1H),5.35(s,1H),3.49(dd,J＝13.6,6.2Hz,1H),3.20(d,J＝4.8Hz,2H),3.05(s,8H),2.63(s,2H),2.49(d,J＝11.0Hz,1H),1.17(s,3H),0.99(s,2H),0.90(s,6H),0.78(s,2H),0.76(s,3H).ESI-MS:m/z 617.5[M+H] + 。
Example 86
N- (3β -hydroxy-oleanane-12-en-28-yl) - (2S) -carboxy-tetrahydropyrrole (Compound B-16)
Referring to the procedure of example 73, N-dimethylethylenediamine was replaced with L-proline benzyl ester hydrochloride to give compound XII-1.
Compound XII-1 (120 mg,0.186 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and methanol (1 mL), and 2N sodium hydroxide solution (1 mL) was added thereto to react at 80℃for 2 hours. TLC detectionAfter the reaction was completed, the solvent was distilled off under reduced pressure, the pH was adjusted to be weakly acidic with a 1N hydrochloric acid solution, dichloromethane extraction (5 mL. Times.2), washing (5 mL. Times.2) the organic phase with water, washing with saturated brine (5 mL. Times.2), drying over anhydrous sodium sulfate, distilled off under reduced pressure, the residue was treated with a mixed solvent of dichloromethane and acetonitrile (5.5 mL, v: v=10:1) in ultrasound to precipitate a white solid, suction filtration, the filter cake was washed twice with a mixed solvent of dichloromethane and acetonitrile (5.5 mL, v: v=10:1), and drying under infrared to give compound B-16 (white solid, 88mg, yield 85%): 1 H NMR(300MHz,DMSO-d 6 )δ5.32–5.24(m,1H),4.66–4.53(m,1H),3.85–3.67(m,1H),3.53(q,J＝9.3Hz,1H),3.26–3.06(m,2H),2.40(dd,J＝13.0,2.5Hz,1H),1.15(s,3H),0.98(s,3H),0.94(s,3H),0.91(s,3H),0.90(s,3H),0.77(s,3H),0.71(s,3H).ESI-MS:m/z 552.3[M-H] - 。
example 87
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -4-methyl-piperazine (Compound B-17)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with N-methylpiperazine produced compound B-17: 1 H NMR(300MHz,CDCl 3 )δ5.30–5.24(m,1H),3.76–3.58(m,4H),3.26–3.18(m,1H),3.10(d,J＝12.3Hz,1H),2.45–2.33(m,4H),2.31(s,3H),1.15(s,3H),1.00(s,3H),0.95(s,3H),0.92(s,3H),0.91(s,3H),0.80(s,3H),0.76(s,3H).ESI-MS:m/z 539.5[M+H] + 。
Example 88
N- (2- (4-methyl-1-piperazinyl) propyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-18)
Referring to the procedure of example 85, substituting 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide with 1- (3-aminopropyl) -4-methylpiperazine produced the compoundB-19： 1 H NMR(300MHz,CDCl 3 )δ6.41–6.18(m,1H),5.41–5.27(m,1H),3.54–3.35(m,1H),3.29–3.15(m,1H),3.15–2.99(m,1H),2.70–2.33(m,11H),2.29(s,3H),1.16(s,3H),0.99(s,3H),0.91(s,9H),0.79(s,3H),0.76(s,3H).ESI-MS:m/z 596.6[M+H] + 。
Example 89
N- (2- (1-tetrahydropyrrolyl) propyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-19)
Referring to the procedure of example 85, substituting 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide with 1- (3-aminopropyl) pyrrolidine produced compound B-19: 1 H NMR(300MHz,CDCl 3 )δ5.63–5.33(m,1H),3.65–3.33(m,4H),3.30–2.98(m,6H),2.75–2.43(m,1H),0.99(s,3H),0.94(s,3H),0.91(s,6H),0.78(s,3H),0.71(s,3H).ESI-MS:m/z 567.5[M+H] + 。
example 90
N- (2- (1, 1-dioxothiomorpholinyl) propyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-20)
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Referring to the procedure of example 85, substituting 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide gives compound B-20: 1 H NMR(300MHz,CDCl 3 )δ6.10–5.98(m,1H),5.43–5.28(m,1H),3.50–3.33(m,1H),3.30–3.18(m,1H),3.12–2.90(m,9H),2.59–2.42(m,3H),1.17(s,3H),0.99(s,3H),0.91(s,9H),0.79(s,3H),0.76(s,3H).ESI-MS:m/z 631.5[M+H] + 。
example 91
N- (2- (1-piperidinyl) propyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-22)
Referring to the procedure of example 85, substituting 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide with 1- (3-aminopropyl) piperidine produced compound B-22: 1 H NMR(300MHz,DMSO-d 6 )δ8.82(s,1H),7.39(s,1H),5.22(s,1H),4.22(s,1H),3.43–3.32(m,2H),3.12–3.02(2H),3.01–2.95(s,2H),2.89–2.79(m,2H),1.09(s,3H),0.89(s,6H),0.88(s,3H),0.85(s,3H),0.68(s,3H),0.67(s,3H).ESI-MS:m/z 581.5[M+H] + 。
example 92
N- (2- (trimethylammonio) ethyl) -3 beta-hydroxy-oleanane-12-en-28-amidebromide (Compound B-23)
Oleanolic acid (OA, 100mg,0.219 mmol) was dissolved in N, N-dimethylformamide (8 mL), triethylamine (122. Mu.L, 0.876 mmol) was added, 2- (7-benzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 108mg,0.284 mmol) was added with stirring at room temperature, and after 1 hour of reaction, compound I-4 (116 mg,0.438 mmol) was added and the reaction solution was warmed to 50 ℃. After completion of TLC detection, the reaction mixture was treated with dichloromethane (10 mL) and deionized water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with deionized water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound B-23 (white solid, 43mg, yield 32%): 1 H NMR(300MHz,methanol-d 4 )δ7.75–7.66(m,1H),5.46–5.39(m,1H),3.79–3.54(m,2H),3.47(t,J＝6.8Hz,2H),3.30–3.14(m,10H),2.91–2.80(m,1H),1.23(s,3H),1.02(s,3H),1.00(s,6H),0.97(s,3H),0.83(s,3H),0.82(s,3H).ESI-MS:m/z 541.5[M-Br] + 。
example 93
N- (3 beta-hydroxy-oleanane-12-en-28-acyl) -piperazine (Compound B-25)
Referring to the procedure of example 73, N-dimethylethylenediamine was replaced with 1-benzylpiperazine to give compound XIII-1.
Compound XIII-1 (100 mg,0.163 mmol) was dissolved in tetrahydrofuran (8 mL), 10% palladium on carbon (10 mg) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of TLC detection reaction, celite was filtered, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound B-25 (white solid, 61mg, yield 72%): 1 H NMR(300MHz,DMSO-d 6 )δ9.28(s,2H),5.15–5.02(m,1H),4.34–4.24(m,1H),3.86–3.60(m,4H),3.09–2.87(m,6H),2.12–1.95(m,1H),1.09(s,3H),0.88(s,9H),0.84(s,3H),0.67(s,3H),0.64(s,3H).ESI-MS:m/z 525.5[M+H] + 。
Example 94
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -tetrahydropyrrole (Compound B-26)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with tetrahydropyrrole produced compound B-26: 1 H NMR(300MHz,CDCl 3 )δ7.10–6.85(m,1H),5.44–5.22(m,1H),3.63–3.42(m,1H),3.29–3.13(m,1H),3.12–2.93(m,1H),2.67–2.48(m,2H),2.48–2.34(m,3H),2.27(s,6H),1.15(s,4H),0.99(s,4H),0.91(s,9H),0.78(s,3H),0.76(s,3H).ESI-MS:m/z 541.5[M+H] + 。
example 95
N- (3 beta-hydroxy-oleanane-12-en-28-yl) - (3S) -amino-tetrahydropyrrole (Compound B-27)
Referring to the procedure of example 73, N-dimethylethylenediamine was replaced with (S) -3-N-benzyloxycarbonyl aminopyrrolidine to give compound XIV-1.
Compound XIV-1 (216 mg,0.328 mmol) was dissolved in tetrahydrofuran (8 mL), 10% palladium on carbon (20 mg) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of TLC detection, celite was filtered, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound B-27 (white solid, 143mg, 83% yield): 1 H NMR(300MHz,CDCl 3 )δ5.29–5.22(m,1H),3.74–3.61(m,2H),3.61–3.49(m,2H),3.37–3.25(m,1H),3.25–3.07(m,2H),1.14(s,3H),0.98(s,3H),0.94(s,3H),0.89(s,6H),0.77(s,3H),0.72(s,3H).ESI-MS:m/z 525.5[M+H] + 。
example 96
N- (3 beta-hydroxy-oleanane-12-en-28-yl) - (3R) -amino-tetrahydropyrrole (Compound B-28)
Referring to the procedure of example 95, (S) -3-N-benzyloxycarbonyl-amino-pyrrolidine was replaced with (R) -3-N-benzyloxycarbonyl-amino-pyrrolidine to give compound B-28: 1 H NMR(300MHz,CDCl 3 )δ5.29–5.20(m,1H),3.90–3.72(m,1H),3.72–3.59(m,1H),3.58–3.40(m,2H),3.26–3.04(m,3H),2.13–1.99(m,2H),1.13(s,3H),0.98(s,3H),0.93(s,3H),0.89(s,6H),0.77(s,3H),0.71(s,3H).ESI-MS:m/z 525.5[M+H] + 。
example 97
N- (3 beta-hydroxy-oleanane-12-en-28-yl) - (3S) -hydroxy-tetrahydropyrrole (Compound B-29)
Reference to example 73The method comprises the steps of replacing N, N-dimethyl ethylenediamine with (S) -3-pyrrolidinol to prepare a compound B-29: 1 H NMR(300MHz,CDCl 3 )δ5.26(m,1H),4.50–4.36(m,1H),3.75–3.61(m,2H),3.61–3.49(m,2H),3.24–3.09(m,2H),1.13(s,3H),0.97(s,3H),0.93(s,3H),0.89(s,3H),0.88(s,3H),0.76(s,3H),0.72(s,3H).ESI-MS:m/z 548.4[M+Na] + 。
example 98
N- (3 beta-hydroxy-oleanane-12-en-28-yl) - (3R) -hydroxy-tetrahydropyrrole (Compound B-30)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with (R) -3-pyrrolidinol produced compound B-30: 1 H NMR(300MHz,CDCl 3 )δ5.24(m,1H),4.49–4.31(m,1H),3.81–3.57(m,3H),3.56–3.43(m,1H),3.29–3.13(m,1H),3.14–2.95(m,1H),2.56–2.16(m,1H),1.13(s,3H),0.97(s,3H),0.93(s,3H),0.89(s,3H),0.88(s,3H),0.76(s,3H),0.70(s,3H).ESI-MS:m/z 548.4[M+Na] + 。
example 99
3 beta-hydroxy-oleanane-12-en-28-oic acid 2- (1-piperidinyl) ethyl ester (Compound B-31)
Oleanolic acid (OA, 5g,10.9 mmol) was dissolved in N, N-dimethylformamide (40 mL), 1, 2-dibromoethane (10.2 mL,109 mmol), potassium carbonate (1.506 g,10.9 mmol) and acetonitrile (4 mL) were sequentially added, and the reaction solution was warmed to 50℃and stirred for 3 hours. After completion of the TLC detection reaction, the reaction solution was treated with dichloromethane (100 mL) and water (100 mL), the aqueous layer was extracted with dichloromethane (50 mL), the organic phases were combined, washed with water (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound XV-1 (white solid, 4.44g, yield 72%).
Compound XV-1 (200 mg,0.35 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), piperidine (70. Mu.L, 0.70 mmol) and potassium carbonate (48 mg,0.35 mmol) were added in this order, and the reaction mixture was warmed to 50℃and stirred for reaction. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic phases were combined, washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound B-31 (white solid, 47mg, yield 24%): 1 H NMR(300MHz,CDCl 3 )δ5.29–5.23(m,1H),4.27–4.09(m,2H),3.26–3.15(m,1H),2.89–2.79(m,1H),2.63(t,J＝5.5Hz,2H),2.54–2.42(m,4H),1.13(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,6H),0.78(s,3H),0.73(s,3H).ESI-MS:m/z 568.6[M+H] + 。
Example 100
3 beta-hydroxy-oleanane-12-en-28-oic acid 2- (4-morpholinyl) ethyl ester (Compound B-32)
Referring to the procedure of example 99, substituting piperidine for morpholine produced compound B-32: 1 H NMR(300MHz,CDCl 3 )δ5.30–5.18(m,1H),4.70–4.52(m,2H),4.42–4.11(m,2H),4.11–3.79(m,2H),3.63–3.31(m,2H),3.31–3.08(m,3H),3.04–2.84(m,2H),2.78(d,J＝12.5Hz,1H),1.14(s,3H),0.99(s,3H),0.91(s,9H),0.78(s,3H),0.70(s,3H).ESI-MS:m/z 570.6[M+H] + 。
example 101
3 beta-hydroxy-oleanane-12-en-28-oic acid 2- (1-tetrahydropyrrolyl) ethyl ester (Compound B-33)
Referring to the procedure of example 99, substituting piperidine for tetrahydropyrrole produced compound B-33: 1 H NMR(300MHz,CDCl 3 )δ5.31–5.21(m,1H),4.67–4.48(m,2H),3.90–3.71(m,2H),3.39–3.12(m,3H),2.92–2.72(m,3H),2.35–2.16(m,2H),2.16–2.02(m,2H),2.02–1.92(m,1H),1.91–1.82(m,2H),1.13(s,3H),0.98(s,3H),0.90(s,9H),0.77(s,3H),0.69(s,3H).ESI-MS:m/z 554.6[M+H] + 。
example 102
N- (2- (acetamido) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-38)
Referring to the procedure of example 85, 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide was replaced with N-acetyl ethylenediamine to produce compound XVI-1.
Compound XVI-1 (120 mg,0.222 mmol) was dissolved in anhydrous pyridine (8 mL), phthalic anhydride (399 mg,2.22 mmol) and 4-dimethylaminopyridine (28 mg,0.222 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of TLC detection, dichloromethane (20 mL) was added to dilute the reaction, which was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound B-38 (white solid, 96mg, yield 63%): to obtain the compound B-38: 1 H NMR(300MHz,methanol-d 4 )δ7.79–7.72(m,1H),7.68–7.63(m,1H),7.60–7.52(m,2H),7.35–7.24(m,1H),5.52–5.44(m,1H),5.41–5.34(m,1H),4.77–4.61(m,1H),3.20–3.05(m,1H),2.83–2.65(m,1H),1.21–1.19(m,6H),0.99(s,3H),0.97(s,3H),0.95(s,3H),0.91(s,6H),0.78(s,3H).ESI-MS:m/z 687.5[M-H] - 。
Example 103
N- (2- (1-piperidinyl) ethyl) -3 beta- (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-39)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 1- (2-aminoethyl) piperidine produced compound B-39: 1 H NMR(300MHz,CDCl 3 )δ7.73–7.61(m,2H),7.50–7.40(m,1H),7.39–7.30(m,1H),7.09(d,J＝13.4Hz,1H),5.41–5.25(m,1H),4.79–4.55(m,1H),3.88–3.55(m,3H),3.17–2.76(m,6H),1.17(s,3H),0.99(s,3H),0.95(s,6H),0.89(s,3H),0.87(s,3H),0.77(s,3H).ESI-MS:m/z 715.7[M+H] + 。
example 104
N- (2- (4-morpholinyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-40)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with N- (2-aminoethyl) morpholine produced compound B-40:1H NMR (300 MHz, methanol-d) 4 )δ7.74–7.63(m,2H),7.60–7.46(m,2H),5.45–5.32(m,1H),4.74–4.62(m,1H),3.82–3.72(m,4H),3.51–3.38(m,1H),3.38–3.24(m,3H),2.83–2.58(m,7H),1.21(s,3H),1.01(s,3H),0.98(s,3H),0.94(s,6H),0.92(s,3H),0.81(s,3H).ESI-MS:m/z 718.6[M+H] + 。
Example 105
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-41)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 1- (2-aminoethyl) pyrrolidine gave compound B-41: 1 H NMR(300MHz,methanol-d 4 )δ7.82–7.61(m,1H),7.59–7.45(m,2H),7.44–7.32(m,1H),5.48(s,1H),5.33(s,1H),4.72–4.64(m,1H),3.67–3.45(m,2H),3.23–3.10(m,2H),2.94–2.76(m,1H),1.20(s,3H),1.00(s,9H),0.93(s,3H),0.90(s,3H),0.80(s,3H).ESI-MS:m/z 702.6[M+H] + 。
example 106
N- (2- (4-morpholinyl) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-47)
Oleanolic acid (OA, 20g,0.044 mol) was dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (6 g,0.044 mol) was added, benzyl bromide (8 mL,0.044 mol) was slowly added dropwise with stirring, and after the addition was completed, the reaction solution was warmed to 85℃and reacted for 10 hours. After the completion of the TLC detection reaction, the reaction was filtered with suction while it was hot, the cake was washed with hot N, N-dimethylformamide (10 mL. Times.3), the filtrate was cooled to room temperature and then dropped into ice water (100 mL. Times.2), a large amount of white solid was precipitated, the filter cake was filtered with suction, washed with water (50 mL. Times.3), washed with N-hexane (50 mL. Times.3), and dried in vacuo to give Compound III-1 (white solid, 22.02g, yield 92%).
Compound III-1 (1 g,1.829 mmol) was dissolved in anhydrous pyridine (10 mL), phthalic anhydride (2.708 g,18.29 mmol) and 4-dimethylaminopyridine (223 mg,1.829 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of TLC detection, dichloromethane (30 mL) was added to dilute the reaction, which was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound XVII-2 (white solid, 925mg, yield 73%).
Compound XVII-2 (150 mg,0.216 mmol) was dissolved in anhydrous dichloromethane (6 mL), and N, N' -dicyclohexylcarbodiimide (134 mg,0.647 mmol), 4-dimethylaminopyridine (27 mg,0.216 mmol) and N-acetylethanolamine (30. Mu.L, 0.324 mmol) were added in this order and the reaction was stirred at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with water (5 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, purification by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) gave compound XVII-3 (white solid, 159mg, yield 95%).
Compound XVII-3 (159 mg,0.204 mmol) was dissolved in tetrahydrofuran (10 mL), 10% palladium on carbon (16 mg) was added thereto, and the reaction was stirred at room temperature under a hydrogen atmosphere overnight. After completion of TLC detection, celite was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound XVII-4 (white solid, 90mg, yield 64%)
Compound XVII-4 (100 mg,0.145 mmol) was dissolved in N, N-dimethylformamide (6 mL), triethylamine (40. Mu.L, 0.290 mmol) was added, 2- (7-benzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (72 mg,0.188 mmol) was added with stirring at room temperature, N- (2-aminoethyl) morpholine (23. Mu.L, 0.174 mmol) was added after 1 hour of reaction, and the reaction solution was warmed to 50 ℃. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic layers were combined, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound B-47 (white solid, 80mg, yield 69%): 1 H NMR(300MHz,CDCl 3 )δ7.78(d,J＝6.1Hz,1H),7.66(d,J＝7.9Hz,1H),7.53–7.42(m,2H),5.34–5.23(m,1H),4.73–4.66(m,1H),4.60–4.49(m,2H),3.52–2.98(m,6H),2.89–2.74(m,1H),1.15(s,3H),0.95(s,3H),0.92(s,9H),0.89(s,3H),0.72(s,3H).ESI-MS:m/z 802.7[M+H] + 。
example 107
N- (2- (4-morpholinyl) ethyl) -3β - (2- (methoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-48)
Referring to the procedure of example 106, N-acetylethanolamine was replaced with methanol to give compound B-48: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.65(m,2H),7.59–7.48(m,2H),6.55–6.45(m,1H),5.43–5.35(m,1H),4.75(dd,J＝11.4,4.5Hz,1H),3.90(s,3H),3.78–3.68(m,4H),3.48–3.37(m,1H),3.28–3.11(m,1H),2.58–2.39(m,7H),1.18(s,3H),0.97(s,3H),0.96(s,3H),0.92(s,9H),0.78(s,3H).ESI-MS:m/z 753.6[M+Na] + 。
example 108
N- (2- (4-morpholinyl) ethyl) -3β - (2- (isopropyloxy) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-49)
Referring to the procedure of example 106, substituting N-acetylethanolamine with isopropanol produced compound B-49: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.65(m,2H),7.57–7.48(m,2H),6.59–6.44(m,1H),5.47–5.36(m,1H),5.34–5.20(m,1H),4.77(dd,J＝11.8,4.6Hz,1H),3.83–3.64(m,4H),3.53–3.39(m,1H),3.29–3.14(m,1H),2.62–2.38(m,7H),1.37(d,J＝6.3Hz,6H),1.20(s,3H),1.00(s,3H),0.98(s,3H),0.94(s,9H),0.80(s,3H).ESI-MS:m/z 759.7[M+H] + 。
Example 109
N- (2- (dimethylamino) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-50)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine with N, N-dimethylethylenediamine produced compound B-50: 1 H NMR(300MHz,CDCl 3 )δ7.87–7.81(m,1H),7.72–7.65(m,1H),7.65–7.53(m,2H),6.93–6.85(m,1H),6.62–6.50(m,1H),5.49–5.41(m,1H),4.79–4.67(m,1H),4.46(t,J＝4.5Hz,2H),3.71–3.63(m,2H),3.60–3.47(m,1H),3.47–3.34(m,1H),3.04–2.92(m,2H),2.75–2.57(m,7H),2.04(s,3H),1.21(s,3H),1.00(s,9H),0.96(s,3H),0.94(s,3H),0.81(s,3H).ESI-MS:m/z 760.6[M+H] + 。
example 110
N- (2- (dimethylamino) ethyl) -3β - (2- (methoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-51)
Referring to the procedure of example 106, substituting N-acetylethanolamine with methanol and substituting N- (2-aminoethyl) morpholine with N, N-dimethylethylenediamine produced compound B-51: 1 H NMR(300MHz,CDCl 3 )δ7.78–7.63(m,2H),7.58–7.48(m,2H),6.60–6.45(m,1H),5.45–5.30(m,1H),4.75(dd,J＝11.1,4.4Hz,1H),3.90(s,3H),3.44–3.30(m,1H),3.23–3.08(m,1H),2.60–2.48(m,1H),2.37(t,J＝5.9Hz,2H),2.23(s,6H),1.18(s,3H),0.97(s,6H),0.91(s,9H),0.81(s,3H).ESI-MS:m/z 689.5[M+H] + 。
example 111
N- (2- (dimethylamino) ethyl) -3β - (2- (isopropyloxy) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-52)
Referring to the procedure of example 106, substituting N-acetylethanolamine with isopropanol and N- (2-aminoethyl) morpholine with N, N-dimethylethylenediamine produced compound B-52: 1 H NMR(300MHz,CDCl 3 )δ7.81–7.65(m,2H),7.61–7.47(m,2H),6.66–6.47(m,1H),5.48–5.36(m,1H),5.35–5.22(m,1H),4.79(dd,J＝11.6,4.6Hz,1H),3.49–3.31(m,1H),3.29–3.09(m,1H),2.67–2.50(m,1H),2.40(t,J＝6.0Hz,2H),2.26(s,6H),1.39(d,6H),1.21(s,3H),1.01(s,6H),0.96(s,3H),0.95(s,6H),0.85(s,3H).ESI-MS:m/z 717.5[M+H] + 。
example 112
N- (2- (1-piperazinyl) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-53)
With reference to the method of example 106,substitution of N- (2-aminoethyl) morpholine to N-aminoethylpiperazine produced compound B-53: 1 H NMR(300MHz,CDCl 3 )δ7.85–7.77(m,1H),7.71–7.63(m,1H),7.64–7.49(m,2H),6.62–6.40(m,2H),5.47–5.31(m,1H),4.78–4.64(m,1H),4.44(t,J＝4.9Hz,2H),3.74–3.58(m,2H),3.52–3.39(m,1H),3.24–3.11(m,1H),2.99–2.87(m,3H),2.64–2.38(m,6H),2.31(2,3H),2.07–1.99(m,3H),1.18(s,3H),0.97(s,9H),0.92(s,6H),0.79(s,3H).ESI-MS:m/z 801.8[M+H] + 。
Example 113
N- (2- (4-methyl-1-piperazinyl) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-54)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) -4-methylpiperazine produced compound B-54: 1 H NMR(300MHz,CDCl 3 )δ7.78(d,J＝6.1Hz,1H),7.66(d,J＝7.9Hz,1H),7.53–7.42(m,2H),5.34–5.23(m,1H),4.73–4.66(m,1H),4.60–4.49(m,2H),3.52–2.98(m,6H),2.89–2.74(m,1H),1.15(s,3H),0.95(s,3H),0.92(s,9H),0.89(s,3H),0.72(s,3H).ESI-MS:m/z 816.7[M+H] + 。
example 114
N- (2- (trimethylammonio) ethyl) -3β - (2- (2-acetamidoethoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide bromide (Compound B-55)
Referring to the procedure of example 107, substituting N- (2-aminoethyl) morpholine for compound I-4 produced compound B-55: 1 H NMR(300MHz,methanol-d 4 )δ7.84–7.74(m,2H),7.72–7.64(m,2H),5.45–5.39(m,1H),4.80–4.70(m,1H),4.40(t,J＝5.5Hz,2H),3.77–3.61(m,2H),3.58(t,J＝5.4Hz,2H),3.46(t,J＝6.9Hz,2H),3.24(s,9H),2.87(d,J＝9.7Hz,1H),2.25–2.11(m,1H),2.00(s,5H),1.26(s,3H),1.07(s,3H),1.02(s,3H),1.01(s,3H),0.98(s,6H),0.86(s,3H).ESI-MS:m/z 774.6[M-Br] + 。
example 115
N- (3- (dimethylamino) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-59)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 3-dimethylaminopropylamine produced compound B-59: 1 H NMR(300MHz,CDCl 3 )δ7.75–7.54(m,2H),7.52–7.30(m,2H),6.97–6.78(m,1H),5.45–5.29(m,1H),4.76–4.62(m,1H),3.92–3.78(m,1H),3.51–3.36(m,1H),3.31–3.14(m,1H),3.07–2.84(m,1H),2.72(s,6H),1.14(s,3H),0.98(s,3H),0.92(s,6H),0.88(s,6H),0.73(s,3H).ESI-MS:m/z 689.7[M+H] + 。
example 116
N- (3- (4-morpholinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-60)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with N- (3-aminopropyl) morpholine produced compound B-60: 1 H NMR(300MHz,CDCl 3 )δ7.82–7.67(m,1H),7.69–7.56(m,1H),7.55–7.36(m,2H),6.54–6.35(m,2H),5.51–5.24(m,1H),4.95–4.60(m,1H),4.04–3.77(m,4H),3.54–3.34(m,1H),3.24–3.03(m,1H),2.91–2.55(m,6H),1.15(s,3H),0.98(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,3H),0.74(s,3H).ESI-MS:m/z 731.7[M+H] + 。
example 117
N- (3- (4-methyl-1-piperazinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-61)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 1- (3-aminopropyl) -4-methylpiperazine produced compound B-61: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.60(m,2H),7.60–7.37(m,2H),6.60–6.19(m,3H),5.44–5.34(m,1H),4.79–4.57(m,1H),3.57–3.33(m,1H),3.27–3.04(m,8H),2.84–2.72(m,2H),1.19–1.15(m,3H),0.96(s,3H),0.92(s,3H),0.90(s,6H),0.74(s,3H).ESI-MS:m/z 744.7[M+H] + 。
example 118
N- (3- (1-tetrahydropyrrolyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-62)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 1- (3-aminopropyl) pyrrolidine gave compound B-62: 1 H NMR(300MHz,CDCl 3 )δ7.70–7.54(m,2H),7.46–7.38(m,1H),7.36–7.30(m,1H),6.99–6.88(m,1H),5.39–5.27(m,1H),4.76–4.60(m,1H),3.52–3.37(m,1H),3.32–2.91(m,7H),2.81–2.65(m,1H),1.13(s,3H),0.99(s,3H),0.93(s,6H),0.88(s,6H),0.73(s,3H).ESI-MS:m/z 715.7[M+H] + 。
example 119
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-63)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide produced compound B-63: 1 H NMR(300MHz,CDCl 3 )δ7.90–7.78(m,1H),7.75–7.65(m,1H),7.59–7.50(m,2H),6.17–6.02(m,1H),5.40–5.34(m,1H),5.32–5.24(m,1H),4.83–4.62(m,1H),3.53–3.33(m,1H),3.16–2.96(m,8H),2.62–2.42(m,3H),1.17(s,3H),0.96(s,3H),0.91(s,12H),0.76(s,3H).ESI-MS:m/z 779.7[M+H] + 。
example 120
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-65)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide produced compound B-65: 1 H NMR(300MHz,CDCl 3 )δ7.84–7.77(m,1H),7.69–7.63(m,1H),7.62–7.50(m,2H),6.56–6.46(m,1H),6.05–5.96(m,1H),5.40–5.33(m,1H),4.74–4.65(m,1H),4.44(t,J＝4.9Hz,2H),3.69–3.58(m,2H),3.42(dd,J＝13.3,6.5Hz,1H),3.10–2.93(m,8H),2.58–2.45(m,3H),2.02(s,4H),1.19(s,3H),0.97(s,9H),0.91(s,6H),0.78(s,3H).ESI-MS:m/z 866.6[M+Na] + 。
example 121
N- (2- (1-piperidinyl) ethyl) -3 beta- (2- (methoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-67)
Referring to the procedure of example 106, substituting N-acetylethanolamine with methanol and N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) piperidine produced compound B-67: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.64(m,2H),7.58–7.48(m,2H),6.68–6.58(m,1H),5.42–5.34(m,1H),4.75(dd,J＝11.3,4.4Hz,1H),3.90(s,3H),3.46–3.32(m,1H),3.27–3.09(m,1H),2.59–2.48(m,1H),2.48–2.28(m,6H),1.18(s,3H),0.96(s,6H),0.92(s,9H),0.79(s,3H).ESI-MS:m/z 729.6[M+H] + 。
example 122
N- (2- (1-piperidinyl) ethyl) -3 beta- (2- (isopropyloxy) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-68)
Referring to the procedure of example 106, substituting N-acetylethanolamine with isopropanol and N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) piperidine produced compound B-68: 1 H NMR(300MHz,CDCl 3 )δ7.76–7.62(m,2H),7.56–7.44(m,2H),6.67–6.57(m,1H),5.43–5.34(m,1H),5.32–5.16(m,1H),4.75(dd,J＝11.7,4.5Hz,1H),3.47–3.31(m,1H),3.25–3.10(m,1H),2.59–2.47(m,1H),2.47–2.27(m,6H),1.35(d,J＝6.2Hz,6H),1.17(s,3H),0.98(s,3H),0.96(s,3H),0.93(s,3H),0.92(s,6H),0.79(s,3H).ESI-MS:m/z757.6[M+H] + 。
example 123
N- (2- (1-piperidinyl) ethyl) -3 beta- (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-69)
Replacement of N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) piperidine produced compound B-69 by the method of example 106: 1 H NMR(300MHz,CDCl 3 )δ7.81(d,J＝6.7Hz,1H),7.66(d,J＝6.6Hz,1H),7.56(p,J＝7.0Hz,2H),7.08–6.93(m,1H),6.59–6.46(m,1H),5.48(s,1H),4.71(t,J＝7.8Hz,1H),4.52–4.35(m,2H),3.72–3.35(m,5H),3.25–2.90(m,5H),2.69–2.56(m,1H),2.01(s,3H),1.18(s,3H),0.97(s,9H),0.94(s,3H),0.92(s,3H),0.77(s,3H).ESI-MS:m/z 800.7[M+H] + 。
example 124
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β - (2- (methoxyacyl) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-70)
Referring to the procedure of example 106, substituting N-acetylethanolamine with methanol and N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) pyrrolidine produced compound B-70: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.64(m,2H),7.58–7.47(m,2H),6.62–6.52(m,1H),5.40–5.28(m,1H),4.75(dd,J＝11.4,4.4Hz,1H),3.90(s,3H),3.50–3.38(m,1H),3.25–3.12(m,1H),2.68–2.41(m,7H),1.81–1.76(m,4H),1.18(s,3H),0.97(s,6H),0.91(s,9H),0.81(s,3H).ESI-MS:m/z 715.5[M+H] + 。
example 125
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β - (2- (isopropyloxy) benzoyl) oxy-oleanane-12-en-28-amide (Compound B-71)
Referring to the procedure of example 106, substituting N-acetylethanolamine with isopropanol and N- (2-aminoethyl) morpholine with 1- (2-aminoethyl) pyrrolidine produced compound B-71: 1 H NMR(300MHz,CDCl 3 )δ7.81–7.60(m,2H),7.59–7.44(m,2H),6.64–6.46(m,1H),5.40–5.31(m,1H),5.30–5.19(m,1H),4.75(dd,J＝11.3,4.1Hz,1H),3.53–3.32(m,1H),3.26–3.09(m,1H),2.69–2.35(m,7H),1.81–1.75(m,4H),1.18(s,3H),0.98(s,6H),0.93(s,3H),0.91(s,6H),0.81(s,3H).ESI-MS:m/z 743.6[M+H] + 。
example 126
N- (2- (1-tetrahydropyrrolyl) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-72)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine for 1- (2-aminoethyl) pyrrolidine produced compound B-72: 1 H NMR(300MHz,CDCl 3 )δ7.85–7.78(m,1H),7.70–7.63(m,1H),7.56(qd,J＝7.3,3.6Hz,2H),7.08–6.96(m,1H),6.64–6.48(m,1H),5.52–5.42(m,1H),4.78–4.65(m,1H),4.45(tq,J＝12.3,6.5,5.6Hz,2H),3.69–3.59(m,2H),3.58–3.34(m,6H),2.71–2.56(m,1H),2.01(s,3H),1.18(s,3H),0.99(s,3H),0.97(s,6H),0.94(s,3H),0.91(s,3H),0.76(s,3H).ESI-MS:m/z 786.7[M+H] + 。
example 127
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-12-en-28-acyl) -morpholine (compound B-73)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-2 produced compound B-73: 1 H NMR(300MHz,DMSO-d 6 )δ13.18(s,1H),7.69(s,1H),7.60(s,3H),5.08(s,1H),4.66–4.55(m,1H),3.50(s,8H),2.97–2.88(m,1H),1.10(s,3H),0.89(s,6H),0.85(s,6H),0.80(s,3H),0.65(s,3H).ESI-MS:m/z 672.5[M-H] - 。
example 128
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-12-en-28-acyl) -thiomorpholine-1, 1-dioxide (compound B-74)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-9 produced compound B-74: 1 H NMR(300MHz,DMSO-d 6 )δ7.71(s,1H),7.58(s,3H),5.12(s,1H),4.62(s,1H),3.94(s,4H),3.15–2.96(m,4H),2.92(s,1H),1.13(s,3H),0.92(s,3H),0.91(s,3H),0.88(s,3H),0.87(s,3H),0.82(s,3H),0.67(s,3H).m/z 720.4[M-H] - 。
example 129
N- (3 beta- (2-carboxybenzoyl) oxy-oleanane-12-en-28-acyl) -tetrahydropyrrole (Compound B-77)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-26 produced compound B-77: 1 H NMR(300MHz,DMSO-d 6 )δ13.20(s,1H),7.71(s,1H),7.63(s,3H),5.11(s,1H),4.62(t,J＝7.8Hz,1H),3.70–3.33(m,4H),3.08–2.98(m,1H),1.12(s,3H),0.90(s,6H),0.89(s,6H),0.82(s,3H),0.65(s,3H).ESI-MS:m/z 656.5[M-H] - 。
Example 130
N- (3 beta- (2-methoxyacyl benzoyl) oxy-oleanane-12-en-28-acyl) -morpholine (compound B-78)
Referring to the procedure of example 106, substituting methanol for N-acetylethanolamine and morpholine for N- (2-aminoethyl) morpholine produced compound B-78: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.65(m,2H),7.57–7.48(m,2H),5.34–5.22(m,1H),4.75(dd,J＝11.3,4.7Hz,1H),3.89(s,3H),3.76–3.54(m,8H),3.17–3.01(m,1H),1.16(s,3H),0.96(s,6H),0.94(s,3H),0.91(s,6H),0.75(s,3H).ESI-MS:m/z 688.5[M+H] + 。
example 131
N- (3 beta- (2-Isopropyloxybenzoyl) oxy-oleanane-12-en-28-acyl) -morpholine (Compound B-79)
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Referring to the procedure of example 106, substituting N-acetylethanolamine with isopropanol and N- (2-aminoethyl) morpholine with morpholine produced compound B-79: 1 H NMR(300MHz,CDCl 3 )δ7.77–7.60(m,2H),7.58–7.42(m,2H),5.37–5.15(m,2H),4.75(dd,J＝11.6,4.7Hz,1H),3.84–3.42(m,8H),3.18–3.01(m,1H),1.35(d,J＝6.1Hz,6H),1.16(s,3H),0.97(s,3H),0.96(s,3H),0.94(s,3H),0.93(s,3H),0.91(s,3H),0.76(s,3H).ESI-MS:m/z 738.5[M+Na] + 。
example 132
N- (3 beta- (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-acyl) -morpholine (compound B-80)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine for morpholine produced compound B-80: 1 H NMR(300MHz,CDCl 3 )δ7.87–7.75(m,1H),7.72–7.61(m,1H),7.61–7.48(m,2H),6.64–6.50(m,1H),5.34–5.24(m,1H),4.80–4.63(m,1H),4.53–4.33(m,2H),3.80–3.41(m,9H),3.20–2.99(m,1H),2.32–2.08(m,1H),2.05(s,3H),1.16(s,3H),0.97(s,9H),0.94(s,3H),0.91(s,3H),0.76(s,3H).ESI-MS:m/z781.7[M+Na] + 。
example 133
3 beta- (2-carboxybenzoyl) oxy-oleanane-12-en-28-oic acid 2- (1-piperidinyl) ethyl ester (Compound B-87)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-31 gives compound B-87: 1 H NMR(300MHz,CDCl 3 )δ7.78(d,J＝6.1Hz,1H),7.66(d,J＝7.9Hz,1H),7.53–7.42(m,2H),5.34–5.23(m,1H),4.73–4.66(m,1H),4.60–4.49(m,2H),3.52–2.98(m,6H),2.89–2.74(m,1H),1.15(s,3H),0.95(s,3H),0.92(s,9H),0.89(s,3H),0.72(s,3H).ESI-MS:m/z 717.6[M+H] + 。
example 134
3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-oic acid 2- (4-morpholinyl) ethyl ester (Compound B-88)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-32 produced compound B-88: 1 H NMR(300MHz,CDCl 3 )δ7.88–7.79(m,1H),7.71–7.63(m,1H),7.56–7.46(m,2H),5.31–5.24(m,1H),4.76(dd,J＝11.5,4.3Hz,1H),4.35–4.22(m,2H),3.88–3.75(m,4H),2.91–2.78(m,3H),2.77–2.62(m,4H),1.15(s,3H),0.97(s,3H),0.93(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.73(s,3H).ESI-MS:m/z 716.5[M+H] + 。
example 135
3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-oic acid 2- (1-tetrahydropyrrolyl) ethyl ester (Compound B-89)
Referring to the procedure of example 102, substituting compound XVI-1 for compound B-33 yields compound B-89: 1 H NMR(300MHz,CDCl 3 )δ7.76(d,J＝7.3Hz,1H),7.59(d,J＝7.5Hz,1H),7.50–7.35(m,2H),5.33–5.25(m,1H),4.79–4.67(m,1H),4.52–4.42(m,2H),3.34–3.11(m,6H),2.91–2.76(m,1H),1.15(s,4H),0.98(s,2H),0.96–0.90(m,9H),0.89(s,3H),0.72(s,3H).ESI-MS:m/z 702.5[M+H] + 。
example 136
3 beta- (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-oic acid 2- (4-morpholinyl) ethyl ester (Compound B-93)
Compound XVII-4 was obtained by the method of example 106, and Compound XVII-4 (300 mg,0.435 mmol) was dissolved in N, N-dimethylformamide (8 mL), 1, 2-dibromoethane (375. Mu.L, 4.348 mmol) and potassium carbonate (60 mg,0.435 mmol) were successively added, and the reaction solution was heated to 50℃and stirred for 3 hours. After completion of the TLC detection reaction, the reaction mixture was diluted with dichloromethane (8 mL), the reaction mixture was washed with water (8 mL), the aqueous layer was extracted with dichloromethane (8 mL), the organic phases were combined, washed with water (8 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound XVIII-1 (white solid, 331mg, 96% yield).
Compound XVIII-1 (200 mg,0.251 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), morpholine (45. Mu.L, 0.52 mmol) and potassium carbonate (48 mg,0.35 mmol) were added sequentially, and the reaction solution was warmed to 50℃and stirred for reaction. After completion of the TLC detection reaction, the reaction mixture was treated with dichloromethane (10 mL) and water (5 mL), the aqueous layer was extracted with dichloromethane (10 ml×2), the organic phases were combined, washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to give compound B-93 (white solid, 97mg, yield 48%): 1 H NMR(300MHz,CDCl 3 )δ7.88–7.76(m,1H),7.71–7.63(m,1H),7.62–7.49(m,2H),6.62–6.51(m,1H),5.37–5.18(m,1H),4.86–4.59(m,1H),4.52–4.36(m,2H),4.31–4.08(m,2H),3.82–3.58(m,6H),2.99–2.81(m,1H),2.71–2.58(m,2H),2.58–2.44(m,3H),2.02(s,3H),1.16(s,3H),0.97(s,9H),0.93(s,3H),0.91(s,3H),0.76(s,3H).ESI-MS:m/z 803.8[M+H] + 。
Example 137
3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-oic acid 2-trimethylammonio ethyl bromide (Compound B-94)
Referring to the procedure of example 136, substituting morpholine to trimethylamine in tetrahydrofuran produced compound B-94: 1 H NMR(300MHz,methanol-d 6 )δ7.84–7.74(m,2H),7.71–7.63(m,2H),5.37–5.31(m,1H),4.79–4.70(m,1H),4.61–4.49(m,2H),4.41(t,J＝5.4Hz,2H),3.86–3.71(m,2H),3.58(t,J＝5.4Hz,2H),3.29(s,9H),2.92(d,J＝10.1Hz,1H),2.23–2.10(m,1H),2.00(s,5H),1.26(s,3H),1.07(s,3H),1.03(s,3H),1.00(s,3H),0.99(s,6H),0.85(s,3H).ESI-MS:m/z 775.7[M-Br] + 。
example 138
3 beta- (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-oic acid 3-trimethylammoniopropyl bromide (Compound B-95)
Referring to the procedure of example 136, substituting 1, 2-dibromoethane for 1, 3-dibromopropane and morpholine for trimethylamine produced compound B-95: 1 H NMR(300MHz,methanol-d 6 )δ7.84–7.75(m,2H),7.72–7.63(m,2H),5.39–5.33(m,1H),4.76(dd,J＝10.2,5.8Hz,1H),4.41(t,J＝5.5Hz,2H),4.25–4.12(m,2H),3.58(t,J＝5.5Hz,2H),3.48(dd,J＝11.0,5.7Hz,2H),3.23(s,9H),2.99–2.89(m,1H),2.28–2.16(m,2H),2.16–2.06(m,1H),2.00(s,5H),1.26(s,3H),1.07(s,3H),1.02(s,3H),1.01(s,3H),0.99(s,6H),0.85(s,3H).ESI-MS:m/z 789.6[M-Br] + 。
example 139
3 beta- (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-oic acid 2- (4-methyl-1-piperazinyl) ethyl ester (Compound B-97)
Referring to the procedure of example 136, substituting morpholine for N-methylpiperazine produced compound B-97: 1 H NMR(300MHz,CDCl 3 )δ7.85–7.78(m,1H),7.69–7.63(m,1H),7.62–7.50(m,2H),6.59–6.48(m,1H),5.30–5.23(m,1H),4.77–4.63(m,1H),4.51–4.37(m,2H),4.28–4.04(m,2H),3.73–3.57(m,2H),2.93–2.80(m,1H),2.73–2.38(m,8H),2.34–2.26(m,2H),2.02(s,3H),1.15(s,3H),0.97(s,9H),0.92(s,3H),0.91(s,3H),0.75(s,3H).ESI-MS:m/z 816.8[M+H] + 。
example 140
N- (2- (acetamido) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-105)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine for N-acetyl ethylenediamine produced compound B-105: 1 H NMR(300MHz,CDCl 3 )δ7.86–7.78(m,1H),7.70–7.63(m,1H),7.57(qt,J＝7.3,3.6Hz,2H),6.68–6.52(m,2H),6.42(t,J＝4.8Hz,1H),5.42(s,1H),4.77–4.64(m,1H),4.44(t,J＝4.8Hz,2H),3.71–3.57(m,2H),3.54–3.16(m,4H),2.62–2.51(m,1H),2.02(s,3H),1.97(s,3H),1.18(s,3H),0.97(s,9H),0.92(s,6H),0.77(s,3H).ESI-MS:m/z 796.7[M+Na] + 。
example 141
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -azetidine (Compound B-106)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with silacyclobutane produced compound B-106: 1 H NMR(300MHz,CDCl 3 )δ5.24(t,J＝3.2Hz,1H),4.50–3.83(m,4H),3.29–3.12(m,1H),2.85(dd,J＝13.4,3.5Hz,1H),2.21(t d,J＝7.5Hz,2H),1.12(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,3H),0.89(s,3H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z 518.4[M+Na] + 。
example 142
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -3-hydroxy-azetidine (Compound B-107)
Reference to the formulation of example 73The method replaces N, N-dimethylethylenediamine with azetidin-3-ol to produce compound B-107: 1 H NMR(300MHz,CDCl 3 )δ5.25(m,1H),4.68–4.53(m,1H),4.49–4.20(m,2H),4.14–3.77(m,2H),3.28–3.12(m,1H),2.87–2.77(m,1H),1.13(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,6H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z510.4[M-H] - 。
example 143
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -3-methoxy-azetidine (Compound B-110)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 3-methoxyazetidine produced compound B-110: 1 H NMR(300MHz,CDCl 3 )δ5.28–5.21(m,1H),4.55–3.75(m,5H),3.28(s,3H),3.25–3.13(m,1H),2.90–2.78(m,1H),1.12(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,3H),0.89(s,3H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 548.5[M+Na] + 。
example 144
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -3-carboxy-azetidine (Compound B-111)
Referring to the procedure of example 86, substituting L-proline benzyl ester hydrochloride for compound VIII-3, compound B-111 is prepared: 1 H NMR(300MHz,CDCl 3 )δ5.34–5.16(m,1H),4.71–4.02(m,4H),3.40–3.28(m,1H),3.28–3.17(m,1H),2.94–2.71(m,1H),1.13(s,3H),0.99(s,3H),0.92(s,3H),0.90(s,6H),0.79(s,3H),0.75(s,3H).ESI-MS:m/z 538.4[M-H] - 。
example 145
N- (2- (1, 1-dioxothiomorpholinyl) ethyl) -3β - (2- (2-acetamido) ethoxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-118)
Referring to the procedure of example 106, substituting N- (2-aminoethyl) morpholine with 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide produced compound B-118: 1 H NMR(300MHz,CDCl 3 )δ7.81(d,J＝6.9Hz,1H),7.66(d,J＝6.7Hz,1H),7.62–7.51(m,2H),6.58–6.47(m,1H),6.27–6.12(m,1H),5.40–5.33(m,1H),4.77–4.66(m,1H),4.48–4.38(m,2H),3.69–3.60(m,2H),3.56–3.43(m,1H),3.23–3.01(m,9H),2.69–2.58(m,2H),2.57–2.45(m,1H),1.19(s,3H),0.98(s,9H),0.92(s,3H),0.91(s,3H),0.79(s,3H).ESI-MS:m/z 872.7[M+Na] + 。
example 146
N- (3- (1-piperidinyl) propyl) -3β - (2-carboxybenzoyl) oxy-oleanane-12-en-28-amide (Compound B-119)
Referring to the procedure of example 102, substituting N-acetyl ethylenediamine with 1- (3-aminopropyl) piperidine gave compound B-119: 1 H NMR(300MHz,DMSO-d 6 )δ7.70(s,1H),7.55(s,2H),7.31(s,1H),5.22(s,1H),4.61(s,1H),3.30(s,3H),3.04(s,3H),2.80(s,2H),1.12(s,3H),1.05(s,3H),0.92(s,3H),0.90(s,3H),0.88(s,3H),0.82(s,3H),0.68(s,3H).ESI-MS:m/z 727.6[M-H] - 。
example 147
N- (3β -hydroxy-oleanane-12-en-28-yl) - (2R) -carboxy-tetrahydropyrrole (Compound B-120)
Referring to the procedure of example 86, substituting L-proline benzyl ester hydrochloride for D-proline benzyl ester hydrochloride produced compound B-120: 1 H NMR(300MHz,DMSO-d 6 )δ5.26(m,1H),4.64–4.56(m,1H),3.84–3.73(m,1H),3.73–3.61(m,1H),3.26–3.15(m,1H),3.12–2.98(m,1H),2.41–2.26(m,1H),1.15(s,3H),0.98(s,3H),0.93(s,3H),0.91(s,3H),0.89(s,3H),0.77(s,3H),0.72(s,3H).ESI-MS:m/z 552.4[M-H] - 。
example 148
N- (2- (N, N-dihydroxyethyl) aminoethyl) -3β -hydroxy-oleanane-13 (18) -en-28-amide (Compound A-76)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with N, N-bis (2-hydroxyethyl) ethylenediamine produced compound A-76: 1 H NMR(300MHz,DMSO-d 6 )δ6.61–6.53(m,1H),4.42–4.32(m,2H),4.30(d,J＝5.0Hz,1H),3.49–3.38(m,4H),3.27–3.16(m,1H),3.15–2.96(m,2H),2.85–2.72(m,1H),2.61–2.54(m,4H),2.43(d,J＝14.1Hz,1H),2.25–2.15(m,1H),1.15(s,3H),0.91(s,3H),0.90(s,6H),0.85(s,3H),0.72(s,3H),0.69(s,3H).ESI-MS:m/z 587.5[M+H] + 。
example 149
N- (2- (N, N-dihydroxyethyl) aminoethyl) -3β -hydroxy-oleanane-12-en-28-amide (Compound B-15)
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Referring to the procedure of example 85, substituting 4- (2-aminoethyl) thiomorpholine-1, 1-dioxide with N, N-bis (2-hydroxyethyl) ethylenediamine produced compound B-15: 1 H NMR(300MHz,DMSO-d 6 )δ7.14–7.05(m,1H),5.27–5.22(m,1H),4.45–4.33(m,2H),4.29(d,J＝5.1Hz,1H),3.49–3.39(m,4H),3.23–3.11(m,1H),3.07–2.92(m,2H),2.80–2.69(m,1H),2.63–2.54(m,4H),1.11(s,3H),0.91(s,3H),0.90(s,6H),0.87(s,3H),0.69(s,6H).ESI-MS:m/z 587.5[M+H] + 。
example 150
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β -acetoxy-oleanane-13 (18) -en-28-amide (Compound A-108)
Referring to the procedure of example 2, compound II-1 was obtained. Compound II-1 (150 mg,0.300 mmol) was dissolved in tetrahydrofuran (8 mL), and N, N-diisopropylethylamine (50. Mu.L, 0.300 mmol) and O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroboric acid (116 mg,0.361 mmol) were added in this order, followed by stirring at room temperature. After completion of TLC detection, the solvent was distilled off under reduced pressure, the residue was dissolved with ethyl acetate (8 mL), washed with water (8 ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give compound XIX-1, which was used directly in the next step.
Compound XIX-1 was dissolved in N, N-dimethylformamide (8 mL), 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide (58 mg,0.300 mmol) and sodium carbonate (32 mg,0.300 mmol) were added in this order, and the reaction was stirred at room temperature. After completion of the TLC detection reaction, the reaction mixture was diluted with ethyl acetate (8 mL), the reaction mixture was washed with water (8 mL), the aqueous layer was extracted with ethyl acetate (8 mL), the organic phases were combined, washed with water (8 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound a-108 (white solid, 179mg, yield 89%): 1 H NMR(300MHz,CDCl 3 )δ5.99(t,J＝5.8Hz,1H),4.51(dd,J＝10.6,5.7Hz,1H),3.34–3.22(m,2H),3.09–2.93(m,8H),2.87–2.76(m,1H),2.57–2.34(m,4H),2.05(s,3H),1.19(s,3H),0.90(s,9H),0.87(s,3H),0.85(s,3H),0.74(s,3H).ESI-MS:m/z 671.5[M-H] - 。
Example 151
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (3-carboxypropionyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-109)
Referring to the procedure of example 13, substituting 3-dimethylaminopropylamine with 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide and phthalic anhydride with butyric anhydride produced compound a-109: 1 H NMR(300MHz,CDCl 3 )δ6.06–5.95(m,1H),4.59–4.48(m,1H),3.39–3.18(m,2H),3.13–2.91(m,8H),2.87–2.75(m,1H),2.73–2.58(m,4H),2.59–2.33(m,4H),1.19(s,3H),0.90(s,9H),0.87(s,3H),0.85(s,3H),0.74(s,3H).ESI-MS:m/z 729.5[M-H] - 。
example 152
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (3-picolyl) oxy-oleanane-13 (18) -en-28-amide (Compound A-110)
Compound A-81 (100 mg,0.158 mmol) was dissolved in anhydrous dichloromethane (8 mL), and N, N' -dicyclohexylcarbodiimide (66 mg,0.317 mmol), 4-dimethylaminopyridine (20 mg,0.158 mmol) and nicotinic acid (30 mg,0.238 mmol) were added in this order and reacted under stirring at room temperature. After the reaction was completed by TLC detection, suction filtration, washing of the filtrate with water (8 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by silica gel column chromatography (dichloromethane: methanol=20:1) gave compound a-110 (white solid, 83mg, yield 72%): 1 H NMR(300MHz,methanol-d 4 )δ5.99(t,J＝5.8Hz,1H),4.51(dd,J＝10.6,5.7Hz,1H),3.34–3.22(m,2H),3.09–2.93(m,8H),2.87–2.76(m,1H),2.57–2.34(m,4H),2.05(s,3H),1.19(s,3H),0.90(s,9H),0.87(s,3H),0.85(s,3H),0.74(s,3H).ESI-MS:m/z 736.6[M+H] + 。
example 153
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2S-amino-3-methylbutanoyl) oxy-oleanane-13 (18) -en-28-amid dihydrochloride (Compound A-111)
Compound A-81 (100 mg,0.158 mmol) was dissolved in anhydrous dichloromethane (8 mL), and N, N' -dicyclohexylcarbodiimide (66 mg,0.317 mmol), 4-dimethylaminopyridine (20 mg,0.158 mmol) and N-Boc-L-valine (52 mg,0.238 mmol) were added in this order and reacted under stirring at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with water (8 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, purification by silica gel column chromatography (dichloromethane: methanol=20:1) gave compound XX-1 (white solid, 127mg, yield 97%).
Compound XX-1 (127 mg,0.158 mmol) is dissolved in absolute ethanol (10 mL), and hydrogen chloride gas is introduced for 30 min, followed by stirring at room temperature. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and methanol to give compound A-111 (white solid, 95mg, yield 77%): 1 H NMR(300MHz,methanol-d 4 )δ4.77–4.69(m,1H),4.00(d,J＝3.8Hz,1H),3.34–3.13(m,8H),2.95(d,J＝13.9Hz,1H),2.87–2.71(m,2H),2.61(d,J＝14.3Hz,1H),2.46–2.37(m,1H),2.37–2.27(m,1H),1.29(s,3H),1.06(s,3H),1.04(s,3H),1.01(s,3H),0.99(s,6H),0.83(s,3H).ESI-MS:m/z 730.6[M+H] + 。
example 154
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β -hydroxy-oleanane-13 (18) -en-28-carboxamide hydrochloride (Compound A-112)
Compound A-81 (100 mg,0.158 mmol) was dissolved in absolute ethanol (10 mL), and hydrogen chloride gas was introduced for 30 minutes to stir the reaction at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure until 2mL remained, and suction filtration was performed, and the cake was washed with ethyl acetate (1 mL. Times.2), and dried to give Compound A-111 (white solid, 52mg, yield 49%) 1 H NMR(300MHz,DMSO-d 6 )δ6.99–6.91(m,1H),3.90–3.51(m,8H),3.21–3.08(m,4H),3.06–2.97(m,1H),2.77(d,J＝13.7Hz,1H),2.42(d,J＝13.7Hz,1H),2.21–2.11(m,1H),1.13(s,3H),0.89(s,9H),0.83(s,3H),0.71(s,3H),0.67(s,3H).ESI-MS:m/z 631.5[M+H] + 。
Example 155
3 beta-hydroxy-oleanane-13 (18) -en-28-oic acid 3- (1, 1-dioxothiomorpholinyl) propyl ester (Compound A-113)
Compound II-1 (200 mg,0.401 mmol) was dissolved in N, N-dimethylformamide (8 mL), 3-bromo-1-propanol (73. Mu.L, 0.802 mmol) and potassium carbonate (111 mg,0.802 mmol) were added in this order, and the mixture was stirred at room temperature to react. After completion of the TLC detection reaction, the reaction solution was diluted with ethyl acetate (8 mL), the reaction solution was washed with water (8 mL), the aqueous layer was extracted with ethyl acetate (8 mL), the organic phases were combined, washed with water (8 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound XXI-1 (white solid, 197mg, yield 88%).
Compound XXI-1 (197mg, 0.354 mmol) is dissolved in dichloromethane (8 mL), pyridinium chlorochromate (153 mg,0.707 mmol) is added and the reaction is stirred at room temperature. After completion of TLC detection, celite was filtered, the filtrate was dried by spin-drying and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound XXI-2 (white solid, 157mg, yield 80%).
Compound XXI-2 (157 mg, 0.284 mmol) and 1, 1-thiomorpholine (39 mg, 0.284 mmol) are dissolved in dichloromethane (8 mL), and sodium triacetoxyborohydride (90 mg, 0.284 mmol) is added after stirring at room temperature for 1 hour and the reaction is stirred at room temperature. After completion of TLC detection, saturated sodium bicarbonate solution (5 mL) was added, the organic phase was separated, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound XXI-3 (white solid, 69mg, yield 36%).
Compound XXI-3 (69 mg,0.102 mmol) is dissolved in methanol (5 mL) and tetrahydrofuranTo a mixed solution of the pyran (5 mL), potassium hydroxide (57 mg,1.024 mmol) was added, and the reaction was stirred at room temperature. After completion of TLC detection, the solvent was distilled off under reduced pressure, the residue was dissolved with ethyl acetate (10 mL), washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound a-113 (white solid, 45mg, yield 69%): 1 H NMR(300MHz,CDCl 3 )δ4.21–4.02(m,2H),3.28–3.17(m,1H),3.14–2.89(m,8H),2.74(d,J＝11.3Hz,1H),2.57(t,J＝7.0Hz,2H),2.43(d,J＝14.0Hz,1H),2.22–2.11(m,1H),1.16(s,3H),0.99(s,3H),0.90(s,3H),0.90(s,3H),0.87(s,3H),0.77(s,3H),0.74(s,3H).ESI-MS:m/z 632.5[M+H] + 。
example 156
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β -acetoxy-oleanane-12-en-28-amide (Compound B-121)
Referring to the procedure of example 73, compound XI-1 was obtained. Compound XI-1 (150 mg,0.300 mmol) was dissolved in tetrahydrofuran (8 mL), N, N-diisopropylethylamine (50. Mu.L, 0.300 mmol) and O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroboric acid (116 mg,0.361 mmol) were added in this order, and the mixture was stirred at room temperature to react. After completion of TLC detection, the solvent was distilled off under reduced pressure, the residue was dissolved with ethyl acetate (8 mL), washed with water (8 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give compound XXII-1, which was directly used in the next step.
Compound XXII-1 is dissolved in N, N-dimethylformamide (8 mL), 4- (3-aminopropyl) thiomorpholine-1, 1-dioxide (58 mg,0.300 mmol) and sodium carbonate (32 mg,0.300 mmol) are added sequentially and the reaction is stirred at room temperature. After completion of TLC detection, the reaction mixture was diluted with ethyl acetate (8 mL), washed with water (8 mL), the aqueous layer was extracted with ethyl acetate (8 mL), the organic phases were combined, washed with water (8 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane): methanol=20: 1) Purification gave compound B-121 (white solid, 172mg, 85% yield): 1 H NMR(300MHz,CDCl 3 )δ6.10–5.97(m,1H),5.41–5.33(m,1H),4.54–4.43(m,1H),3.50–3.34(m,1H),3.17–2.92(m,8H),2.63–2.43(m,3H),2.05(s,3H),1.16(s,3H),0.93(s,3H),0.91(s,3H),0.90(s,3H),0.87(s,3H),0.86(s,3H),0.76(s,3H).ESI-MS:m/z673.6[M+H] + 。
example 157
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (3-carboxypropionyl) oxy-oleanane-12-en-28-amide (Compound B-122)
Compound B-20 (100 mg,0.158 mmol) was dissolved in anhydrous pyridine (8 mL), succinic anhydride (159 mg,1.585 mmol) and 4-dimethylaminopyridine (20 mg,0.158 mmol) were added, and the reaction was warmed to 115℃and stirred overnight. After completion of TLC detection, dichloromethane (20 mL) was added to dilute the reaction, the reaction was washed with 1N diluted hydrochloric acid (10 ml×3) and water (10 ml×3) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound B-122 (white solid, 64mg, yield 55%): 1 H NMR(300MHz,CDCl 3 )δ6.07–5.97(m,1H),5.39–5.33(m,1H),4.59–4.45(m,1H),3.50–3.34(m,1H),3.12–2.90(m,8H),2.74–2.57(m,4H),2.57–2.42(m,4H),1.16(s,3H),0.93(s,3H),0.91(s,3H),0.90(s,3H),0.86(s,6H),0.76(s,3H).ESI-MS:m/z 731.6[M+H] + 。
Example 158
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (3-picolyl) oxy-oleanane-12-en-28-amide (Compound B-123)
Dissolving compound B-20 (141 mg,0.223 mmol) in anhydrous dichloromethane (8 mL), and sequentially adding N, N' -diCyclohexylcarbodiimide (184 mg,0.894 mmol), 4-dimethylaminopyridine (28 mg,0.223 mmol) and nicotinic acid (55 mg,0.447 mmol) were reacted under stirring at room temperature. After the reaction was completed by TLC detection, suction filtration, washing of the filtrate with water (8 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by silica gel column chromatography (dichloromethane: methanol=20:1) gave compound B-123 (white solid, 118mg, yield 72%): 1 H NMR(300MHz,CDCl 3 )δ9.23(s,1H),8.77(d,J＝4.7Hz,1H),8.29(d,J＝8.0Hz,1H),7.39(dd,J＝8.0,4.9Hz,1H),6.07–5.96(m,1H),5.41–5.33(m,1H),4.83–4.70(m,1H),3.51–3.34(m,1H),3.11–2.92(m,8H),2.59–2.45(m,3H),1.19(s,3H),1.02(s,3H),0.99(s,3H),0.95(s,3H),0.92(s,3H),0.91(s,3H),0.78(s,3H).ESI-MS:m/z 736.6[M+H] + 。
example 159
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β - (2S-amino-3-methylbutanoyl) oxy-oleanane-12-en-28-amid dihydrochloride (Compound B-124)
Compound B-20 (100 mg,0.158 mmol) was dissolved in anhydrous dichloromethane (8 mL), and N, N' -dicyclohexylcarbodiimide (66 mg,0.317 mmol), 4-dimethylaminopyridine (20 mg,0.158 mmol) and N-Boc-L-valine (52 mg,0.238 mmol) were added in this order and reacted under stirring at room temperature. After completion of TLC detection, suction filtration, washing of the filtrate with water (8 ml×2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, purification by silica gel column chromatography (dichloromethane: methanol=20:1) gave compound XXIII-1 (white solid, 125mg, yield 95%).
Compound XXIII-1 (125 mg,0.158 mmol) is dissolved in absolute ethanol (10 mL), and the reaction is stirred at room temperature under hydrogen chloride gas for 30 min. After completion of the TLC detection, the solvent was distilled off under reduced pressure, the residue was slurried with ethyl acetate, suction-filtered, and the cake was washed with ethyl acetate (2 ml. Times.2), and dried to give Compound B-124 (white solid, 110mg, yield 91%): 1 H NMR(300MHz,methanol-d 4 )δ5.45–5.39(m,1H),4.76–4.65(m,1H),4.00(d,J＝3.7Hz,1H),3.64–3.40(m,8H),3.32–3.18(m,1H),3.17–2.94(m,2H),2.93–2.82(m,1H),2.49–2.33(m,1H),1.25(s,3H),1.05(s,3H),1.01(s,6H),1.00(s,3H),0.97(s,3H),0.86(s,3H).ESI-MS:m/z 730.6[M+H] + 。
example 160
N- (3- (1, 1-dioxothiomorpholinyl) propyl) -3β -hydroxy-oleanane-12-en-28-amide hydrochloride (Compound B-125)
Compound B-20 (70 mg,0.111 mmol) was dissolved in absolute ethanol (10 mL), and hydrogen chloride gas was introduced for 30 minutes to stir the reaction at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was slurried with ethyl acetate, suction filtered, and the cake was washed with ethyl acetate (2 ml×2), and dried to give compound B-125 (white solid, 69mg, yield 93%): 1 H NMR(300MHz,methanol-d 4 )δ5.47–5.41(m,1H),3.96–3.78(m,4H),3.73–3.60(m,4H),3.46–3.26(m,4H),3.26–3.17(m,1H),2.92–2.82(m,1H),1.25(s,3H),1.04(s,3H),1.03(s,3H),1.01(s,3H),0.99(s,3H),0.85(s,3H),0.84(s,3H).ESI-MS:m/z 631.6[M+H] + 。
example 161
3 beta-hydroxy-oleanane-12-en-28-oic acid 3- (1, 1-dioxothiomorpholinyl) propyl ester hydrochloride (Compound B-126)
Compound XI-1 (200 mg,0.401 mmol) was dissolved in N, N-dimethylformamide (8 mL), 3-bromo-1-propanol (73. Mu.L, 0.802 mmol) and potassium carbonate (111 mg,0.802 mmol) were added in this order, and the reaction was stirred at room temperature. After completion of the TLC detection reaction, the reaction solution was diluted with ethyl acetate (8 mL), the reaction solution was washed with water (8 mL), the aqueous layer was extracted with ethyl acetate (8 mL), the organic phases were combined, washed with water (8 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound XXIV-1 (white solid, 220mg, yield 98%).
Compound XXIV-1 (220 mg, 0.399mmol) is dissolved in dichloromethane (10 mL), pyridinium chlorochromate (170 mg, 0.79mmol) is added and the reaction is stirred at room temperature. After completion of TLC detection, celite was filtered, the filtrate was dried by spin-drying and purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give compound XXIV-2 (white solid, 164mg, yield 75%).
Compound XXIV-2 (220 mg, 0.390 mmol) and 1, 1-thiomorpholine (54 mg, 0.390 mmol) are dissolved in dichloromethane (8 mL), and sodium triacetoxyborohydride (126 mg,0.595 mmol) is added after stirring at room temperature for 1 hour and the reaction is stirred at room temperature. After completion of TLC detection, saturated sodium bicarbonate solution (5 mL) was added, the organic phase was separated, washed with water (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give compound XXIV-3 (white solid, 131mg, yield 49%).
Compound XXIV-3 (131 mg,0.194 mmol) is dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), potassium hydroxide (109 mg,1.943 mmol) is added, and the reaction is stirred at room temperature. After completion of TLC detection, the solvent was distilled off under reduced pressure, the residue was dissolved with ethyl acetate (10 mL), washed with water (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound XXIV-4 (white solid, 75mg, yield 61%).
Compound XXIV-4 (75 mg,0.119 mmol) is dissolved in absolute ethanol (10 mL), and the reaction is stirred at room temperature by bubbling hydrogen chloride gas for 30 min. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was slurried with ethyl acetate, suction filtered, and the cake was washed with ethyl acetate (2 ml×2), and dried to give compound B-126 (white solid, 78mg, yield 60%): 1 H NMR(300MHz,methanol-d 4 )δ5.36–5.27(m,1H),4.16(t,J＝6.3Hz,2H),3.28–3.09(m,8H),2.99–2.89(m,1H),2.82–2.71(m,2H),1.23(s,3H),1.03(s,3H),1.01(s,3H),1.00(s,3H),0.97(s,3H),0.84(s,3H),0.83(s,3H).ESI-MS:m/z 654.5[M+Na] + 。
example 162
N- (3β -acetoxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide (compound A-114)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 1, 1-thiomorpholine produced compound A-114: 1 H NMR(300MHz,CDCl3)δ4.55–4.46(m,1H),4.36–4.13(m,4H),3.05–2.93(m,4H),2.76(d,J＝13.0Hz,1H),2.48(d,J＝13.5Hz,1H),2.39(d,J＝12.5Hz,1H),2.05(s,3H),1.18(s,3H),0.92(s,3H),0.90(s,3H),0.87(s,3H),0.86(s,3H),0.85(s,3H),0.79(s,3H).ESI-MS:m/z 616.5[M+H] + 。
example 163
N- (3 beta- (3-picolyl) oxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide (compound A-115)
Referring to the procedure of example 152, substituting compound A-81 with compound A-85 produced compound A-115: 1 H NMR(300MHz,CDCl 3 )δ9.27–9.19(m,1H),8.77(d,J＝3.8Hz,1H),8.29(d,J＝7.8Hz,1H),7.47–7.34(m,1H),4.85–4.72(m,1H),4.39–4.11(m,4H),3.13–2.90(m,4H),2.78(d,J＝13.3Hz,1H),2.49(d,J＝13.1Hz,1H),2.43–2.32(m,1H),1.21(s,3H),1.01(s,3H),0.95(s,6H),0.92(s,3H),0.89(s,3H),0.80(s,3H).ESI-MS:m/z 679.5[M+H] + 。
example 164
N- (3 beta- (3-carboxypropionyl) oxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide (compound A-116)
Referring to the procedure of example 2, substituting N, N-dimethylethylenediamine with 1, 1-thiomorpholine and phthalic anhydride with butyric anhydride produced compound A-116: 1 H NMR(300MHz,CDCl 3 )δ4.59–4.48(m,1H),4.38–4.12(m,4H),3.06–2.92(m,4H),2.83–2.73(m,1H),2.71–2.57(m,4H),2.48(d,J＝13.2Hz,1H),2.38(d,J＝12.4Hz,1H),1.18(s,3H),0.91(s,3H),0.90(s,3H),0.86(s,6H),0.85(s,3H),0.79(s,3H).ESI-MS:m/z 674.5[M+H] + 。
Example 165
N- (3 beta- (2S-amino-3-methylbutanoyl) oxy-oleanane-13 (18) -en-28-yl) -thiomorpholine-1, 1-dioxide hydrochloride (A-117)
Referring to the procedure of example 153, substituting compound A-81 with compound A-85 produced compound A-117: 1 H NMR(300MHz,DMSO-d 6 )δ8.55–8.28(m,3H),5.61(d,J＝8.1Hz,1H),4.63–4.52(m,1H),4.15–3.93(m,4H),3.88(d,J＝3.8Hz,1H),3.22–3.01(m,4H),2.71(d,J＝11.9Hz,1H),2.38(d,J＝12.9Hz,1H),2.31–2.14(m,2H),1.14(s,3H),0.89(s,3H),0.88(s,6H),0.85(s,3H),0.83(s,3H),0.75(s,3H).ESI-MS:m/z 673.6[M+H] + 。
example 166
N- (3β -acetoxy-oleanane-12-en-28-yl) -thiomorpholine-1, 1-dioxide (compound B-127)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 1, 1-thiomorpholine produced compound B-127: 1 H NMR(300MHz,CDCl 3 )δ5.32–5.25(m,1H),4.53–4.44(m,1H),4.16–4.05(m,4H),3.12–2.90(m,5H),2.21(t,J＝13.6Hz,1H),2.04(s,3H),1.14(s,3H),0.93(s,6H),0.91(s,3H),0.86(s,3H),0.85(s,3H),0.71(s,3H).ESI-MS:m/z 616.5[M+H] + 。
example 167
N- (3 beta- (3-picolyl) oxy-oleanane-12-en-28-yl) -thiomorpholine-1, 1-dioxide (compound B-128)
Referring to the procedure of example 152, substituting compound A-81 for compound B-9 produced compound B-128: 1 H NMR(300MHz,CDCl 3 )δ9.23(s,1H),8.77(d,J＝4.0Hz,1H),8.29(d,J＝8.0Hz,1H),7.42–7.35(m,1H),5.32–5.27(m,1H),4.82–4.72(m,1H),4.18–4.02(m,4H),3.14–2.91(m,5H),2.30–2.13(m,1H),1.17(s,3H),1.02(s,3H),0.98(s,3H),0.94(s,6H),0.92(s,3H),0.74(s,3H).ESI-MS:m/z 679.5[M+H] + 。
example 168
N- (3 beta- (3-carboxypropionyl) oxy-oleanane-12-en-28-yl) -thiomorpholine-1, 1-dioxide (compound B-129)
Referring to the procedure of example 127, substituting compound B-2 for compound B-9 produced compound B-129: 1 H NMR(300MHz,DMSO-d 6 )δ12.19(s,1H),5.14–5.06(m,1H),4.45–4.35(m,1H),4.01–3.84(m,4H),3.15–2.88(m,5H),1.10(s,3H),0.88(s,9H),0.81(s,6H),0.66(s,3H).ESI-MS:m/z 674.5[M+H] + 。
example 169
N- (3 beta- (2S-amino-3-methylbutanoyl) oxy-oleanane-12-en-28-acyl) -thiomorpholine-1, 1-dioxide hydrochloride (Compound B-130)
Referring to the procedure of example 159, substituting compound B-20 with compound B-9 produced compound B-130: 1 H NMR(300MHz,DMSO-d 6 )δ8.53–8.37(m,3H),5.15–5.06(m,1H),4.60–4.50(m,1H),4.02–3.82(m,5H),3.18–2.87(m,5H),1.11(s,3H),1.01(s,3H),0.99(s,3H),0.90(s,3H),0.87(s,6H),0.66(s,3H).ESI-MS:m/z 671.5[M+H] + 。
Example 170
3 beta- (2- (2-Acetaminophen-yl) benzoyl) oxy-oleanane-12-en-28-oic acid 3- (4-morpholinyl) propyl ester (Compound B-131)
Referring to the procedure of example 136, substituting 1, 2-dibromoethane for 1, 3-dibromopropane produced compound B-131: 1 H NMR(300MHz,CDCl 3 )δ7.85–7.79(m,1H),7.69–7.63(m,1H),7.62–7.51(m,2H),6.60–6.50(m,1H),5.32–5.26(m,1H),4.75–4.66(m,1H),4.48–4.39(m,2H),4.13–4.01(m,2H),3.75–3.68(m,4H),3.68–3.59(m,2H),2.87(d,J＝10.3Hz,1H),2.52–2.31(m,6H),2.02(s,3H),1.15(s,3H),0.97(s,9H),0.93(s,3H),0.91(s,3H),0.75(s,3H).ESI-MS:m/z 817.7[M+H] + 。
example 171
3 beta- (2- (2-Acetaminophen-yl) benzoyl) oxy-oleanane-12-en-28-oic acid 3- (1, 1-dioxothiomorpholinyl) propyl ester (Compound B-132)
Referring to the procedure of example 161, substituting compound XI-1 for compound XVII-4 gives compound B-132: 1 H NMR(300MHz,CDCl 3 )δ7.89–7.77(m,1H),7.73–7.63(m,1H),7.62–7.50(m,2H),6.60–6.45(m,1H),5.34–5.24(m,1H),4.75–4.64(m,1H),4.52–4.36(m,2H),4.14–4.01(m,2H),3.73–3.54(m,2H),3.02(d,J＝13.2Hz,8H),2.86(d,J＝14.1Hz,1H),2.65–2.51(m,2H),1.16(s,3H),0.97(s,9H),0.92(s,6H),0.75(s,3H).ESI-MS:m/z 865.6[M+H] + 。
example 172
N- (3β -hydroxy-oleanane-12-en-28-yl) -4-benzyl-piperazine (Compound B-133)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 1-benzylpiperazine produced compound B-133: 1 H NMR(300MHz,CDCl 3 )δ7.39–7.27(m,5H),5.28–5.21(m,1H),3.78–3.60(m,4H),3.57(s,2H),3.27–3.16(m,1H),3.14–3.01(m,1H),2.58–2.31(m,4H),2.16–2.02(m,1H),1.13(s,3H),0.99(s,3H),0.92(s,3H),0.90(s,3H),0.89(s,3H),0.78(s,3H),0.71(s,3H).ESI-MS:m/z 615.6[M+H] + 。
example 173
N- (3β -hydroxy-oleanane-12-en-28-yl) -4-cyclopropyl-piperazine (Compound B-134)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 1-cyclopropylpiperazine produced compound B-134: 1 H NMR(300MHz,CDCl 3 )δ5.32–5.21(m,1H),3.72–3.44(m,4H),3.27–3.15(m,1H),3.15–3.03(m,1H),2.70–2.45(m,4H),2.19–2.03(m,1H),1.14(s,3H),0.99(s,3H),0.93(s,3H),0.90(s,3H),0.90(s,3H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 565.6[M+H] + 。
example 174
N- (3β -hydroxy-oleanane-12-en-28-yl) -4-ethyl-piperazine (Compound B-135)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with N-ethylpiperazine produced compound B-135: 1 H NMR(300MHz,CDCl 3 )δ5.32–5.23(m,1H),3.77–3.58(m,4H),3.29–3.16(m,1H),3.16–3.02(m,1H),2.54–2.30(m,6H),2.20–2.03(m,1H),1.14(s,3H),0.99(s,3H),0.93(s,3H),0.90(s,6H),0.78(s,3H),0.74(s,3H).ESI-MS:m/z 553.6[M+H] + 。
Example 175
N- (3β -hydroxy-oleanane-12-en-28-yl) -4-oxo-piperidine (Compound B-136)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 4-piperidone produced compound B-136: 1 H NMR(300MHz,CDCl 3 )δ5.33–5.26(m,1H),3.98–3.79(m,4H),3.26–3.16(m,1H),3.15–3.04(m,1H),2.56–2.33(m,4H),2.27–2.11(m,1H),1.16(s,3H),0.99(s,3H),0.95(s,3H),0.91(s,3H),0.91(s,3H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 560.5[M+Na] + 。
example 176
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -4-hydroxy-piperidine (Compound B-137)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 4-hydroxypiperidine produced compound B-137: 1 H NMR(300MHz,CDCl 3 )δ5.30–5.23(m,1H),4.18–3.99(m,2H),3.97–3.84(m,1H),3.28–3.01(m,4H),1.14(s,3H),0.99(s,3H),0.93(s,3H),0.90(s,6H),0.78(s,3H),0.75(s,3H).ESI-MS:m/z 540.5[M+H] + 。
example 177
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -3-hydroxymethyl-azetidine (Compound B-138)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 3-azetidinemethanol produced compound B-138: 1 H NMR(300MHz,CDCl 3 )δ5.26(t,J＝3.0Hz,1H),4.54–3.82(m,4H),3.81–3.70(m,2H),3.27–3.14(m,1H),2.86(dd,J＝13.6,3.1Hz,1H),2.79–2.63(m,1H),1.13(s,3H),0.99(s,3H),0.93(s,3H),0.91(s,3H),0.89(s,3H),0.78(s,3H),0.77(s,3H).ESI-MS:m/z 524.5[M-H] - 。
example 178
N- (3 beta-hydroxy-oleanane-12-en-28-yl) -3-methoxyformyl-azetidine (Compound B-139)
Referring to the procedure of example 73, substituting N, N-dimethylethylenediamine with 3-methyl formate azetidine hydrochloride produced compound B-139: 1 H NMR(300MHz,CDCl 3 )δ5.38–5.19(m,1H),4.69–4.00(m,4H),3.75(s,3H),3.42–3.29(m,1H),3.21(dd,J＝9.1,4.7Hz,1H),2.82(dd,J＝13.8,3.5Hz,1H),1.13(s,3H),0.99(s,3H),0.93(s,3H),0.91(s,3H),0.90(s,3H),0.79(s,3H),0.76(s,3H).ESI-MS:m/z 552.5[M-H] - 。
example 179
N- (3 beta- (pyridine-3-formyl) oxy-oleanane-12-en-28-acyl) -3-methoxy-azetidine (Compound B-140)
Referring to the procedure of example 158, substituting compound B-20 for compound B-110 produced compound B-140: 1 H NMR(300MHz,CDCl 3 )δ9.23(s,1H),8.77(d,J＝3.8Hz,1H),8.37–8.23(m,1H),7.39(dd,J＝7.9,4.9Hz,1H),5.27(t,J＝2.9Hz,1H),4.86–4.70(m,2H),4.44–3.86(m,5H),3.30(s,3H),2.87(dd,J＝13.5,3.6Hz,1H),1.15(s,3H),1.02(s,3H),0.99(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.78(s,3H).ESI-MS:m/z 631.5[M+H] + 。
Example 180
N- (3 beta- (pyridine-2-formyl) oxy-oleanane-12-en-28-acyl) -3-methoxy-azetidine (Compound B-141)
Referring to the procedure of example 158, substituting compound B-20 with compound B-110 and nicotinic acid with 2-picolinic acid produced compound B-141: 1 H NMR(300MHz,CDCl 3 )δ8.83–8.74(m,1H),8.06(d,J＝7.8Hz,1H),7.82(td,J＝7.7,1.6Hz,1H),7.49–7.40(m,1H),5.27(d,J＝2.9Hz,1H),4.93–4.80(m,1H),4.45–3.81(m,5H),3.30(s,3H),2.93–2.79(m,1H),1.15(s,3H),1.04(s,3H),0.99(s,3H),0.96(s,3H),0.93(s,3H),0.90(s,3H),0.78(s,3H).ESI-MS:m/z 631.5[M+H] + 。
example 181
N- (3 beta- (furan-2-formyl) oxy-oleanane-12-en-28-acyl) -3-methoxy-azetidine (Compound B-142)
Referring to the procedure of example 158, substituting compound B-20 with compound B-110 and nicotinic acid with furoic acid produced compound B-142: 1 H NMR(300MHz,CDCl 3 )δ8.06–7.98(m,1H),7.45(t,J＝1.7Hz,1H),6.81–6.73(m,1H),5.30(t,J＝3.2Hz,1H),4.70(dd,J＝9.3,6.8Hz,1H),4.55–3.86(m,5H),3.33(s,3H),2.89(dd,J＝13.3,3.2Hz,1H),1.18(s,3H),1.00(s,3H),0.98(s,3H),0.96(s,3H),0.95(s,3H),0.93(s,3H),0.81(s,3H).ESI-MS:m/z 631.5[M+H] + 。
example 182
N- (3 beta- (6-fluoropyridine-2-formyl) oxy-oleanane-12-en-28-acyl) -3-methoxy-azetidine (Compound B-143)
Referring to the procedure of example 158, substituting compound B-20 with compound B-110 and nicotinic acid with 2-fluoropyridine-6-carboxylic acid gave compound B-143: 1 H NMR(300MHz,CDCl 3 )δ8.00–7.87(m,2H),7.17–7.09(m,1H),5.30–5.24(m,1H),4.38–3.87(m,5H),3.30(s,3H),2.92–2.81(m,1H),1.15(s,3H),1.03(s,3H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.78(s,3H).ESI-MS:m/z 649.5[M+H] + 。
example 183
N- (3 beta- (6-chloropyridine-2-formyl) oxy-oleanane-12-en-28-acyl) -3-methoxy-azetidine (Compound B-144)
Referring to the procedure of example 158, substituting compound B-20 with compound B-110 and nicotinic acid with 2-chloropyridine-6-carboxylic acid produced compound B-144: 1 H NMR(300MHz,CDCl 3 )δ7.97(d,J＝7.5Hz,1H),7.78(t,J＝7.7Hz,1H),7.49(d,J＝7.9Hz,1H),5.30–5.24(m,1H),4.88–4.76(m,1H),4.43–3.85(m,5H),3.30(s,3H),2.92–2.81(m,1H),1.15(s,3H),1.02(s,3H),0.98(s,3H),0.94(s,3H),0.93(s,3H),0.90(s,3H),0.78(s,3H).ESI-MS:m/z 665.5[M+H] + 。
example 184
Evaluation of Activity of Compounds on Huh-7 cell AMPK agonism
The agonistic activity of the compounds on Huh-7 cell AMPK was detected by Western Blot.
1. Cell line: huh-7 cells (human liver cancer cells, purchased from stem cell bank of China academy of sciences) were cultured in DMEM complete medium (containing 10% fetal bovine serum and 1% streptomycin/penicillin) at 37deg.C with 5% CO 2 Is cultured in a cell culture incubator.
2. Antibody: anti-AMPK (Cell Signaling Technology 2532S); anti-pAMPK (Thr 172, cell Signaling Technology 2535S); GAPDH (arigobio) HRP-labeled goat anti-rabbit IgG secondary, HRP-labeled goat anti-mouse IgG secondary (bi-cloud).
3. Western Blot experiments: the effect of the compounds on the level of AMPK phosphorylation of Huh-7 cells was examined.
The experiment was performed by taking cells with a proportion of viable cells of 90% or more. Huh-7 cells were plated in 20 ten thousand wells in 12-well plates. Containing 5% CO at 37 DEG C 2 Is cultured in an incubator for 24 hours and is attached. Test compounds were administered under complete medium conditions, with final concentrations of compounds set at 10 μm and administration times of 12 hours, using AICAR (100 μm) as positive control compound. The protein was then extracted for Western Blot detection. The method comprises the following specific steps:
protein sample preparation: the stock culture was discarded, washed 3 times with 1 XPBS, PBS was discarded, 100. Mu.l of RIPA buffer (1 XPBS, 1% NP40,0.5% sodium deoxycholate, 0.1% SDS, PMSF, etc.) was added to each well, incubated on ice for 15min, the cells were scraped off with a cell scraper, aspirated into a fresh 1.5ml EP tube, 4 ℃,12000g, centrifuged for 15min, the supernatant was transferred into a fresh 1.5ml EP tube, placed on ice, 1/5 volume of 6X loading buffer was added, and after 10min heating with a metal bath at 95℃the cells were centrifuged for 1min and frozen to-20℃for use.
Protein quantification: protein samples were diluted 20-fold, 20. Mu.l of diluted protein samples, 200. Mu.l of BCA (solution A: solution B=5:1) reagent were sequentially added to a 96-well plate, incubated at 37℃for 30min, OD values were measured at 562nm wavelength on a microplate reader, and protein concentrations were calculated from a standard curve.
Electrophoresis: SDS-PAGE gel was packed with a separation gel concentration of 10% and a concentration of 4% in the gel concentrate. The protein samples were previously heated in a metal bath at 95℃for 4min and centrifuged for 1min, each sample was loaded with 30. Mu.g of total protein, and each sample was loaded individually with a microsyringe. The power supply is connected (note positive and negative connection), the constant voltage electrophoresis is carried out at 60V at first, and when the protein sample enters the separation gel, the voltage is adjusted to 100V to continue the constant voltage electrophoresis. When bromophenol blue reaches the bottom of the separation gel, electrophoresis is terminated according to the separation condition of the protein marker.
Transferring: the gel after electrophoresis was gently taken out, unnecessary portions were cut off, and the required gel was immersed in a Transfer buffer. A PVDF film of the same size as the glue was prepared, and before use, the PVDF film was saturated with methanol for 1min, transferred to a Transfer buffer, and simultaneously the filter paper was put into the Transfer buffer for saturation. And sequentially paving a sponge, filter paper, glue, PVDF film, filter paper and sponge on an electrode plate of the cathode of the transfer printing instrument. Air bubbles are avoided between each layer. And (5) switching on a power supply, and carrying out 200mA constant-flow ice bath transfer printing for 2.5h.
Antibody hybridization: after completion of transfer, the PVDF membrane was taken out, washed 1 time with l×TBST, and put into a previously prepared blocking solution (5% BSA solution containing 0.1% Tween20 in 1×TBS configuration), and blocked at room temperature for 1 hour. Incubation was performed overnight at 4 ℃. The next day (after 12 h), wash 3 times with 1 XTBE for 10min each. Secondary antibody incubation: secondary antibody diluted with 5% bsa (1:10000) was incubated for 1h at room temperature, washed 3 times with 1×tbst for 10min each. Sucking off excessive liquid on PVDF film, spreading on exposure plate, adding ECL kit liquid Tanon mixed in equal volume TM High-sig ECL Western Blotting Peroxide Buffer and Tanon TM High-sig ECL Western Blotting Luminol/Enhancer Solution, immune response bands were collected by ECL development using a Tanon chemiluminescent imager.
4. Experimental results: after gray scanning is carried out on the Western Blot experiment result, the p-AMPK/AMPK ratio of the negative control DMSO is defined as 1, the p-AMPK/AMPK ratio of the synthesized tested compound is the relative ratio of the negative control group, and the larger the value is, the stronger the AMPK agonistic activity of the compound is indicated, and the activity data result is shown in Table 1.
Table 1 AMPK agonistic Activity of Compounds
( The positive control AICAR concentration was 100 μm; the concentration of the test compound was 10. Mu.M )
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As shown in the experimental results of table 1, the novel derivatives of oleanolic acid and delta-oleanolic acid provided by the present invention have remarkable AMPK agonistic activity at a concentration of 10 μm. For example, compounds A-9, A-12, A-23, A-25, A-27, A-28, A-68, A-81, A-85, A-108, A-109, A-110, A-112, B-9, B-20, B-63, B-65, B-80, B-94, B-110, B-121, B-122, B-123, B-125, and the like are potent AMPK agonists and have significantly better activity than 100. Mu.M AICAR as well as oleanolic acid and delta-oleanolic acid. Wherein, the AMPK agonistic activity (pAMPK/ampk=5.48) of compound a-68 is 3 times or more than the delta-oleanolic acid activity (pAMPK/ampk=1.45). The experimental result shows that the compound has remarkable agonistic activity on the AMPK, so that the compound can be used for preparing an AMPK agonist with the activity of enhancing the phosphorylation level of the AMPK, and further can be used for preparing a medicament for preventing or treating diseases mediated by the AMPK. The synthesis method of other compounds not listed in the embodiment of the invention can be referred to the above embodiment, and also has remarkable agonistic activity to AMPK.
Example 185
Effect of Compounds on the downstream Signal pathway of Huh-7 cell AMPK
The effect of the compounds on the downstream signaling pathway of Huh-7 cell AMPK was examined using the Western Blot method.
Cell culture conditions: huh-7 cells: DMEM complete medium (containing 10% fetal bovine serum and 1% streptomycin/penicillin) at 5% CO 2 Is cultured in an incubator at 37 ℃.
Antibody: anti-ACC (CST, 3676S); anti-pACC (CST, 11818S); anti-mTOR (CST, 2983S); anti-pmTOR (CST, ser 2448).
Western Blot experiments: the effect of the compounds on the downstream signaling pathway of Huh-7 cell AMPK was examined:
the experiment was performed by taking cells with a proportion of viable cells of 90% or more. Huh-7 cells were plated in 25 ten thousand wells in 12-well plates and placed in a medium containing 5% CO 2 After 12 hours in a 37℃incubator, the original medium was discarded, and the complete medium containing the compound was added, and the final concentration of the test compound was set to 10. Mu.M for 12 hours. The positive control compound used AICAR (100 μm). The protein was then extracted for Western Blot detection to detect protein changes in pACC/ACC and pmTOR/mTOR. The experimental results are shown in FIG. 1.
The experimental results (figure 1) show that the compounds of the invention can effectively cause the change of the downstream protein of the AMPK, and the change trend of the compounds is related to the stimulation of the AMPK. For example, compounds B-125, A-112, B-122, A-109, B-121, A-108, B-123, A-110, B-20, and A-81, etc. all increase the level of AMPK, decrease mTOR's phosphorylation and simultaneously increase ACC's phosphorylation. In addition, other compounds of the invention can increase the phosphorylation level of AMPK, decrease the phosphorylation level of mTOR, and simultaneously increase the phosphorylation level of ACC.
Example 186
Tablet formulation
The compound A-81 produced in example 41 or the compound of other examples (50 g), hydroxypropylmethyl cellulose E (150 g), starch (200 g), a proper amount of povidone K30 and magnesium stearate (1 g) were mixed, granulated and tableted.
In addition, the compounds prepared in examples 1 to 183 may be formulated into capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches, etc. by giving different pharmaceutical excipients according to the conventional formulation method of pharmacopoeia 2015.

Claims (6)

1. A delta-oleanolic acid derivative or oleanolic acid derivative, a pharmaceutically acceptable salt thereof, characterized in that said derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of:
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2. use of a delta-oleanolic acid derivative or oleanolic acid derivative, a pharmaceutically acceptable salt thereof, according to claim 1, for the manufacture of an AMPK agonist having activity of enhancing the phosphorylation level of AMPK or for the manufacture of a medicament for the prevention or treatment of AMPK mediated diseases.
3. The use according to claim 2, wherein the AMPK mediated disease comprises metabolic disease, cardiovascular disease, inflammatory disease, autoimmune disease, organ fibrosis disease, neurodegenerative disease, disease secondary to infection by a pathogen, mitochondrial dysfunction or disorder, or tumor.
4. The use according to claim 3, the AMPK mediated disease includes insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, gout, stroke, cerebral infarction, pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibrosis pulmonary disease, allergic rhinitis, inflammatory bowel disease, polycystic kidney disease, polycystic ovary syndrome, behcet's disease, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans phlebitis, intermittent claudication, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, parkinson's disease, alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, down syndrome, halrewon-Shi Pabing, huntington's chorea, wilson's disease, muscle weakness, myoclonus, exercise intolerance, kans-seeer syndrome, chronic fatigue syndrome, li's syndrome, mitochondrial myopathy-cerebral palsy-hyperlactic acid, stroke syndrome, stroke-like attacks, duchenne muscular dystrophy, friedel-crafts disease or tumors.
5. A pharmaceutical composition for preventing or treating AMPK-mediated diseases, comprising the delta-oleanolic acid derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable adjuvant of claim 1.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
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