CN109897022B - Sphaelactone derivative, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
Sphaelactone derivative, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a new class of michelia lactone derivatives (formula I, II) or salts, a preparation method thereof, a pharmaceutical composition thereof and application thereof, in particular to application in preparing anti-tumor and immunotherapy drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel michelia lactone derivatives, a pharmaceutical composition containing the derivatives and application of the derivatives in preparation of antitumor and anti-inflammatory immune medicaments.
Background
In recent thirty years, despite significant advances in various levels of diagnosis and treatment of tumors, the incidence and mortality of tumors has increased worldwide. According to the prediction of the World Health Organization (WHO), the number of tumor diseases is increased to 2000 ten thousand and the number of death is increased to 1200 ten thousand all over the world in 2020. In 2015, 820 ten thousand people died from cancer worldwide, 280 ten thousand of China. 7500 people die of cancer every day in China. China is the first to die due to cancer. In china, the prevalence rate of cancer is 280 parts per 10 ten-thousandth, showing a rapid growth trend year by year. The main biological characteristics of malignant tumor are invasion and metastasis, which are the main clinical death cause of tumor patients, accounting for 83% of tumor deaths. Therefore, the prevention and treatment of tumors is one of the major problems in the disease treatment field today.
In recent years, considerable progress is made in tumor chemotherapy, the survival time of tumor patients is obviously prolonged, and particularly, the treatment of leukemia, malignant lymphoma and the like is broken through, but the treatment of solid tumors which are most serious in harm to human life health and account for more than 90 percent of malignant tumors cannot achieve satisfactory effect. Pharmacologists and oncologists are increasingly aware of: to improve the curative effect of tumor treatment, a new breakthrough progress must be made by starting from the mechanism of tumor occurrence and development. In recent years, the development of molecular oncology and molecular pharmacology has gradually clarified the nature of tumors; the invention and the application of the advanced technologies such as large-scale rapid screening, combinatorial chemistry, genetic engineering and the like accelerate the drug development process; research and development of anti-tumor drugs have entered a new era. Today's antineoplastic agentsThe development of the object has the following points: solid tumors which account for more than 90 percent of malignant tumors are taken as main attacking objects; ②Search for active ingredients from natural products(ii) a Thirdly, aiming at the mechanism of tumor occurrence and development, new molecular action (enzyme, receptor and gene) targets are searched; fourthly, large-scale rapid screening; introduction and application of a new technology: combinatorial chemistry, structural biology, computer aided design, genetic engineering, DNA chips, pharmacogenomics (a combination of functional genomics and pharmacology), and the like.
The anti-tumor drugs are developing from traditional cytotoxic drugs to novel anti-tumor drugs with multi-link effect aiming at tumor mechanisms, and the current new targets and corresponding novel anti-tumor agents or means concerned at home and abroad have the following characteristics: taking a cell signal transduction molecule as a target: including protein kinase inhibitors, farnesyl transferase inhibitors, MAPK signal transduction pathway inhibitors, cell cycle modulators, and the like; using the new blood vessel as a target: an angiogenesis inhibitor; ③ reduction of cancer cell shedding, adhesion and degradation of basement membrane: anti-tumor metastasis agents; fourthly, taking telomerase as a target: a telomerase inhibitor; fifthly, aiming at the drug resistance of the tumor cells: a drug resistance reversal agent; sixthly, promoting the malignant cell to mature and differentiate: a differentiation-inducing agent; and (c) specifically killing cancer cells: (antibody or toxin) directed therapy; enhancing the curative effects of radiotherapy and chemotherapy: a sensitizer for tumor therapy; ninthly, the immune function of the organism is improved or adjusted: a biological response modifier; immunotherapy of tumor in r: the existing relatively popular monoclonal antibody medicines for treating PD-1, PD-L1 and the like[5]。
In recent years, the search for anticancer active compounds from natural products has become a hot spot for developing anticancer drugs, and in the last 20 years, 61% of new chemical entities of drug small molecules launched worldwide can be traced back to natural products. Natural products are very high in occurrence in certain therapeutic areas: 78% of the antibacterial compound and 74% of the antitumor compound are natural products or are derived from a natural product, and the practice proves that the unique effect of the natural product in the discovery of the anticancer drugs draws high attention again. The traditional chemotherapy drugs for treating tumors have the problem of drug resistance, and particularly, the tumor stem cells are less sensitive. The anticancer Chinese medicine has powerful effect, high efficiency and low toxicity, and may be used in screening out efficient tumor killing stem cell to treat malignant tumor.
Sesquiterpene lactones Parthenolide (Parthenolide) is a compound extracted from feverfew that was originally used to treat skin infections, rheumatism, and migraine. Recent studies indicate that parthenolide can inhibit the growth of cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia cancer, renal cancer, lung cancer, colon adenocarcinoma, medulloblastoma and the like, and can treat skin cancer caused by ultraviolet rays in animal models. Research on the action mechanism of the derivative discovers that parthenolide can inhibit the activation of transcription factor NF-kB, the activity of parthenolide is probably mainly from the Michael addition reaction between sulfydryl on Cys38 of p65/NF-kB subunit and parthenolide, and because NF-kB is an important gene for regulating and controlling tumor invasion, metastasis and drug resistance, the inhibition of the activation of NF-kB is likely to improve the sensitivity of tumor to apoptosis caused by tumor suppressor. Recently, Joedan, C.T. doctor and colleagues at the medical college of New York Rochester, discovered that parthenolide can specifically destroy the stem cells causing acute and chronic myelogenous leukemia without substantially damaging the normal stem cells, thereby possibly fundamentally suppressing leukemia relapse, and the unique mechanism of action of parthenolide has attracted much attention.
Micheliolide (Micheliolide) also belongs to sesquiterpene lactone compounds, and is a guaiane type sesquiterpene lactone compound, and is distributed in the root bark of michelia Champaca l. and the root bark of sarg. michelia Compressa (Maxim.) in the magnolia. There are reports on the finding that michelia lactone has almost the same effect as parthenolide in treating leukemia, and has no obvious killing effect on normal cells [ j.nat. prod.1993,6, 90-98; bioorg.Med.chem.Lett.2003,11,1503-1510 ]. The michelia lactone and its derivatives were previously found to be useful in the treatment of the following cancers: leukemia, breast cancer, prostate cancer, liver cancer, esophageal cancer, stomach cancer, oral cancer, hodgkin's lymphoma, pancreatic cancer, colorectal cancer, cervical cancer, non-hodgkin's lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer, prostate cancer, and kaposi's sarcoma, and have been patented [ application No.: 201010153701.0, respectively; 201010153685.5]. The prior method for preparing michelia lactone mainly adopts chemical synthesis, and Chinese patent application No. 201010153685.5 discloses a preparation method of michelia lactone, which uses parthenolide as a raw material, and rearranges the parthenolide in a proper organic solvent under the catalysis of Lewis acid to obtain the michelia lactone, wherein the yield reaches more than 60 percent.
FIG. 1 chemical Structure of ACT001
ACT001 is a derivative of sphaelactone dimethylamine (figure 1), and is prepared from a natural extract parthenolide as a raw material through rearrangement reaction, dimethylamide and salt-forming reaction, and ACT001 has the effects of resisting glioma and leukemia, and is currently in phase I clinical research in Australia and China. The parthenolide and the michelia lactone are sesquiterpene lactone compounds, and have the characteristics of anti-inflammation, immunoregulation, platelet aggregation resistance and the like. The natural product has anti-inflammatory effect by inhibiting the expression of tumor necrosis factor (TNF-alpha), interleukin-1 (IL-1), IL-12 and cyclooxygenase-2 (COX-2); it has also been reported in the literature that the inhibition of NF-kB activation and phosphorylation promotes cancer cell apoptosis, and the inhibition of L-8, Vascular Endothelial Growth Factor (VEGF) production plays an anti-tumor role; at present, the michelia lactone and dimethylamine adduct ACT001 is mainly used for treating diseases such as skin infection, migraine, rheumatism, tumor and the like. Research shows that ACT001 and parthenolide have the characteristics of resisting inflammation, resisting tumor, resisting platelet aggregation, inhibiting proliferation of vascular smooth muscle cells, inhibiting activity of osteoclasts and the like.
Disclosure of Invention
The invention provides a new class of michelia lactone derivatives (5-hydroxy michelia lactone and ester derivatives thereof, 5-oxo michelia lactone) and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparing anti-tumor and anti-inflammatory immune medicaments.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a michelia lactone derivative shown by the following general formula and pharmaceutically acceptable salts thereof:
wherein:
R1is hydrogen or C1-8Acyl, tetrahydropyrroloyl, tetrahydrofuroyl, Ar-C1-4Acyl, Ar-O-C1-4Acyl, Ar-S-C1-4Acyl, Y-N-C1-4An acyl group; wherein C is1-8The acyl group is preferably selected from the group consisting of straight or branched alkanoyl, alkenoyl and alkynoyl;
ar is aryl or substituted aryl; y is a heterocyclic aryl or substituted heterocyclic aryl; ar is preferably selected from phenyl, benzoyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, pyridazinyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, purinyl, benzoxazolyl, benzothiazolyl, and the like; y is preferably selected from the group consisting of a uracil radical, a tetrahydroisoquinolinyl radical, a phthalimidyl radical, and a naphthalimide radical. R2Is C1-7Acyl radical, C1-6An alkyl group; wherein, C1-7The acyl group is preferably selected from acetyl, propionyl, butyryl, isobutyryl, chloroacetyl, benzoyl and the like; c1-6The alkyl group is preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, etc.; or R1＝R2；
R3、R4Combined into a double bond, or
R3Is hydrogen, R4is-CH2NR5R6Wherein R is5And R6Are respectively C1-4A hydrocarbyl group.
The invention provides michelia lactone derivatives of formula (I) and pharmaceutically acceptable salts thereof,
it is characterized in that hydroxyl at the C5 site is in a structure of (RS) -, (S) -, (R) -;
of the above-mentioned michelia lactone derivatives of formula (I, II)
Preferably, R1Acyl, in particular substituted benzoyl, substituted phenylacetyl, substituted naphthoyl, substituted quinolinoyl, substituted thiophenoyl, substituted thiopheneacetyl, substituted benzimidazolebutyryl.
Preferably, the michelia lactone derivative is of the following structure:
preferably, R2Is hydrogen or acyl, especially acyl having 1 to 7 carbon atoms.
Preferably, R3Is hydrogen, R4is-NR5R6Substituted C1-8Alkyl, preferably wherein R5And R6Are respectively C1-4An alkyl group.
Wherein when R is1Is H, R2Is H and R3＝R4When the double bond is 5-hydroxy michelia lactone.
In a second aspect of the present invention, there is provided a method for preparing a michelia lactone derivative of formula (I, II) as follows:
part of the compounds of the present invention contain basic groups in the molecule, which can be converted to pharmaceutically acceptable salts by acid treatment, as is recognized in the art. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate or bisulfate, nitrate, phosphate or bisulfate, and the like, and organic acid salts such as formate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like.
The third aspect of the present invention provides an application of the michelia lactone derivative of formula (I, II) and its pharmaceutically acceptable salt in the first aspect or the pharmaceutical composition of the third aspect in preparing a medicament for preventing or treating tumors or inflammatory immune diseases, wherein the tumors are preferably non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, brain glioma, liver cancer, and the like, but are not limited to the above tumors. The inflammatory immune disease is preferably selected from rheumatoid arthritis, diabetic nephropathy, and organ fibrosis.
The present invention also provides a pharmaceutical composition comprising the michelia lactone derivative of formula (I, II) above, wherein the pharmaceutical composition comprises the michelia lactone derivative of any of claims 1-5 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
When used as a medicament, the compounds of the present invention may be used as such or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the invention, and the balance pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers and/or excipients for humans and animals or in combination with other anti-cancer drugs. The pharmaceutical composition can be prepared into injections, tablets, capsules, pills, powder and the like.
The pharmaceutical composition of the invention can be a controlled release administration form, a sustained release administration form and various microparticle administration systems.
The invention relates to application of michelia lactone derivatives and pharmaceutically acceptable salts thereof in preparing antitumor and anti-inflammatory immune medicaments.
The tumor of the invention is preferably non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, brain glioma and the like, but is not limited to the tumors.
The inflammatory immune diseases are preferably immune diseases such as rheumatoid arthritis, diabetic nephropathy, organ fibrosis, psoriasis and the like, but are not limited to the diseases.
In a fourth aspect of the technical scheme of the present invention, a pharmaceutical composition is provided, where the pharmaceutical composition includes the michelia lactone derivative according to the first aspect of the present invention and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
The compounds of the present invention may be administered orally, for example, in the form of capsules, tablets, powders, granules, syrups or the like, or parenterally by injection, ointment, suppository or the like. Such pharmaceutical preparations may be produced in a conventional manner by using auxiliary agents well known in the art, such as binders, excipients, stabilizers, disintegrants, flavoring agents, lubricants and the like, and although the dosage varies depending on the symptoms and age of the patient, the nature and severity of the disease or disorder and the route and manner of administration, in the case of oral administration to adult patients, the compound of the present invention is normally administered in a total dose of 1 to 1000mg, preferably 5 to 500mg, per day, in a single dose, or in a divided dose form; e.g., twice or three times daily; in the case of intravenous injection, a dose of 0.1 to 100mg, preferably 0.5 to 50mg, may be administered in one to three times a day.
Advantageous technical effects
The invention provides the michelia lactone derivative shown in general formulas (I) and (II), wherein oxygen and hydroxyl are mainly introduced to the 5-position carbon of the michelia lactone, and the hydroxyl is esterified to obtain the ester derivative; addition of unsaturated double bonds and amines forms amides. The primary activity screening shows that the derivative has higher anti-tumor activity than the michelia lactone. The derivatives are suggested to have better anti-tumor prospect.
Drawings
FIG. 1: structure of ACT001 Compound being tested in clinical trials
FIG. 2: growth inhibition effect of compound on mouse liver cancer H22
FIG. 3: growth inhibitory effect of compounds on mouse brain tumor G422 note: MCL3 represents the compound of example 3.
Detailed Description
Abbreviations:
boc: tert-butyloxycarbonyl radical
DCM: methylene dichloride
DMA: dimethylamine
DMF: n, N-dimethylformamide
DMAP: 4-dimethylaminopyridine
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
MCL is sphaelactone
PTL parthenolide
PTMA: p-toluenesulfonic acid
5-OHMCL 5-hydroxy sphaelactone
THF: tetrahydrofuran (THF)
TMZ: temozolomide
The invention discloses application of michelia lactone derivatives, salts, solvates, prodrugs and pharmaceutical compositions containing the michelia lactone derivatives, and a person skilled in the art can realize the michelia lactone derivatives by appropriately improving process parameters by referring to the contents. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention is further illustrated by the following examples:
synthetic reaction formula of michelia lactone derivative
Example 1 Sphaelactone (MCL)
80ml of methylene chloride and p-toluenesulfonic acid (2.0mmol) were charged in a 200ml three-necked flask, and a solution prepared from parthenolide (PTL,50mmol) and 18ml of methylene chloride was added dropwise with stirring, and after completion of the addition, stirring was continued overnight at room temperature. After TLC confirmed complete conversion of PTL starting material, NaHCO was used3(0.35g) and 3.5ml of water are prepared into a solution, the solution is added into the reaction solution and stirred for 1 hour, the reaction solution gradually fades from purple red to yellow in the stirring process, an aqueous phase is separated, an organic phase is washed for 2 times by saturated saline, yellow solid is obtained by concentration, and the yellow solid MCL (82%) is obtained by recrystallization and low-temperature cooling by acetone.
1H NMR(400MHz,Chloroform-d)δ6.22(s,1H,H-13),5.50(s,1H, H-13),3.82(t,1H,H-12),2.75-2.64(m,2H,H-3,H-11),2.62(s,1H, OH),2.50-1.25(m,8H,),1.69(s,3H,CH3),1.33(s,3H,CH3).
Example 25-Hydroxymichelia lactone (5-OH MCL)
Subjecting michelia lactone (MCL) (1.0mmol), SeO2(0.3mmol), t-butylhydroperoxide TBHP (2.0mmol), 30ml of methylene chloride were placed in a 100ml round-bottomed flask and reacted under reflux for 3 hours. Filtration through celite, concentration of the filtrate, and column chromatography (eluent) gave a yellow solid (52.6%).
1H NMR(400MHz,Chloroform-d):δ6.22(s,1H,H-13),5.52(s,1H, H-13),4.33(s,1H,H-5),3.90-3.82(m,1H,H-12),3.37(t,J＝9.5Hz,1H, H-3),2.91(d,J＝12.8Hz,1H,H-11),2.67-1.58(m,11H),1.29(s,3H, H-15).
Example 35 Sphaelactone
5-Hydroxysphaelactone (1.0mmol), Dess-Martin reagent (0.5mmol), sodium bicarbonate (10mmol), and 30ml of methylene chloride were placed in a 100ml round-bottomed flask and the reaction was stirred at room temperature for 3 hours. After the reaction of the starting materials was completed, the reaction was quenched with saturated sodium bisulfite solution, 30ml of dichloromethane was added, and the organic phase was washed with water and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (93.6%).
1H NMR(400MHz,Chloroform-d)δ6.34(s,1H,H-13),5.61(s,1H, H-13),4.28(t,J＝10.0Hz,1H,H-12),3.16-3.12(m,1H,H-3),3.00(d,J ＝10.9Hz,1H,H-11),2.76-1.60(m，10H),1.33(s,3H,H-15).
EXAMPLE 45 chromone-2-carboxylate of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), chromone-2-carboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (40.6%).1H NMR(400MHz,Chloroform-d)δ8.56(s,1H,Ar-H),8.03(t,J＝10.0 Hz,2H,Ar-H),7.91(d,J＝10.0Hz,2H,Ar-H),6.24(d,J＝3.4Hz,1H, H-13),5.78(d,J＝5.0Hz,1H,H-5),5.51(d,J＝3.4Hz,1H,H-13),3.99 (t,J＝10.0Hz,1H,H-12),3.39(t,J＝15.0Hz,1H,H3),3.10(d,J＝15.0 Hz,1H,H-11),2.53-1.52(m,9H),1.38(s,3H,H-15).
Example 55 2-Naphthalenecarboxylic acid ester of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), 2-naphthoic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonateWashed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (47.8%).1H NMR(400MHz,Chloroform-d)δ8.55(s,1H,Ar-H),8.04-7.86(m, 4H,Ar-H),7.64-7.51(m,2H,Ar-H),6.23(d,J＝3.4Hz,1H,H-13),5.78 (d,J＝3.4Hz,1H,H-5),5.50(d,J＝3.4Hz,1H,H-13),4.00(t,J＝15.0 Hz,1H,H-12),3.39(t,J＝15.0Hz,1H,H-3),3.10(d,J＝15.0Hz,1H, H-11),2.67(s,1H,-OH),2.60-1.71(m,9H),1.36(s,3H,H-15).
Example 65 3-methyl-2-thiophenecarboxylic acid ester of michelia lactone
5-hydroxy michelia lactone (1.0mmol), 3-methyl-2-thiophenecarboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottom flask, and the reaction was stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (37.5%).
1H NMR(400MHz,Chloroform-d)δ7.41(d,J＝5.0Hz,1H,H-20), 6.92(d,J＝5.0Hz,1H,H-19),6.22(d,J＝3.3Hz,1H,H-13),5.63(dd,J ＝4.9,1.9Hz,1H,H-5),5.49(d,J＝3.1Hz,1H,H-13),4.01–3.85(m, 1H,H-12),3.40–3.24(m,1H,H-3),3.01(dt,J＝10.9,2.5Hz,1H, H-11),2.64(s,1H,-OH),2.55(s,3H,H-21),2.51–1.58(m,9H),1.34(s, 3H,H-15).
Example 75 alpha-Furanoic acid ester of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), α -furancarboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction solution was transferred to liquid separationTo the funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (43.4%).1H NMR(400MHz,Chloroform-d)δ7.58(s,1H,Ar-H),7.17(d,J＝3.5 Hz,1H,Ar-H),6.52(d,J＝3.5Hz,1H,Ar-H),6.23(d,J＝3.4Hz,1H, H-13),5.65(d,J＝4.9Hz,1H,H-5),5.48(d,J＝3.4Hz,1H,H-13),3.92 (t,J＝10.0Hz,1H,H-12),3.30(t,J＝15.0Hz,1H,H3),3.01(d,J＝15.0 Hz,1H,H-11),2.60-1.60(m,9H),1.33(s,3H,H-15).
EXAMPLE 85 Phenoxyacetic acid ester of Hydroxymichaelide
5-hydroxy michelia lactone (1.0mmol), phenoxyacetic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane are put into a 50ml round-bottom flask and stirred at normal temperature until no residue is left. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (52.7%).1H NMR(400MHz,Chloroform-d)δ7.31–7.27(m,2H,Ar-H), 7.02–6.94(m,1H,Ar-H),6.89–6.83(m,2H,Ar-H),6.24(d,J＝3.3Hz, 1H,H-13),5.84(d,J＝6.4Hz,1H,H-5),5.52(d,J＝3.1Hz,1H,H-13), 4.61(d,J＝2.6Hz,2H,H-17),3.84(t,J＝10.3Hz,1H,H-12),2.78(d,J ＝10.8Hz,1H,H-11),2.72–2.59(m,1H,H-3),2.37-1.61(m,10H),1.34 (s,3H,H-15).
Example 95 2-phenylquinoline-4-carboxylic acid ester of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), 2-phenylquinoline-4-carboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (38.3%).
1H NMR(400MHz,Chloroform-d)δ8.65–8.57(m,1H,Ar-H),8.28(s, 1H,Ar-H),8.27-8.21(m,1H,Ar-H),8.20-8.13(m,2H,Ar-H),7.70(dd, 2H，Ar-H),7.59–7.53(m,2H,Ar-H),7.53–7.47(m,1H,H-30),6.25(d,J ＝3.4Hz,1H,H-13),5.91(dd,J＝4.8,2.2Hz,1H,H-5),5.54(d,J＝3.1 Hz,1H,H-13),3.99(dd,J＝10.8,10.2Hz,1H,H-12),3.30(d,J＝9.6Hz, 1H,H-3),3.05(dt,J＝10.9,2.5Hz,1H,H-11),2.64(s,1H,-OH),2.62– 1.81(9H,H-4,H-8,H-9,H-14),1.37(s,3H,H-15).
Example 105 5-Fluorouracil-N of Hydroxymichaelide1-acetic acid ester
5-hydroxy michelia lactone (1.0mmol), 2-acetic acid-5-fluorouracil (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 15ml DMF were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. After the reaction solution was concentrated, it was transferred to a separatory funnel, 50ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (32.9%).
1H NMR(400MHz,Chloroform-d)δ8.01(s,1H,-NH),7.76–7.46(m, 1H,H-18),6.23(d,J＝3.4Hz,1H,H-13),5.52(q,J＝3.9,3.1Hz,2H, H-5,H-13),4.54–4.34(m,2H,H-17),3.88(t,J＝10.5Hz,1H,H-12), 3.24–3.13(m,1H,H-3),2.95–2.89(m,1H,H-11),2.72(s,1H,-OH), 2.48–1.36(9H,H-4,H-8,H-9,H-14),1.32(s,3H,H-15)。
Example 115 5-Nitro-2-carboxylate of michelia lactone
5-Hydroxymichelia lactone (1.0mmol), 5-nitro-2-carboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 15ml DMF were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. After the reaction solution was concentrated, it was transferred to a separatory funnel, 50ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (43.3%).
1H NMR(400MHz,Chloroform-d)δ7.38–7.28(m,2H,H-18,H-19), 6.25(d,J＝3.4Hz,1H,H-13),5.72(dd,J＝4.8,2.1Hz,1H,H-5),5.51 (d,J＝3.1Hz,1H,H-13),4.01–3.86(m,1H,H-12),3.28(s,1H,H-3), 3.01(d,J＝10.9Hz,1H,H-11),2.65(s,1H,-OH),2.55–1.74(9H,H-4, H-8,H-9,H-14),1.35(s,3H,H-15).
Example 3,4, 5-trimethoxybenzoate of 125-Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), 3,4, 5-trimethoxybenzoic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (37, 9%).
1H NMR(400MHz,Chloroform-d)δ7.25(s,2H,Ar-H),6.23(d,J＝3.4 Hz,1H,H-13),5.69(dd,J＝4.8,2.2Hz,1H,H-5),5.50(d,J＝3.1Hz, 1H,H-13),3.95(dd,J＝10.9,10.1Hz,1H,H-12),3.90(d,J＝0.8Hz,9H, H-23,H-24,H-25),3.33–3.19(m,1H,H-3),2.99(dt,J＝10.9,2.8Hz, 1H,H-11),2.63(s,1H,-OH),2.55-1.69(9H,H-4,H-8,H-9,H-14),1.35 (s,3H,H-15).
EXAMPLE 135 p-fluorophenyl thioacetate of michelia lactone
5-Hydroxymichelia lactone (1.0mmol), p-fluorophenylthioacetic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at normal temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (68.3%).1H NMR(400MHz,Chloroform-d)δ7.41-7.33(m,2H,Ar-H),7.04-6.94 (m,2H,Ar-H),6.20(d,J＝3.4Hz,1H,H-13),5.42–5.36(m,2H,H-13, H-5),3.87-3.79(m,1H,H-12),3.60(d,J＝3.5Hz,2H,H-18),3.05-2.92 (m,1H,H-3),2.83(dt,J＝10.9,2.6Hz,1H,H-11),2.59(s,1H,-OH), 2.42–1.53(9H,H-4,H-8,H-9,H-14),1.29(s,3H,H-15).
Example 145 nicotinic acid ester of Hydroxysphaelactone
5-Hydroxymichelia lactone (1.0mmol), nicotinic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 20ml of dichloromethane were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (37.5%).
1H NMR(400MHz,Chloroform-d)δ9.21(dd,J＝2.2,0.9Hz,1H, H-18),8.80(dd,J＝4.9,1.7Hz,1H,H-19),8.29–8.23(m,1H,H-21), 7.41(ddd,J＝8.0,4.9,0.9Hz,1H,H-20),6.24(d,J＝3.4Hz,1H,H-13), 5.74(dd,J＝4.9,2.1Hz,1H,H-5),5.50(d,J＝3.1Hz,1H,H-13),3.95 (dd,J＝10.9,10.1Hz,1H,H-12),3.36–3.21(m,1H,H-3),3.10–2.93 (m,1H,H-11),2.67(s,1H,-OH),2.56–1.72(m,9H),1.35(s,3H,H-15).
Example 155-4-Biphenylacetic acid ester of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), 4-biphenylacetic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 15ml DMF were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. After the reaction solution was concentrated, it was transferred to a separatory funnel, 50ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (44.7%).
1H NMR(400MHz,Chloroform-d)δ7.57–7.30(m,9H,Ar-H),6.16(d, J＝3.4Hz,1H,H-13),5.43(dd,J＝4.8,2.0Hz,1H,H-5),5.35(d,J＝ 3.1Hz,1H,H-13),3.89–3.79(m,1H,H-12),3.66(m,2H,H-17),3.07– 2.97(m,1H,H-3),2.84(dt,J＝10.9,2.5Hz,1H,H-11),2.57(s,1H, -OH),2.38–1.54(9H,H-4,H-8,H-9,H-14),1.29(s,3H,H-15).
Example 165 ibuprofen ester of hydroxy Spirolactone
5-hydroxy michelia lactone (1.0mmol), ibuprofen (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (31.9%).
1H NMR(400MHz,Chloroform-d)δ7.16–7.04(m,4H,Ar-H),6.22(t, J＝3.5Hz,1H,H-13),5.65(d,J＝6.4Hz,1H,H-5),5.51(d,J＝2.9Hz, 1H,H-13),3.82(t,J＝10.3Hz,1H,H-12),3.63(q,J＝7.1Hz,1H,H-17), 2.71(d,J＝10.5Hz,1H,H-11),2.68–2.57(m,1H,H-3),2.59(s,1H, -OH),2.48–1.59(m,15H),1.46(d,J＝7.1Hz,3H,H-15),0.87(dd,J＝ 6.6,2.1Hz,6H,H-26,H-28).
Example 175 2-Pyrrolecarboxylate of Hydroxymichaelide
5-Hydroxymichelia lactone (1.0mmol), 2-pyrrolecarboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane were placed in a 50ml round-bottomed flask and stirred at room temperature until no starting material remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (45.3%).
1H NMR(400MHz,Chloroform-d)δ9.22(s,1H,-NH),7.01-6.96(m, 1H,H-20),6.93(s,1H,H-18),6.28(d,J＝3.7Hz,1H,H-19),6.22(d,J＝ 3.4Hz,1H,H-13),5.64(d,J＝2.8Hz,1H,H-5),5.48(d,J＝3.1Hz,1H, H-13),3.99-3.88(m,1H,H-12),3.37-3.21(m,1H,H-3),3.05-2.96(m, 1H,H-11),2.67(s,1H,-OH),2.52-1.66(9H,H-4,H-8,H-9,H-14),1.34 (s,3H,H-15).
Example 185N-phthaloyl glycine ester of hydroxy michelia lactone
5-Hydroxymichelia lactone (1.0mmol), phthaloylglycine (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (39.4%).
1H NMR(400MHz,Chloroform-d)δ7.82(m,4H,Ar-H),6.24(d,J＝3.4 Hz,1H,H-13),5.53(d,J＝3.1Hz,1H,H-12),5.50(dd,J＝4.8,2.0Hz, 1H,H5),4.45(d,J＝3.2Hz,2H,H-17),3.83(t,J＝10.5Hz,1H,H-12), 3.09-2.97(m,1H,H3),2.74-2.65(m,1H,H-11),2.43-1.63(10H,H-4, H-8,H-9,H-14,-OH),1.27(s,3H,H-15).
Example 195 proline ester of Hydroxypropionolactone
5-Hydroxymichelia lactone (1.0mmol), Boc protected proline (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at ambient temperature until no starting material remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, the organic phase was washed with saturated sodium bicarbonate, water and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and column chromatography (eluent) was performed to obtain a white solid, which was dissolved in 10ml of dichloromethane, reacted with trifluoroacetic acid (1.0mmol) for 3 hours, and then concentrated to obtain a white solid (30.3%).
1H NMR(400MHz,Chloroform-d)δ6.21(dd,J＝9.2,3.4Hz,1H,H-13), 5.45(m,2H,H-5,H-13),4.32–4.21(m,1H,H-17),3.87(m,1H,H-12), 3.58–3.32(m,2H,H-20),3.13(m,1H,H-3),2.62(d,J＝14.4Hz,1H, H-11),2.50–1.49(m,15H),1.31(s,3H,H-15).
EXAMPLE 205 benzofuran-2-carboxylic acid ester of hydroxy michelia lactone
5-Hydroxymichelia lactone (1.0mmol), benzofuran-2-carboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (45.2%).
1H NMR(400MHz,Chloroform-d)δ7.72-7.57(m,2H,H-10,H-23), 7.53(d,J＝0.9Hz,1H,H-18),7.50-7.28(m,2H,H-21,H-22),6.24(d,J ＝3.4Hz,1H,H-13),5.74(dd,J＝4.9,2.0Hz,1H,H-5),5.51(d,J＝3.1 Hz,1H,H-13),3.96(dd,J＝10.8,10.2Hz,1H,H-12),3.41-3.32(m,1H, H-3),3.07(dt,J＝11.0,2.6Hz,1H,H-11),2.64(s,1H,-OH),2.59-1.77 (9H,H-4,H-8,H-9,H-14),1.36(s,3H,H-15).
Example 215 2-indole carboxylate of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), 2-indolecarboxylic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (42.9%).
1H NMR(400MHz,Chloroform-d)δ8.86(s,1H,H-NH),7.75-7.11(m, 5H,H-18,H-20,H-21,H-22,H-23),6.24(d,J＝3.4Hz,1H,H-13),5.73 (dd,J＝4.8,2.0Hz,1H,H-5),5.50(d,J＝3.1Hz,1H,H-13),3.96(t,J＝ 10.5Hz,1H,H-12),3.40–3.29(m,1H,H-3),3.07(dt,J＝11.0,2.4Hz, 1H,H-11),2.67(s,1H,-OH),2.57-1.76(9H,H-4,H-8,H-9,H-14),1.36 (s,3H,H-15).
Example 225 (1, 8-Dinaphthalimide) -N-propanoate of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), (1, 8-dinaphthylimide) -N-propionic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottomed flask and stirred at room temperature until no starting material remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (48.2%).
1H NMR(400MHz,Chloroform-d)δ8.86(dd,J＝8.8,1.0Hz,1H,Ar-H), 8.72(dd,J＝7.3,1.0Hz,1H,Ar-H),8.68(d,J＝8.0Hz,1H,Ar-H),8.41 (d,J＝8.0Hz,1H,Ar-H),8.00(dd,J＝8.7,7.3Hz,2H,Ar-H),6.25(d,J ＝3.4Hz,1H,H-13),5.57(d,J＝3.1Hz,1H,H-5),5.47(dd,J＝4.7,2.1 Hz,1H,H-13),4.50(td,J＝7.0,3.7Hz,2H,H-18),3.93–3.83(m,1H, H-12),3.24–3.14(m,1H,H-3),2.93–2.84(m,1H,H-11),2.80(t,J＝ 7.1Hz,2H,H-17),2.58(s,1H,-OH),2.46–1.57(s,9H),1.30(s,3H).
Example 235 (4-bromophenyl) -4-oxobutanoate of hydroxy michelia lactone
5-Hydroxymichelia lactone (1.0mmol), (4-bromophenyl) -4-oxobutanoic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no starting material remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (38.0%).
1H NMR(400MHz,Chloroform-d)δ7.87–7.76(m,2H,Ar-H),7.68– 7.52(m,2H,Ar-H),6.24(d,J＝3.4Hz,1H,H-13),5.53(d,J＝3.1Hz, 1H,H-13),5.45(dd,J＝4.7,2.1Hz,1H,H-5),3.94–3.80(m,1H,H-12), 3.36–3.14(m,3H,H-18,H-3),2.92–2.82(m,1H,H-11),2.74(td,J＝ 6.1,1.3Hz,2H,H-17),2.60(s,1H,-OH),2.45–1.58(m,9H),1.30(s, 3H).
EXAMPLE 245 (6, 7-Dimethoxytetrahydroisoquinoline) -N-propionate of Hydroxymichelia lactone
5-hydroxy michelia lactone (1.0mmol), (6, 7-dimethoxy tetrahydroisoquinoline) -N-propionic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (41.8%).
1H NMR(400MHz,Chloroform-d)δ6.49(d,J＝26.0Hz,2H,Ar-H), 6.03(d,J＝3.3Hz,1H,H-13),5.41(dd,J＝4.7,2.0Hz,1H,H-5),5.28 (d,J＝3.2Hz,1H,H-13),3.82(d,J＝5.7Hz,7H,H-12,H-28,H-29), 3.66–3.42(m,2H,H-19),3.10(m,1H,H-3),2.91–1.38(m,19H),1.27 (s,3H).
Example 255 (3-Chloroacetamido) benzoate of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), (3-chloroacetylamino) benzoic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol), and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (43.2%).
1H NMR(400MHz,Chloroform-d)δ8.33(s,1H,-NH),8.06(t,J＝1.9 Hz,1H,Ar-H),7.99–7.67(m,2H,Ar-H),7.46(t,J＝8.0Hz,1H,Ar-H), 6.21(d,J＝3.4Hz,1H,H-13),5.70(dd,J＝4.9,2.0Hz,1H,H-5),5.48 (d,J＝3.1Hz,1H,H-13),4.20(s,2H,H-24),3.94(dd,J＝10.8,10.2Hz, 1H,H-12),3.39–3.24(m,1H,H-3),3.13–3.01(m,1H,H-11),2.70(s, 1H,-OH),2.55–1.38(m,9H),1.35(s,3H).
EXAMPLE 265 naproxen ester of Hydroxymichelia lactone
5-Hydroxymichelia lactone (1.0mmol), naproxen (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at room temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (44.7%).
1H NMR(500MHz,Chloroform-d)δ7.75–7.64(m,3H,Ar-H),7.38(d, J＝8.3Hz,1H,Ar-H),7.16(m,2H,Ar-H),6.25(s,1H,H-13),5.74(d,J ＝5.8Hz,1H,H-5),5.54(s,1H,H-13),3.96(s,3H,H-29),3.84(t,J＝8.9 Hz,2H,H-5,H-17),2.74(d,J＝10.2Hz,1H,H-2),2.66(s,1H,H-11), 2.34(s,1H,-OH),2.21–1.23(m,12H),1.01(s,3H,H-15).
EXAMPLE 275 Phenylthioacetate of Hydroxymichelia lactone
Chemical Formula:C23H26O5S
Molecular Weight:414.51600
5-Hydroxymichelia lactone (1.0mmol), phenylthioacetic acid (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml of dichloromethane were placed in a 50ml round-bottom flask and stirred at normal temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (65.2%).
1H NMR(400MHz,Chloroform-d)δ7.27-7.34(m,5H,Ar-H),6.16(d,J ＝3.4Hz,1H,H-13),5.36(d,J＝12.0Hz,1H,H-5),5.34(d,J＝3.4Hz, 1H,H-13),3.79(t,1H,J＝12.0Hz,H-12),3.65(d,J＝3.5Hz,2H,H-18), 2.50(m,2H),2.35-2.15(m,3H),1.75(m,2H),1.71(s,3H,CH3),1.28 (s,3H,CH3).
Example 285 Bendaloxetine ester of Hydroxymichelia lactone
5-hydroxy michelia lactone (1.0mmol), bendamustine hydrochloride (1.0mmol), EDCI (1.5mmol), DMAP (0.1mmol) and 20ml dichloromethane were placed in a 50ml round bottom flask and stirred at normal temperature until no residue remained. The reaction mixture was transferred to a separatory funnel, 30ml of dichloromethane was added, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent) to give a white solid (48.3%).1H NMR(400MHz,Chloroform-d)δ7.17(d,J＝8.8Hz,1H,Ar-H),7.06 (d,J＝2.3Hz,1H,Ar-H),6.77(dd,J＝8.8,2.4Hz,1H,Ar-H),6.21(d,J ＝3.4Hz,1H,H-13),5.46(d,J＝3.1Hz,1H,H-13),5.43(dd,J＝4.8,2.1 Hz,1H,H-5),3.86(dd,J＝10.9,10.1Hz,1H,H-12),3.77–3.56(m, 11H),3.23–3.12(m,1H,H-3),2.93(dd,J＝4.5,1.8Hz,1H,H-11),2.92 –1.40(m,16H),1.30(s,3H,H-15).
Example 295, 9-bis [ (4-dichloroethylamino) phenylbutyryl ] michelia lactone
Chemical Formula:C43H54Cl4N2O6
Molecular Weight:836.71300
5-Hydroxymichelia lactone (1.0mmol), chlorambucil (2.0mmol), EDCI (2.5 mmol), DMAP (0.2mmol), and 20ml of dichloromethane were placed in a 50ml round-bottomed flask and stirred at room temperature until no starting material remained. Transferring the reaction solution to a separating funnel, adding 30ml dichloromethane, washing the organic phase with saturated sodium bicarbonate, water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (eluent) to obtain white solid (31.9%)。1H NMR(400MHz,Chloroform-d)δ7.06(t,4H,Ar-H),6.65(d,J＝12 Hz,4H,Ar-H),6.25(s,1H,H-13),5.49(s,1H,H-13),5.45(m,1H,H-5), 3.89(t,J＝12Hz,1H,H-12),3.74–3.58(m,16H,ClCH2CH2N),3.24(t, J＝10Hz,1H,H-3),2.92(d,J＝12Hz,1H,H-11),2.56(m,6H),2.38(m, 8H),1.83(m,7H),1.77(s,3H,H-14),1.64(t,J＝16Hz,2H,H-9),1.31 (s,3H,H-15).
Example 305 p-fluorophenyl thioglycolate of Hydroxydimethylamino michelia lactone
Chemical Formula:C26H36FNO5S
Molecular Weight:493.63440
P-fluorophenyl thioglycolate (1.0mmol) of 5-hydroxy michelia lactone is dissolved in 10mL of dichloromethane, 5mL of dichloromethane solution of dimethylamine is added under stirring, and the reaction is stirred at normal temperature until no raw material is left. The reaction was concentrated to give a white solid (52.7%).
1H NMR(400MHz,Chloroform-d)δ7.38(t,J＝3.4Hz,2H,Ar-H),7.00 (t,J＝3.4Hz,2H,Ar-H),5.20(d,2H,H-5),3.98(t,1H,J＝8.0Hz H-12), 3.54(s,2H,H-21),3.00(m,3H,H-2,3,4),2.70(m,3H),2.69(s,3H, NCH3),2.65(s,3H,NCH3),2.42-2.25(m,5H),1.85(d,1H),1.61(s,3H, H-16),1.5(m,1H),1.29(s,3H,H-15).
Example 315 Phenylthioacetate of Hydroxydimethylamino michelia lactone
Chemical Formula:C25H33NO5S
Molecular Weight:459.60100
5-Hydroxymichelia lactone benzenethioacetate (1.0mmol) was dissolved in 10mL of dichloromethane, and 5mL of a dimethylamine solution in dichloromethane was added under stirring, and the reaction was stirred at room temperature until no starting material remained. The reaction was concentrated to give a white solid (63.9%).
1H NMR(400MHz,Chloroform-d)δ7.37(m,2H,Ar-H),7.29(m,2H, Ar-H),7.21(m,1H,Ar-H),5.32(d,J＝5.2Hz,1H,H-5),3.91–3.81(m, 1H,H-12),3.62(m,2H,H-21),2.73(m,1H,H-3),2.63(d,J＝12.8Hz, 1H,H-11),2.54–2.25(m,6H),2.20(s,6H,NCH3),1.78(d,J＝9.6Hz, 2H),1.70(s,3H,H-14),1.65–1.50(m,2H),1.28(s,3H,H-15).
Pharmacological experiments
Experimental example 1 in vitro antitumor assay of Sphaelactone derivatives
Determination of tumor cell survival rate by MTT method
Cells in logarithmic phase are digested with pancreatin to prepare single cell suspension with certain concentration, and according to the difference of cell growth speed, 3000 cells are inoculated into a 96-well plate at 1500-. The next day, fresh medium containing different concentrations of drug and corresponding solvent control was added, 100. mu.l per well (DMSO final concentration)<0.1%), 4 dose groups (0.05, 0.5, 5, 50 μmol/L) per test compound with three parallel wells per group. After further incubation for 96h at 37 ℃ with 5% CO2, the supernatant was discarded and 200. mu.L of freshly prepared serum-free medium containing 0.5mg/mL MTT was added to each well. Continuously culturing for 4h, removing supernatant, adding 200 μ L DMSO into each well to dissolve MTT formazan precipitate, shaking with a micro-oscillator, mixing, measuring Optical Density (OD) with an enzyme-labeling instrument at detection wavelength of 570nm, using solvent control-treated tumor cells as control group, calculating the inhibition rate of the drug on the tumor cells according to the following formula, and calculating IC according to the middle effect equation50：
The in vitro anti-tumor screening results of the derivatives are shown in tables 1, 2 and 3
TABLE 1 Michelolactone derivative MTT screening results
TABLE 2 Michelolactone derivative MTT screening results
HCT 116: a human colon cancer cell line; NCI-H1650: a human lung cancer cell line; MGC 803: human gastric cancer cell lines; HL-60: a human promyelocytic leukemia cell line; k562: human chronic myeloid leukemia cell line;
K562/A02: human chronic myeloid leukemia doxorubicin-resistant cell line; u-87 MG: human glioblastoma cell lines; HT 29: a human colon cancer cell line; MCF-7: a human breast cancer cell line; MCF-7/Taxol: human breast cancer cell strain with drug resistance to paclitaxel.
TABLE 3 Michelolactone derivative MTT screening results
SVGP 12: human brain glial cells (normal cells); u-87 MG: human glioblastoma cell lines; hs 683: human neuroblastoma cell line; u251: human glioblastoma cell lines; T98G: human glioblastoma cell lines; daoy: a human medulloblastoma cell line; SH-SY 5Y: a human neuroblastoma cell line; SK-N-SH: a human neuroblastoma cell line; HCT 116: a human colon cancer cell line; HepG 2: a human hepatoma cell line; BGC 823: human gastric cancer cell lines; NCI-H460: a human lung cancer cell line.
Experimental example 2 Sphaelactone derivatives against mouse liver cancer H in vivo22Effect
Mouse liver cancer transplantable tumor H22Experiment of
KM mice (16-18 g) and males are selected under aseptic condition, ascites tumor cells which grow well after 7 days of subculture are diluted by aseptic normal saline, and the cell density is adjusted to 5 multiplied by 1070.2ml of the seed/ml is inoculated to the axilla of the mouse. Randomly grouping and administering the medicines the next day, and orally administering the intragastric distilled water to a control group every day, wherein the intragastric administration is carried out once a day for each 20g of mice; CTX (Cyclophosphamide)Prepared into 6.0mg/ml, 0.2ml is injected into the abdominal cavity of each 20g mouse, and the administration is carried out for 1 time; the tested medicine components are respectively prepared into liquid medicine with the concentration of 5.0mg/ml, and the liquid medicine is administrated by intragastric administration of 0.4ml per 20g of mice, and is administrated once a day and continuously administrated for 9 days. At the end of the experiment, mice were sacrificed by dislocation, then the tumors were detached, weighed and photographed. And finally calculating the tumor inhibition rate.
The effect of the antitumor activity in vivo is shown in table 4 and fig. 2.
TABLE 4 Compound on mouse liver cancer H22Growth inhibition of
P <0.001, compared to the solvent control group.
Experimental example 3 in vivo anti-mouse ectopic glioma Effect of Sphaelactone derivative
Mouse ectopic glioma G422 experiment
KM mice (19-21G), male, well-grown G422 tumor tissue was harvested, minced, ground, and treated with sterile physiological saline at a ratio of 1: diluting the mixture in a proportion of 3 to prepare tumor cell suspension, and inoculating 0.2ml of tumor solution to the axillary back of each mouse. Animals were randomly assigned, weighed, and dosing was started the following day after inoculation. The solvent control group was gavaged with 0.4ml of sterile distilled water per 20g of mice 1 time a day for 11 days. TMZ (temozolomide) is prepared into 1.5mg/ml, the administration volume is 0.4ml per 20g of mice by intragastric administration, the administration is carried out for 1 time per day, the administration is carried out for 5 days continuously, the administration volume is 0.4ml per 20g of mice by intragastric administration and 4.0mg/ml are respectively prepared in example 3, and the administration is carried out for 1 time per day, and the administration is carried out for 11 days. At the end of the experiment, mice were sacrificed by dislocation, then the tumors were detached, weighed and photographed. And finally calculating the tumor inhibition rate. See tables 5, 6,7, 8, 9-1, 9-2.
Growth inhibition of mouse brain tumor G422 by Compounds of Table 5
P <0.001, compared to the solvent control group.
Growth inhibition of mouse brain tumor G422 by Compounds of Table 6
P <0.001, compared to the solvent control group.
TABLE 7 Effect of Compounds on spleen index and thymus index in brain tumor G422 mice
P <0.05, p <0.01, compared to the solvent control group.
TABLE 8 Effect of Compounds on peripheral blood count in brain tumor G422 mice
P <0.05, p <0.01, compared to the solvent control group;
WBC: white blood cell count
LYM%: lymphocyte ratio
MON%: monocyte fraction
NEUT%: neutrophil ratio
TABLE 9-1 Effect of Compounds on peripheral blood count in brain tumor G422 mice
TABLE 9 Effect of Compounds on peripheral blood count in brain tumor G422 mice
P <0.05, compared to solvent control group;
RBC: erythrocyte count
HGB: hemoglobin
HCT: hematocrit of red blood
MCV: mean volume of red blood cells
MCH: mean hemoglobin content of erythrocytes
MCHC: mean hemoglobin concentration of erythrocytes
RDW: width of distribution of red blood cells
TABLE 10 Effect of Compounds on peripheral blood count in brain tumor G422 mice
PLT: platelet count
PCT: specific area of blood platelet
MPV: mean volume of platelets
PDW: width of platelet volume distribution.
Claims (8)
1. A michelia lactone derivative and pharmaceutically acceptable salts thereof are characterized in that the compound is selected from the following compounds:
2. a process for the preparation of the michelia lactone derivative of claim 1, characterized in that the compound is prepared as follows:
r' is as defined in claim 1.
3. A pharmaceutical composition comprising the michelia lactone derivative of claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
4. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition is selected from the group consisting of an injection, a tablet, a capsule, a pill, and a powder.
5. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition is selected from the group consisting of controlled release dosage forms, sustained release dosage forms, and various microparticle delivery systems.
6. Use of the michelia lactone derivative and its pharmaceutically acceptable salts as claimed in claim 1 in the preparation of medicaments for preventing or treating tumors or inflammatory immune diseases.
7. The use according to claim 6, wherein said tumor is selected from the group consisting of non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, brain glioma.
8. Use according to claim 6, characterized in that said inflammatory immune diseases are selected from the group consisting of rheumatoid arthritis, diabetic nephropathy, and organ fibrosis.
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