CN115572247B - Vitamin K 3 Derivatives and medical use thereof - Google Patents
Vitamin K 3 Derivatives and medical use thereof Download PDFInfo
- Publication number
- CN115572247B CN115572247B CN202211290172.8A CN202211290172A CN115572247B CN 115572247 B CN115572247 B CN 115572247B CN 202211290172 A CN202211290172 A CN 202211290172A CN 115572247 B CN115572247 B CN 115572247B
- Authority
- CN
- China
- Prior art keywords
- vitamin
- pharmaceutically acceptable
- derivative
- acceptable salt
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses vitamin K shown in formula I 3 Derivatives or pharmaceutically acceptable salts or esters thereof, R 1 Selected from hydrogen, fluorine, bromine, methyl, tert-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is R 2 Is methyl. Pharmacological experiments prove that the compound or pharmaceutically acceptable salt or ester thereof can achieve the purpose of resisting tumor by inhibiting proliferation of tumor cells and inducing apoptosis of the tumor cells, has an anti-tumor effect, has lower toxicity to normal cells and has better safety. The invention also discloses the vitamin K 3 The application of the derivative or the pharmaceutically acceptable salt or ester thereof in preparing STAT3 inhibitor or preparing tumor prevention and/or treatment medicine.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and relates to a vitamin K 3 The derivative and the medical application thereof in preparing STAT3 small molecule inhibitors and preparing medicines for treating tumors.
Background
Signal transduction and transcription activator (STATs) is a family of cytoplasmic transcription factor proteins responsible for signal transduction of extracellular cytokines and growth factors and for initiating transcription of downstream genes. Among them, STAT3 (signal transduction and transcription activator 3) is a transcription factor involved in regulating physiological activities such as cell proliferation, apoptosis, invasion, migration and immune response, and its abnormal activation plays an important role in the development and progression of tumors. At present, abnormal or constitutively activated STAT3 proteins have been observed in many different types of cancers, and the activated STAT3 proteins enter the nucleus to promote expression of various anti-apoptotic protein genes, thereby supporting the development and progression of tumors. The target has become an important anti-tumor target.
Upon binding of cytokines or growth factors to surface receptors, a cascade of reactions occurs through the JAK-STAT3 pathway. JAK kinases phosphorylate the pTyr705 residue of STAT3 monomers, and the two phosphorylated STAT3 monomers bind at the pTyr705-SH2 domain and form a dimeric complex of STAT3, which then enters the nucleus, inducing expression of the relevant tumor genes, thus the pTyr705-SH2 domain plays a key role in the overall pathway.
However, existing small molecule SH2 domain inhibitors have had insufficient activity or no statistically different distress compared to positive control. Therefore, the design and synthesis of novel small molecule SH2 domain inhibitors plays an important role in blocking the JAK-STAT3 cell pathway.
Disclosure of Invention
The SH2 domain of STAT3 plays a key role in activating STAT3 recruitment and formation of STAT3 homodimers and STAT3/DNA complex formation. The object of the present invention is to provide a potent STAT3 inhibitor against the SH2 domain of STAT 3.
The invention aims at realizing the following technical scheme:
vitamin K with structure shown in formula I 3 A derivative or a pharmaceutically acceptable salt or ester thereof:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl,Halogen substituted C1-C4 alkyl, hydroxy, C1-C3 alkoxy, halogen substituted C1-C4 alkoxy, cyano, nitro, amino, - (CH) 2 ) n COOH, aromatic, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-2 hetero atoms; n is an integer of 0 to 2; the heteroatom is selected from N, O, S;
R 2 selected from the group consisting of hydrogen, halogen, amino, methylamino, ethylamino, C1-C3 alkyl, C1-C3 alkoxy.
Preferably, R 1 Selected from hydrogen, fluorine, bromine, methyl, tert-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is R 2 Is methyl.
More preferably, R 1 Selected from fluorine, trifluoromethyl, methoxy, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is R 2 Is methyl.
Halogen means fluorine, chlorine, bromine or iodine.
In particular, said vitamin K 3 The derivative is selected from:
as the most preferable technical scheme of the invention, vitamin K 3 The structural formula of the derivative is as follows:
chemical name: 2- (3- ((3-methyl-1, 4-dioxo-8-sulphonamido-1, 4-dihydronaphthalen-2-yl) methyl) phenyl) acetic acid;
chemical name: 3- ((3-methyl-1, 4-dioxo-8-sulphonamido-1, 4-dihydronaphthalen-2-yl) methyl) benzoic acid.
Said vitamin K 3 Pharmaceutically acceptable salts of the derivatives are sodium salts and hydrochloride salts.
Said vitamin K 3 Pharmaceutically acceptable esters of the derivatives are methyl ester, ethyl ester and tert-butyl ester.
Pharmacological experiments prove that the vitamin K provided by the invention 3 The derivative can inhibit proliferation of tumor cells and induce apoptosis of tumor cells to achieve the purpose of resisting tumor, has anti-tumor effect, and has low toxicity to normal cells. In particular, the compounds CH3-3 and CH3-10 have strong growth inhibition effect on lung cancer cells A549, and have better safety.
Another object of the present invention is to provide said vitamin K 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the preparation of a STAT3 inhibitor.
Another object of the present invention is to provide said vitamin K 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for the prevention and/or treatment of a tumour.
The tumor is lung cancer.
Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of vitamin K 3 A derivative or a pharmaceutically acceptable salt or ester thereof.
Drawings
FIG. 1 is an IC of compound CH3-3 against A549 cells 50 。
FIG. 2 is a graph showing the IC of compound CH3-9 against A549 cells 50 。
FIG. 3 shows the survival rate of MCF-10A cells treated with 10. Mu.M of compounds CH3-1 to CH 3-9.
Detailed Description
In order to further clarify the technical solution of the present invention, a series of examples are given below, which are purely illustrative and are intended to be a specific description of the invention and should not be interpreted as limiting the same.
Example 1
1) Preparation of 1-naphthalenesulfonamide
1-naphthalenesulfonyl chloride (10 g,21.9 mmol) was added to a 1L round-bottom flask containing 40mL of tetrahydrofuran, stirred, 15mL of aqueous ammonia (25% -28% strength) at 0 ℃ was added dropwise to an ice bath, after the addition was completed, the reaction was followed by thin layer chromatography, after the completion of the reaction, ammonia gas decomposed from the organic solvent and aqueous ammonia was distilled off under reduced pressure, a solid was precipitated, filtered, and dried under vacuum to give 1-naphthalenesulfonamide (8.70 g, yield 96.7%), which was used directly for the next reaction without further purification.
1 H NMR(400MHz,DMSO-d 6 )δ8.65(d,J＝8.3Hz,1H,Ar-H),8.20(d,J＝8.2Hz,1H,Ar-H),8.17–8.06(m,2H,Ar-H),7.75–7.69(m,1H,Ar-H),7.69–7.68(m,1H,Ar-H),7.67(d,J＝3.9Hz,2H,NH 2 ),7.63(d,J＝7.9Hz,1H,Ar-H).
2) Preparation of 5, 8-dioxo-dihydronaphthalene-1-sulfonamide
Anhydrous ceric sulfate (160 g,677.45 mmol) was dissolved in 750mL of dilute sulfuric acid with a concentration of 2mol/L, and the temperature was controlled at 65 ℃; 1-naphthalene sulfonamide (8.70 g,41.98 mmol) was added to a 500mL round bottom flask containing 200mL acetonitrile, the temperature was controlled at 65 ℃, stirring was performed, the mixture was slowly added dropwise to a ceric sulfate aqueous phase system, the reaction was stopped after 20 minutes from the start of the dropwise addition, after cooling the reaction solution, filtration was performed, the filtrate was extracted with 1200mL dichloromethane, drying was performed, and then low pressure rotary evaporation was performed after drying to obtain a pale yellow solid, and vacuum drying was performed, to obtain 5, 8-dioxo-dihydronaphthalene-1-sulfonamide (5.85 g, yield 58.43%) which was directly used in the next reaction without purification.
1 H NMR(300MHz,DMSO-d 6 )δ8.45(d,J＝9.2Hz,1H,Ar-H),8.28(d,J＝8.9Hz,1H,Ar-H),8.06(t,J＝7.8Hz,1H,Ar-H),7.38(s,2H,NH 2 ),7.23–7.10(m,2H,Ar-H).
3) Synthesis of 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide
3g of 5, 8-dioxo-dihydronaphthalene-1-sulfonamide and 1.37mL of glacial acetic acid are taken and dissolved in 120mL of a mixed solution of acetonitrile and dichloromethane (the volume ratio of acetonitrile to dichloromethane is 1:1), an aqueous solution 120mL containing 233mg of silver nitrate and 6.25g of ammonium persulfate is rapidly added dropwise, the mixture is refluxed and stirred at 80 ℃ for 4 hours, and the reaction is monitored by thin layer chromatography. After the reaction, the aqueous phase was extracted with 450mL of dichloro, the organic layer was washed once with water and saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, suction filtered, and rotary distilled under reduced pressure to give a tan powdery solid, which was purified by beating with methanol to give 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (2.6 g, yield 58.56%).
1 H NMR(300MHz,Chloroform-d)δ8.58(d,J＝8.0Hz,1H,Ar-H),8.40(d,J＝7.9Hz,1H,Ar-H),7.92(t,J＝7.8Hz,1H,Ar-H),6.93(s,1H,Ar-H),5.96(s,2H,NH 2 ),2.28(s,3H,CH 3 ).
4) Synthesis of 7- (3-methoxybenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-1)
300mg of 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide and 1.59mmol of m-methoxyphenylacetic acid are dissolved in 30mL of a mixed solution of acetonitrile and dichloromethane (the volume ratio of acetonitrile to dichloromethane is 1:1), 30mL of an aqueous solution containing 13.52mg of silver nitrate and 363.28mg of ammonium persulfate is rapidly added dropwise, the mixture is stirred at 80 ℃ under reflux for 4 hours, and the reaction is monitored by thin layer chromatography. After the reaction, the aqueous phase was extracted with 150ml of dichloro, the organic layer was washed once with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered off with suction, and evaporated under reduced pressure to give a pale yellow powdery solid, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1v/V) to give compound CH3-1 (yield 14.21%).
1 H NMR(300MHz,DMSO-d 6 )δ8.49–8.38(m,1H),8.35–8.23(m,1H),8.01(t,J＝7.9Hz,1H),7.38(s,2H),7.18(t,J＝7.8Hz,1H),6.87–6.69(m,3H),3.96(s,2H),3.71(s,3H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.96,183.58,159.83,146.16,143.72,142.86,139.91,134.33,134.11,133.78,130.57,130.04,129.79,120.95,114.82,111.90,55.40,32.00,13.98。
Example 2
Synthesis of 7- (3-methylbenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-2)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar m-methylphenylacetic acid to give compound CH3-2 in 47.13% yield as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.30(dd,J＝7.8,1.4Hz,1H),8.01(t,J＝7.9Hz,1H),7.39(s,2H),7.15(t,J＝7.5Hz,1H),7.01(dd,J＝13.0,6.2Hz,3H),3.95(s,2H),2.24(s,3H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.97,183.55,146.06,143.94,142.87,138.30,138.15,134.34,134.10,133.79,130.59,129.77,129.39,128.89,127.38,125.88,31.97,21.47,13.98。
Example 3
Synthesis of 2- (3- ((3-methyl-1, 4-dioxo-8-sulphonamido-1, 4-dihydronaphthalen-2-yl) methyl) phenyl) acetic acid (Compound CH 3-3)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 1, 3-benzenediacetic acid to give compound CH3-3 in 45.76% yield as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ12.30(s,1H),8.42(dd,J＝7.9,1.3Hz,1H),8.30(dd,J＝7.8,1.4Hz,1H),8.01(t,J＝7.9Hz,1H),7.38(s,2H),7.20(d,J＝7.5Hz,1H),7.16–7.01(m,3H),3.98(s,2H),3.52(s,2H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.94,183.54,173.15,146.17,143.81,142.88,138.31,135.77,134.35,134.11,133.80,130.60,129.85,129.76,128.92,127.82,127.06,31.93,13.97。
Example 4
Synthesis of 7- (3-cyanobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-4)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-cyanophenylacetic acid to give compound CH3-4 in 37.53% yield as a pale yellow powdered solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.4Hz,1H),8.28(dd,J＝7.8,1.4Hz,1H),8.00(t,J＝7.9Hz,1H),7.75(d,J＝1.8Hz,1H),7.65(ddt,J＝14.1,8.0,1.4Hz,2H),7.54–7.35(m,3H),4.05(s,2H),2.16(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.82,183.54,146.91,142.87,142.55,140.26,134.27,134.24,133.97,133.71,132.23,130.63,130.53,130.10,129.87,119.30,111.94,31.70,14.04。
Example 5
Synthesis of 7- (3-trifluoromethoxybenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-5)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-trifluoromethoxyphenylacetic acid to give compound CH3-5 in a yield of 38.56% as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.40(d,J＝6.7Hz,3H),7.28(dd,J＝7.7,1.5Hz,2H),7.23–7.16(m,1H),4.05(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.85,183.56,148.97,148.95,146.66,142.92,142.88,141.30,134.30,134.18,133.76,130.82,130.54,129.83,127.91,121.53,119.15,31.74,13.98。
Example 6
Synthesis of 7- (3-nitrobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-6)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-nitrophenylacetic acid, to give compound CH3-6 in 33.73% yield as a pale yellow powdered solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.30(dd,J＝7.8,1.3Hz,1H),8.14(t,J＝2.0Hz,1H),8.09–7.98(m,2H),7.72(dt,J＝7.8,1.4Hz,1H),7.57(t,J＝7.9Hz,1H),7.39(s,2H),4.14(s,2H),2.20(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.82,183.56,148.36,146.80,142.90,142.70,140.84,135.67,134.33,134.18,133.79,130.56,130.42,129.83,123.66,121.82,31.76,14.08。
Example 7
Synthesis of 7- (3-bromobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-7)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-bromophenylacetic acid, and compound CH3-7 was obtained in 36.34% yield as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.48(d,J＝2.2Hz,1H),7.39(d,J＝7.1Hz,3H),7.30–7.18(m,2H),4.00(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.86,183.54,146.57,143.02,142.87,141.33,134.29,134.18,133.76,131.53,131.10,130.56,129.83,129.66,127.92,122.29,31.72,14.03。
Example 8
Synthesis of 7- (3-trifluoromethylbenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-8)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-trifluoromethylphenylacetic acid to give compound CH3-8 in a yield of 37.20% as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.66(d,J＝2.2Hz,1H),7.60–7.47(m,3H),7.39(s,2H),4.10(s,2H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.85,183.60,146.67,142.95,142.88,140.04,134.30,134.20,133.77,132.89,130.55,130.02,129.84,129.43,126.49,125.56,125.51,123.54,31.89,14.04。
Example 9
Synthesis of 7- (3-fluorobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-9)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-fluorophenylacetic acid, and compound CH3-9 was obtained in a yield of 39.87% as a pale yellow powdery solid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.44–7.27(m,3H),7.15–6.97(m,3H),4.01(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.88,183.54,164.36,161.14,146.57,143.07,142.86,141.39,141.29,134.29,134.17,133.76,130.86,130.75,130.56,129.83,124.96,124.92,115.76,115.48,113.66,113.39,31.76,13.99。
Example 10
Synthesis of 3- ((3-methyl-1, 4-dioxo-8-sulphonamido-1, 4-dihydronaphthalen-2-yl) methyl) benzoic acid (Compound CH 3-10)
Referring to the synthesis of compound CH3-1 of example 1, only m-methoxyphenylacetic acid was replaced with equimolar 3-carboxymethylphenylacetic acid to give compound CH3-10 in 40.25% yield as a pale yellow powdered solid.
1 H NMR(300MHz,DMSO-d 6 )δ12.96(s,1H),8.42(d,J＝7.9Hz,1H),8.30(d,J＝7.7Hz,1H),8.01(t,J＝7.9Hz,1H),7.77(d,J＝7.6Hz,2H),7.49(d,J＝7.7Hz,1H),7.44–7.30(m,3H),4.06(s,2H),2.20(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.90,183.55,167.70,146.33,143.51,142.91,139.00,134.38,134.08,133.84,133.36,131.45,130.59,129.78,129.72,129.32,127.77,31.92,14.03。
Example 11
Evaluation of antitumor cell proliferation Activity of Compounds CH3-1 to CH3-10
1.1 testing the inhibitory Activity of Compounds CH3-1 to CH3-10 and LY-17 against tumor cells by MTT method
Non-small cell lung cancer cells (a 549) were purchased from the cell bank of the institute of biochemistry and cell biology, academy of sciences of china (Shanghai, china). Non-small cell lung cancer cells (A549) were cultured in DMEM medium containing 50. Mu.g/mL penicillin, 50. Mu.g/mL streptomycin, 10% fetal bovine serum. Cells were cultured in tissue culture flasks at 37℃and 5% CO 2 Grown to 80% confluence in a humid environment, then trypsinized and split with 1 x Trypsin-Versene.
Test compound: the compounds CH3-1 to CH3-10; positive control: compound LY-17 (WO 2014028909 A1):
preparing a liquid medicine: test compounds and positive control were prepared by preparing a 10mM compound mother solution using biological grade 99.9% DMSO, and diluting the compound with the corresponding medium to obtain a 20. Mu.M solution.
MTT experiment: after the A549 cells are passaged and counted, preparing a cell suspension according to the density of 3500-4000 cells/hole, uniformly mixing, sucking the cell suspension, inoculating the cell suspension into a 96-well plate, attaching 100 mu L of the cell suspension to each hole overnight, taking the cell suspension on the next day, sucking the cell culture solution in the 96-well plate out, and the experimental group: media containing different compounds (20. Mu.M) were added at 100. Mu.L per well, blank: adding 100 mu L of culture medium without medicine into each well; after 72 hours of incubation, 100. Mu.L of medium containing 10% CCK-8 was added to each well, incubated in the dark for 4 hours, and after the end, the 96 well plates were removed, absorbance was measured for each well using a fluorescence microplate reader, the detection wavelength was 470nm, and the reference wavelength was 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition ratio (%) = (1-a) Experimental group /A Blank group )×100％
Table 1 shows the results of the inhibitory activity of the compounds on a549 cells, as follows: the 10 compounds have proliferation inhibition effect on A549 cells, especially the inhibition activity of the compounds CH3-1, CH3-3, CH3-4, CH3-6, CH3-9 and CH3-10 on A549 cells is obvious, the inhibition activity is obviously superior to that of a positive drug LY-17 or is close to that of the positive drug LY-17, and especially the compounds CH3-3 and CH3-10 can achieve complete inhibition (> 95%) on tumor growth at the concentration of 20 mu m.
TABLE 1 inhibition of A549 cells by compounds
1.2 testing of IC of Compounds CH3-3, CH3-9 by MTT method 50 (semi-inhibitory concentration) value
MTT experiment: after the A549 cells are passaged and counted, preparing a cell suspension according to the density of 3500-4000 cells/hole, uniformly mixing, sucking the cell suspension, inoculating the cell suspension into a 96-well plate, 100 mu L of each hole, adhering overnight, adopting 99.9% DMSO of biological grade to prepare 10mmol compound mother liquor the next day, diluting the compound with corresponding culture medium to final concentration of 0, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16 and 32 mu M respectively for 10 concentration gradients, sucking out the cell culture solution in the 96-well plate, adding the culture medium containing different concentration compounds according to 100 mu L of each hole, and blank group: adding 100 mu L of culture medium without medicine into each well; incubation was performed for 72 hours, and then the solution was aspirated from the 96-well plate, and 100. Mu.L of medium containing 10% CCK-8 was added to each well, and incubated for 4 hours in the dark. And taking out the 96-well plate after the detection, measuring the absorbance value of each well by using a fluorescence enzyme-labeled instrument, wherein the detection wavelength is 470nm, and the reference wavelength is 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition ratio (%) = (1-a) Experimental group /A Blank group )×100％
FIG. 1 shows the result of the inhibitory activity of Compound CH3-3 on A549 cells, IC 50 5.828. Mu.M.
FIG. 2 shows the result of the inhibitory activity of Compound CH3-9 on A549 cells, IC 50 (semi-inhibitory concentration) was 8.451. Mu.M.
Example 12
Evaluation of Normal cytotoxicity of Compounds CH3-1 to CH3-9
2.1 testing toxicity of Compounds CH3-1 to CH3-9 and LY-17 to Normal cells Using MTT method
Human normal mammary epithelial cells (MCF-10A) were purchased from the cell bank of Shanghai Biochemical and cell biology institute, national academy of sciences (Shanghai, china). Human normal mammary epithelial cells (MCF-10A) were cultured in DMEM medium containing 50. Mu.g/mL penicillin, 50. Mu.g/mL streptomycin, 10% fetal bovine serum. Cell in groupThe culture flask contains 5% CO at 37deg.C 2 Grown to 80% confluence in a humid environment, then trypsinized and split with 1 x Trypsin-Versene.
Test compound: the compounds CH3-1 to CH3-9; positive control: compound LY-17.
Preparing a liquid medicine: test compounds and positive control were prepared by preparing a 10mM compound mother solution from 99.9% DMSO at a biological level, and diluting the compound with the corresponding medium to obtain a 10. Mu.M solution.
MTT experiment: MCF-10A cells are counted after passage, cell suspensions are prepared according to the density of 3500-4000 cells/hole, after uniform mixing, the cell suspensions are sucked into 96-well plates, 100 mu L of each hole is inoculated, the wall is stuck overnight, the cell suspensions in the 96-well plates are sucked out after the next day of administration, and the experimental group: media containing different compounds (10. Mu.M) were added at 100. Mu.L per well, blank: adding 100 mu L of culture medium without medicine into each well; after 72 hours of incubation, 100. Mu.L of medium containing 10% CCK-8 was added to each well, incubated in the dark for 4 hours, and after the end, the 96 well plates were removed, absorbance was measured for each well using a fluorescence microplate reader, the detection wavelength was 470nm, and the reference wavelength was 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition ratio (%) = (1-a) Experimental group /A Blank group )×100％
FIG. 3 shows the toxicity of the compound at 10. Mu.M to MCF-10A cells, showing that the survival rate of MCF-10A cells is significantly higher than that of control LY-17 under the treatment of 9 compounds, demonstrating that vitamin K of the present invention 3 The derivative has better safety.
Claims (11)
1. Vitamin K with structure shown in formula I 3 A derivative or a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, hydroxy,C1-C3 alkoxy, halogen substituted C1-C4 alkoxy, cyano, nitro, amino, - (CH) 2 ) n COOH; n is an integer of 0 to 2;
R 2 selected from the group consisting of hydrogen, halogen, amino, methylamino, ethylamino, C1-C3 alkyl, C1-C3 alkoxy.
2. Vitamin K according to claim 1 3 A derivative, characterized in that: r is R 1 Selected from hydrogen, fluorine, bromine, methyl, tert-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is R 2 Is methyl.
3. Vitamin K according to claim 1 3 A derivative, characterized in that: r is R 1 Selected from fluorine, trifluoromethyl, methoxy, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is R 2 Is methyl.
4. Vitamin K according to claim 1 3 A derivative, characterized in that: vitamin K 3 The derivatives are selected from the following compounds:
5. vitamin K having the structure shown in the formula 3 A derivative or a pharmaceutically acceptable salt or ester thereof:
6. vitamin K according to any of claims 1-4 3 A derivative or a pharmaceutically acceptable salt thereof, characterized in that: said vitamin K 3 Pharmaceutically acceptable salts of the derivatives are sodium salts and hydrochloride salts.
7. Vitamin K according to claim 5 3 A derivative or a pharmaceutically acceptable salt or ester thereof, characterized in that: said vitamin K 3 Pharmaceutically acceptable salts of the derivatives are sodium salt and hydrochloride, and the vitamin K is 3 Pharmaceutically acceptable esters of the derivatives are methyl ester, ethyl ester and tert-butyl ester.
8. Vitamin K as claimed in any of claims 1-4 3 A derivative or a pharmaceutically acceptable salt thereof, vitamin K as claimed in claim 5 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the preparation of a STAT3 inhibitor.
9. Vitamin K as claimed in any of claims 1-4 3 A derivative or a pharmaceutically acceptable salt thereof, vitamin K as claimed in claim 5 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for the prevention and/or treatment of a tumour.
10. Use according to claim 9, characterized in that: the tumor is lung cancer.
11. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of vitamin K as defined in any one of claims 1-4 3 A derivative or a pharmaceutically acceptable salt thereof or vitamin K as claimed in claim 5 3 A derivative or a pharmaceutically acceptable salt or ester thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211290172.8A CN115572247B (en) | 2022-10-21 | 2022-10-21 | Vitamin K 3 Derivatives and medical use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211290172.8A CN115572247B (en) | 2022-10-21 | 2022-10-21 | Vitamin K 3 Derivatives and medical use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115572247A CN115572247A (en) | 2023-01-06 |
| CN115572247B true CN115572247B (en) | 2023-08-11 |
Family
ID=84587604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211290172.8A Active CN115572247B (en) | 2022-10-21 | 2022-10-21 | Vitamin K 3 Derivatives and medical use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115572247B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632060A (en) * | 2015-10-30 | 2017-05-10 | 中国药科大学 | N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof |
| CN108530394A (en) * | 2017-03-06 | 2018-09-14 | 中国科学院成都有机化学有限公司 | A kind of synthesis vitamin K3The method of epoxides |
| CN112939824A (en) * | 2021-02-20 | 2021-06-11 | 中国药科大学 | Compound and medical application thereof in colorectal cancer |
| CN113845476A (en) * | 2021-11-08 | 2021-12-28 | 中国药科大学 | Quinolone derivative and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2013302390A1 (en) * | 2012-08-16 | 2015-02-26 | Ohio State Innovation Foundation | Stat3 inhibitors and their anticancer use |
-
2022
- 2022-10-21 CN CN202211290172.8A patent/CN115572247B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632060A (en) * | 2015-10-30 | 2017-05-10 | 中国药科大学 | N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof |
| CN108530394A (en) * | 2017-03-06 | 2018-09-14 | 中国科学院成都有机化学有限公司 | A kind of synthesis vitamin K3The method of epoxides |
| CN112939824A (en) * | 2021-02-20 | 2021-06-11 | 中国药科大学 | Compound and medical application thereof in colorectal cancer |
| CN113845476A (en) * | 2021-11-08 | 2021-12-28 | 中国药科大学 | Quinolone derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| "The electro-synthesized imprinted PEDOT film as a simple voltammetric sensor for highly sensitive and selective detection of vitamin K3 in poultry drug samples";Zhouxiang Zhang et al.;Synthetic metals;第230卷;第79-88页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115572247A (en) | 2023-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7705151B2 (en) | 1,6 Naphthridines useful as inhibitors of SYK kinase | |
| GB2449293A (en) | Compounds having Hsp90 inhibitory activity | |
| CN108191874A (en) | A kind of C-Kit inhibitor and its application | |
| JP2005534619A (en) | Azaindole as C-JUNN-terminal kinase inhibitor | |
| JP2019524883A (en) | Heterocyclic compounds as FGFR inhibitors | |
| KR20190140966A (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compound | |
| WO2022174525A1 (en) | Compound, preparation method therefor and use thereof | |
| CN113527299B (en) | Nitrogen-containing condensed ring compound, preparation method and application | |
| JP2021501215A (en) | Amino-substituted nitrogen-containing condensed ring compound, its preparation method and use | |
| CN111704646A (en) | Steroid compound and preparation method and application thereof | |
| CN110156817B (en) | Anti-tumor derivative of bi-evodiamine molecule and preparation and application thereof | |
| CN115572247B (en) | Vitamin K 3 Derivatives and medical use thereof | |
| CN111732584B (en) | Diaryl substituted fused heterocycle compound and preparation method and application thereof in pharmacy | |
| CN107973788B (en) | BBI608 derivative and preparation and application thereof | |
| WO2019223548A1 (en) | 3-oxazolinone compound, preparation method therefor and pharmaceutical application thereof | |
| CN115490689B (en) | Irreversible KRAS G12C Preparation and application of inhibitor | |
| WO2019109647A1 (en) | Parp/pi3k double-target inhibitor containing pyridopyrimidine structure | |
| CN113072550B (en) | High-selectivity fibroblast growth factor receptor inhibitor and application thereof | |
| JPH0733743A (en) | 2-aryl-4-quinolinol derivative | |
| CN112824396B (en) | Acrylic ketone derivative of N-acetyl lomefloxacin and preparation method and application thereof | |
| WO2016127949A1 (en) | Pyrimidine derivative as inhibitor for t790 mutation | |
| CN108358841B (en) | 4- ((2-substituted quinoline-4-yl) amino) benzoyl hydrazine derivatives, and preparation method and application thereof | |
| JP2022516922A (en) | Fluorine-containing substituted benzothiophene compounds and their pharmaceutical compositions and applications | |
| CN111057004A (en) | N-ortho-substituted phenyl benzamide-4-methylaminoacridine compound and preparation method and application thereof | |
| CN116730943A (en) | Compound and medical application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |