CN115109058B - Medicine for treating gastric cancer and preparation method thereof - Google Patents
Medicine for treating gastric cancer and preparation method thereof Download PDFInfo
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- CN115109058B CN115109058B CN202210891387.9A CN202210891387A CN115109058B CN 115109058 B CN115109058 B CN 115109058B CN 202210891387 A CN202210891387 A CN 202210891387A CN 115109058 B CN115109058 B CN 115109058B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a medicine for treating gastric cancer and a preparation method thereof. The drug is a beta-carboline alkaloid derivative and has a structure shown in a formula (I). The beta-carboline alkaloid derivative has good gastric cancer cell proliferation inhibition activity, and therefore, can be used as a potential drug for treating gastric cancer.
Description
Technical Field
The invention relates to the field of medicines, in particular to a medicine for treating gastric cancer and a preparation method thereof.
Background
Gastric cancer is one of the most common malignant tumors in the world, and although the incidence and the mortality rate of gastric cancer are reduced in recent years, the incidence rate and the mortality rate of gastric cancer are still 5 th and 3 rd among all malignant tumors. Surgical operation is the only radical treatment means for gastric cancer, but more than 80% of gastric cancer patients are diagnosed at a late stage, most of the patients are accompanied by wide invasion and distant metastasis, the chance of radical operation is lost, and more comprehensive treatments including chemotherapy, radiotherapy, targeted therapy, immunotherapy and the like are needed at the moment. The chemotherapy medicine for gastric cancer comprises platinum compounds, fluoropyrimidines, taxoids, anthracyclines, irinotecan and the like, and has curative effects on the treatment of gastric cancer. Combination chemotherapy can extend the overall survival of patients more than single agent chemotherapy.
Carboline (carbolines) alkaloids are a large class of indole alkaloids widely distributed in the natural world, belong to one of non-monoterpene indole alkaloids derived from tryptophan, are a tricyclic system consisting of indolopyridine, and comprise alpha-carboline, beta-carboline, gamma-carboline and delta-carboline, wherein the beta-carboline (beta-carbolines) alkaloids are the carboline alkaloids which are widely distributed in the natural world, have relatively simple structures and are numerous in quantity and are most deeply researched. The reported natural beta-carboline alkaloids are as many as hundreds, are widely distributed in nature and comprise plants, marine organisms, blue-green algae, mushrooms and even animals, and representative compounds comprise harmine, demethylharmine and the like. Different beta-carboline alkaloids have different biological activities including anti-inflammatory, antibacterial, antiviral, antitumor, antimalarial, bactericidal, GABAA, 5-HT2serotonin, imidazoline receptor binding activity, PDE5 receptor inhibitory activity and the like.
Disclosure of Invention
The invention provides a novel beta-carboline alkaloid derivative based on the existing beta-carboline alkaloid, which has good gastric cancer cell proliferation inhibition activity and can be used for treating gastric cancer.
The invention provides a compound shown as a formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof:
wherein R is 0 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, amino, hydroxy, C1-6 alkyl, C1-C6 alkoxy, haloC 1-C6 alkyl, substituted or unsubstituted C6-C14 aryl;
R 1 、R 2 independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, halogenated C1-C6 alkyl, and R 1 、R 2 At least one of which is not hydrogen; or R 1 、R 2 Together form- (CH) 2 ) n -；
R 3 Selected from C1-C6 alkyl, substituted or unsubstituted C6-C14 aryl-C1-2 alkylene;
l is selected from C1-C6 alkylene;
het is selected from substituted or unsubstituted 5-10 membered heteroaryl;
m is selected from 1, 2, 3, 4 or 5;
n is selected from 2, 3, 4, 5 or 6.
In some preferred embodiments, R 0 Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, amino, hydroxyl, methyl, ethyl, isopropylTert-butyl, methoxy, ethoxy, trifluoromethyl, phenyl.
Preferably, R 0 Selected from hydrogen.
In some preferred embodiments, R 1 、R 2 Independently selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, t-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and R 1 、R 2 At least one of which is not hydrogen; or R 1 、R 2 Together form-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -。
Preferably, R 1 Selected from hydrogen, methyl, R 2 Selected from methyl, isopropyl, cyclopropyl; or R 1 、R 2 Together form-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -。
Preferably, R 1 Selected from hydrogen, R 2 Selected from isopropyl, cyclopropyl; or R 1 Selected from methyl, R 2 Is selected from methyl; or R 1 、R 2 Together form-CH 2 CH 2 CH 2 CH 2 CH 2 -。
In some preferred embodiments, R 3 Selected from methyl, ethyl, phenyl, benzyl.
Preferably, R 3 Selected from methyl and ethyl.
In some preferred embodiments, L is selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -。
Preferably, L is selected from-CH 2 -、-CH 2 CH 2 -。
In some preferred embodiments, het is selected from substituted or unsubstituted 5-7 membered heteroaryl, and "substituted or unsubstituted" means unsubstituted or substituted with a group selected from deuterium, halogen, cyano, nitro, amino, hydroxy, C1-4 alkyl, C1-C4 alkoxy, haloC 1-C4 alkyl.
Preferably, het is selected from substituted or unsubstituted: oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" means unsubstituted or substituted with 1-3 groups selected from deuterium, fluoro, chloro, bromo, cyano, nitro, amino, hydroxy, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, trifluoromethyl.
More preferably, het is selected from substituted or unsubstituted: isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" meaning unsubstituted or substituted by 1 to 3 groups selected from fluorine, chlorine, methyl, ethyl, isopropyl, n-propyl, trifluoromethyl.
In the present invention, the "substituted or unsubstituted" means unsubstituted or substituted by a group selected from: deuterium, halogen, cyano, nitro, amino, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, haloC 1-C4 alkyl.
Preferably, the "substituted or unsubstituted" means unsubstituted or substituted by a group selected from: deuterium, fluoro, chloro, bromo, cyano, nitro, amino, hydroxy, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, trifluoromethyl.
In some preferred embodiments, the compound of formula (I) has the structure of formula (II) below:
wherein R is 1 、R 2 Independently selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and R 1 、R 2 Is not hydrogen; or R 1 、R 2 Together form-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -；
R 3 Selected from methyl, ethyl, phenyl, benzyl;
l is selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -；
Het is selected from substituted or unsubstituted: oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" meaning unsubstituted or substituted with 1-3 groups selected from deuterium, fluoro, chloro, bromo, cyano, nitro, amino, hydroxy, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, trifluoromethyl.
In some preferred embodiments, R 1 Selected from hydrogen, methyl, R 2 Selected from methyl, isopropyl, cyclopropyl; or R 1 、R 2 Together form-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -；
R 3 Selected from methyl, ethyl;
l is selected from-CH 2 -、-CH 2 CH 2 -；
Het is selected from substituted or unsubstituted: isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" meaning unsubstituted or substituted by 1 to 3 groups selected from fluorine, chlorine, methyl, ethyl, isopropyl, n-propyl, trifluoromethyl.
In some preferred embodiments, the compound of formula (I) is selected from:
in the present invention, the term "halogen" means fluorine, chlorine, bromine and iodine. The term "halo" means substituted with fluoro, chloro, bromo or iodo.
In the present invention, the term "heteroaryl" refers to any aromatic ring structure containing at least 1 heteroatom selected from O, N and S, optionally 1 to 3 additional heteroatoms independently selected from O, N and S. The heteroaryl group may be monocyclic (e.g., a 5-6 membered monocyclic heteroaryl group), or bicyclic (e.g., a 9-10 membered bicyclic heteroaryl group), and may be attached to any of the N or C atoms of the ring so as to form a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, indolizinyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
For use in medicine, the term "pharmaceutically acceptable salt" in the present invention includes acid addition salts, which are formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid. Representative pharmaceutically acceptable salts include the following: hydrochloride, dihydrochloride, hydrobromide, nitrate, bisulfate, sulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, carbonate, bicarbonate, borate, acetate, benzenesulfonate, benzoate, bitartrate, camphorsulfonate, clavulanate, citrate, edetate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, hydroxynaphthoate, isothionate, lactate, lactobionate, laurate, malate, maleate, fumarate, succinate, mandelate, methanesulfonate, naphthalenesulfonate, oleate, palmitate, pantothenate, polygalacturonate, salicylate, stearate, tannate, tosylate, and valerate.
When the compounds of the invention have at least 1 chiral center, they may accordingly exist in enantiomeric form. When the compounds have 2 or more chiral centers, they may accordingly exist in diastereomeric forms. It is to be understood that all such stereoisomers and mixtures thereof are included within the scope of the present invention.
In the present invention, the term "tautomer" refers to structural isomers of different energies that are converted to each other via a low energy barrier. The compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.
In the present invention, the term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid.
In the present invention, the term "prodrug" refers to a functional derivative of a compound of the present invention, which is readily converted in vivo to the desired compound. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", h.bundgaard, elsevier, 1985.
Another aspect of the present invention is to provide a pharmaceutical composition comprising a compound represented by formula (I), pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof.
In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.
Typical pharmaceutical compositions are: powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections, sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches and the like.
The term "excipient" refers to: anti-adhesion agent, antioxidant, adhesive, coating agent, tabletting auxiliary agent, disintegrating agent, lubricating agent, emulsifying agent and the like. Typical excipients include: starch, calcium carbonate, calcium phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, polyethylene glycol, sodium citrate, sorbitol, stearic acid, sucrose, talc, titanium dioxide, and the like.
The daily dosage of the compounds of the invention may vary widely, for example from 0.01 to 1000mg per adult per day. For oral administration, it is preferred to provide the composition in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The effective amount of the drug is typically provided at a dosage level of about 0.01mg/kg to about 300mg/kg of body weight per day. Preferably, the range is from about 0.5 to about 5.0mg/kg body weight per day, most preferably from about 1.0 to about 3.0mg/kg body weight per day. The present compounds may be administered 1-4 times per day according to a dosing regimen.
The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound employed, the mode of administration, the strength of the formulation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and number of administrations, will result in the need to adjust the dosage.
The invention also provides a pharmaceutical composition, which is a pharmaceutical product and can comprise the compound shown in the formula (I), pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof, and other agents which can be used for treating cancer or are helpful for treating cancer.
The invention discovers that the compound has excellent inhibitory activity on the proliferation of tumor cells, particularly gastric cancer cells, such as SGC-7901, NCI-N87, AGS and the like, and is even stronger than a positive control drug.
Therefore, the invention also provides the application of the compound shown in the formula (I), the pharmaceutically acceptable salt, the stereoisomer, the tautomer, the solvate and the prodrug thereof in preparing medicaments for resisting tumors.
Preferably, the medicament is for the treatment of gastric cancer.
The invention also provides a method for preparing the compound shown in the formula (I) in the invention, which comprises the following steps:
condensing the compound a and the compound b in glacial acetic acid to generate an intermediate c, carrying out esterification reaction on the intermediate c and the compound d to generate an intermediate e, and reacting the intermediate e with the intermediate f to generate the compound shown in the formula (I);
wherein R is 0 -R 3 L, het, m are as defined herein.
Advantageous effects
The invention provides a medicine for treating gastric cancer and a preparation method thereof. The medicament is a beta-carboline alkaloid derivative, has good gastric cancer cell (SGC-7901, NCI-N87 and AGS) proliferation inhibition activity, and can be used as a potential medicament for treating gastric cancer.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications.
Example 1: preparation of Compound 1
To a round-bottomed flask was added compound 1-a (4.08g, 20mmol), and 30ml of glacial acetic acid was further added, and dissolved with stirring, and heated to reflux, and then compound 1-b (15 ml) was slowly added dropwise with stirring, and the reaction was refluxed until completion (TLC monitoring). Concentrated to dryness under reduced pressure and the residue recrystallized from methanol-cyclohexane (5).
To a round-bottomed flask, intermediate 1-c (2.56g, 10mmol) was added, 100ml of anhydrous ethanol was further added, the mixture was stirred to dissolve, the mixture was ice-cooled to 0 to 5 ℃ and SOCl was slowly added dropwise at that temperature 2 (1.43g, 12mmol), removal of the ice bath after the dropwise addition was complete and vigorous stirring for 4h, removal of the solvent and excess SOCl in vacuo 2 And the obtained intermediate 1-e is directly put into the next step.
To intermediate 1-e was added 65ml of anhydrous dichloromethane, and then 2ml of triethylamine was added, and while stirring, compound 1-f (1.93g, 10mmol) was added in portions, and the reaction mixture was stirred at room temperature for 15 hours. Diluted with 50ml of dichloromethane and washed with 120ml of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent removed in vacuo, and the residue chromatographed on silica gel, eluting with a volume gradient of 0.
HR-ESI-MS m/z 441.1580[M+H] + (theoretical value)441.1597)。
Elemental analysis: c 22 H 24 N 4 O 4 S measured value: c,59.92; h,5.47; n,12.70; o,14.43; s,7.38 (theoretical values: C, 59.98H, 5.49N, 12.72O, 14.53.
1 H NMR(400MHz,DMSO-d 6 )δ9.61(s,1H),8.63(d,J＝7.0Hz,2H),7.51(d,J＝7.1Hz,1H),7.35(d,J＝7.2Hz,1H),7.19(t,J＝7.0Hz,1H),7.14–7.02(m,2H),5.19(d,J＝6.8Hz,1H),4.85–4.72(m,3H),4.12(q,J＝6.4Hz,2H),3.19–3.05(m,2H),2.22(dp,J＝6.8,5.6Hz,1H),1.23(t,J＝6.4Hz,3H),0.63–0.42(m,4H)。
Example 2: preparation of Compound 2
To a round-bottomed flask was added compound 1-a (4.08g, 20mmol), and 30ml of glacial acetic acid was further added, and dissolved with stirring, and heated to reflux, and then compound 2-b (20 ml) was slowly added dropwise with stirring, and the reaction was refluxed until completion (TLC monitoring). Concentrated to dryness under reduced pressure, and the residue was recrystallized from methanol to give intermediate 2-c (4.4 g, 77%).
To a round-bottomed flask, intermediate 2-c (2.84g, 10mmol) was added, 120ml of anhydrous ethanol was further added, the mixture was dissolved by stirring, the mixture was ice-cooled to 0 to 5 ℃ and SOCl was slowly added dropwise at that temperature 2 (1.43g, 12mmol), removal of the ice bath after the dropwise addition was complete and vigorous stirring for 4h, removal of the solvent and excess SOCl in vacuo 2 And the obtained intermediate 2-e is directly put into the next step.
To intermediate 2-e was added 80ml of anhydrous dichloromethane, and then 2ml of triethylamine was added, and while stirring, compound 1-f (1.93g, 10mmol) was added in portions, and the reaction mixture was stirred at room temperature for 18 hours. Diluted with 60ml of dichloromethane and washed with 120ml of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent removed in vacuo, and the residue chromatographed on silica gel, eluting with a volume gradient of 0 to 35 of ethyl acetate: petroleum ether, to give compound 2 (3.75g, 80%) as a pale yellow solid.
HR-ESI-MS m/z 469.1922[M+H] + (theoretical 469.1910).
Elemental analysis: c 24 H 28 N 4 O 4 S measured value: c,61.58; h,6.05; n,11.99; o,13.76; s,6.69 (theoretical values: C, 61.52H, 6.02N, 11.96O, 13.66S, 6.84.
1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),8.63(d,J＝7.0Hz,2H),7.47–7.38(m,2H),7.19(t,J＝7.1Hz,1H),7.15–7.03(m,2H),4.76(s,2H),4.71(t,J＝8.6Hz,1H),4.12(q,J＝6.4Hz,2H),3.17–3.02(m,2H),2.20(m,2H),2.02–1.91(m,2H),1.88–1.74(m,4H),1.55–1.38(m,2H),1.23(t,J＝6.4Hz,3H)。
Example 3: preparation of Compound 3
Compound 3 was obtained in the same manner as in example 1 except that 3-b was used in place of 1-b and 3-f was used in place of 1-f.
HR-ESI-MS m/z 463.1225[M+H] + (theoretical 463.1207).
Elemental analysis: c 21 H 23 ClN 4 O 4 S measured value: c,54.39; h,5.05; cl,7.60; n,12.14; o,13.93; s,6.90 (theory: C, 54.48H, 5.01 Cl, 7.66N, 12.10O, 13.82, S, 6.93.
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.07(s,2H),7.49–7.40(m,2H),7.17–7.05(m,2H),4.80(s,2H),4.73(t,J＝8.6Hz,1H),4.12(q,J＝6.4Hz,2H),3.17–3.02(m,2H),1.78(s,3H),1.73(s,3H),1.23(t,J＝6.4Hz,3H)。
Example 4: preparation of Compound 4
Compound 4 is obtained by the same procedures as in example 1 except for using 3-b in place of 1-b and 4-f in place of 1-f.
HR-ESI-MS m/z 463.1225[M+H] + (theoretical value 442.1801).
Elemental analysis: c 23 H 27 N 3 O 4 S measured value: c,62.63; h,6.19; n,9.54; o,14.38; s,7.20 (theoretical values: C, 62.56H, 6.16N, 9.52O, 14.49S, 7.26.
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.43-8.41(m,2H),7.54(d,J＝7.7,1H),7.49–7.40(m,2H),7.29–7.22(m,1H),7.17–7.05(m,2H),4.72(t,J＝8.6Hz,1H),4.12(q,J＝6.4Hz,2H),3.60–3.42(m,2H),3.16–2.94(m,4H),1.78(s,3H),1.73(s,3H),1.23(t,J＝6.4Hz,3H)。
Example 5: preparation of Compound 5
Compound 5 is obtained in the same manner as in example 1 except that 2-b is used in place of 1-b and 5-f is used in place of 1-f.
HR-ESI-MS m/z 458.1770[M+H] + (theoretical 458.1750).
Elemental analysis: c 23 H 27 N 3 O 5 S measured value: c,60.35; h,5.96; n,9.23; o,17.44; s,7.06 (theoretical: C, 60.38H, 9.18O, 17.48S, 7.01.
1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),8.61(d,J＝7.2Hz,1H),7.47–7.38(m,2H),7.15–7.03(m,2H),6.53(d,J＝7.2Hz,1H),4.76(t,J＝8.6Hz,1H),4.65–4.56(m,2H),4.12(q,J＝6.4Hz,2H),3.17–3.02(m,2H),2.20(m,2H),2.02–1.91(m,2H),1.88–1.74(m,4H),1.56–1.37(m,2H),1.23(t,J＝6.4Hz,3H)。
Example 6: preparation of Compound 6
Compound 6 is obtained by the same procedures as in example 1 except for using 6-b in place of 1-b and 6-f in place of 1-f.
HR-ESI-MS m/z 491.1535[M+H] + (theoretical value 491.1520).
Elemental analysis: c 23 H 27 ClN 4 O 4 S measured value: c,56.28; h,5.55; cl,7.17; n,11.40; o,13.09; s,6.43 (theoretical values: C, 56.26H, 5.54 Cl, 7.22N, 11.41O, 13.03S, 6.53.
1 H NMR(400MHz,DMSO-d 6 )δ9.29(s,1H),7.48(d,J＝7.2Hz,1H),7.31(d,J＝7.2Hz,1H),7.12–7.00(m,2H),6.84(s,1H),5.26(d,J＝7.4Hz,1H),4.79(s,2H),4.74(t,J＝8.6Hz,1H),4.12(q,J＝6.4Hz,2H),3.19–3.05(m,2H),2.38(s,3H),2.13(septet,J＝6.6Hz,1H),1.23(d,J＝8.6Hz,3H),0.97(d,J＝6.6Hz,6H)。
The drug effect example: MTT method for testing activity of inhibiting gastric cancer cells
Returning liquid and passaging SGC-7901, NCI-N87 and AGS cells (from Shanghai Life sciences research institute cell bank of Chinese academy of sciences) according to conventional tumor cell culture method, collecting cell strains in logarithmic growth phase, inoculating to 96-well culture plate, wherein the cell number in each well is 1.0 × 10 5 Per100. Mu.L, then put at 5% CO 2 Culturing in an incubator, removing the culture medium the next day, adding 100 μ L of drugs with different concentrations (drug concentration adopts double dilution), setting 3 parallel samples for each drug, adding no drug in a negative control group, taking 5-fluorouracil (5-FU) as a positive control, adding 10 μ L of MTT into each well after 48h, continuing culturing for 4h, adding 100 μ L of DMSO into each well to terminate the reaction, standing for 1h at normal temperature, detecting the absorbance OD value of each well at 570nm by using an microplate reader, and calculating the cell growth inhibition rate (%) = [ (OD) = Control -OD Experiment of )/(OD Control -OD Blank space )]X 100%). Fitting the obtained cell growth inhibition rate with SPSS 22.0 to obtain half inhibition rate IC of different drugs on SGC-7901, NCI-N87 and AGS cell growth 50 . The results are shown in table 1 below:
table 1: gastric cancer cell proliferation inhibitory Activity
As shown in Table 1, the compounds of the present invention have excellent inhibitory activity on proliferation of gastric cancer cells (SGC-7901, NCI-N87, AGS), particularly R 1 、R 2 Compounds 2 and 5 of the present invention, which together form cyclohexane, have better inhibitory activity.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (8)
1. A compound of formula (I), pharmaceutically acceptable salts, stereoisomers and tautomers thereof:
wherein R is 0 Independently selected from hydrogen;
R 1 、R 2 independently selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, cyclopropyl, cyclobutyl, and R 1 、R 2 At least one of which is not hydrogen; or R 1 、R 2 Together form-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -；
R 3 Selected from methyl, ethyl;
l is selected from-CH 2 -、-CH 2 CH 2 -；
Het is selected from substituted or unsubstituted: isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" meaning unsubstituted or substituted with 1 to 3 groups selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, n-propyl, methoxy, ethoxy, trifluoromethyl;
m is selected from 1, 2, 3 or 4.
2. The compound of formula (I), pharmaceutically acceptable salts, stereoisomers and tautomers thereof according to claim 1, wherein R is 1 Selected from hydrogen, methyl, R 2 Selected from methyl, isopropyl, cyclopropyl.
3. The compound of formula (I), pharmaceutically acceptable salts, stereoisomers and tautomers thereof according to claim 1, wherein said compound of formula (I) has the structure represented by the following formula (II):
wherein R is 1 、R 2 Independently selected from hydrogen, methyl, isopropyl, cyclopropyl, and R 1 、R 2 At least one of which is not hydrogen; or R 1 、R 2 Together form-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -；
R 3 Selected from methyl, ethyl;
l is selected from-CH 2 -、-CH 2 CH 2 -；
Het is selected from substituted or unsubstituted: isoxazolyl, pyridyl, pyrimidinyl, said "substituted or unsubstituted" meaning unsubstituted or substituted by 1 to 3 groups selected from deuterium, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl.
4. The compound of formula (I), pharmaceutically acceptable salts, stereoisomers and tautomers thereof according to claim 1, wherein said compound of formula (I) is selected from the group consisting of:
5. a pharmaceutical composition comprising a compound according to any one of claims 1-4, pharmaceutically acceptable salts, stereoisomers and tautomers thereof.
6. Use of a compound according to any one of claims 1-4, pharmaceutically acceptable salts, stereoisomers and tautomers thereof, for the preparation of a medicament for anti-tumor.
7. The use according to claim 6, wherein the medicament is for the treatment of gastric cancer.
8. A process for the preparation of a compound of formula (I) as claimed in claim 1, comprising the steps of:
condensing the compound a and the compound b in glacial acetic acid to generate an intermediate c, carrying out esterification reaction on the intermediate c and the compound d to generate an intermediate e, and reacting the intermediate e with the intermediate f to generate the compound shown in the formula (I);
wherein R is 0 -R 3 L, het, m are as defined in claim 1.
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