CN108864117A - A kind of diphenyl chlorin compound and the preparation method and application thereof - Google Patents

A kind of diphenyl chlorin compound and the preparation method and application thereof Download PDF

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CN108864117A
CN108864117A CN201810491842.XA CN201810491842A CN108864117A CN 108864117 A CN108864117 A CN 108864117A CN 201810491842 A CN201810491842 A CN 201810491842A CN 108864117 A CN108864117 A CN 108864117A
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diphenyl
potassium
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acid
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陈志龙
朱维
高迎华
廖平永
吴晓锋
王来兴
阮氏芳英
代伏·马格替克
严懿嘉
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Abstract

The present invention relates to a kind of diphenyl chlorin compound and the preparation method and application thereof, which has following structures (I)：Wherein R1、R2Ortho position (o-) or meta position (m-) or contraposition (p-) in phenyl ring；R1=-H or-OMe；R2=-OCH2COOH or-OCH2CH2CH2COOH.The present invention relates to photosensitive drug (also referred to as photosensitizers or photo-dynamical medicine) and photodynamic therapy field, more particularly, to a kind of diphenyl chlorophyll derivative photosensitizer and preparation method thereof and in the application of field of medicaments.Diphenyl chlorophyll derivative photosensitizer chemical property prepared by the present invention is stablized, and has very strong photodynamic activity, can be used as the drug of the diseases such as light power diagnosis and treatment tumour, macular degeneration, actinic keratoma, nevus flammeus, condyloma acuminatum.

Description

A kind of diphenyl chlorin compound and the preparation method and application thereof
Technical field
The present invention relates to photosensitive drugs and photodynamic therapy field, more particularly to a kind of diphenyl chlorin chemical combination Object and the preparation method and application thereof.
Background technique
Compared with traditional surgical operation therapy, chemotherapy, radiotherapy etc., photodynamic therapy (PDT) is with its selection Property is good, toxic side effect is small, favorable repeatability, safety, minimal invasive, can concertedness and the advantages that relatively low cost, increasingly cured Raw and patient favor；Show huge potentiality and powerful vitality.The principle of photodynamic therapy is that photosensitizer enters machine After body, selectively it is gathered in target tissue with blood circulation, then shines directly into tumor group using the laser of certain wavelength It knits, generates the free radical (such as singlet oxygen) of high oxidation activity, act on target cell, cause cell metabolism disorder, kill target Cell.
Although PDT has been developed more than 100 years, only a small number of photosensitive drugs can be listed.Porfimer Sodium (phytochrome II) it is to be applied to clinical photosensitive drug (photosensitizer) earliest, achieves significant therapeutic effect, but there are still can not neglect Depending on the shortcomings that such as constituent it is complicated, have stronger skin light toxic action and absorption in red light district weaker.People are to porphines class Structure improves, and has developed chlorin analog derivative, such compound is monomeric compound, structure determination, preparation process In be easy to carry out quality control, red light district absorb be significantly enhanced, antitumous effect increases.However the dihydro listed Porphin photosensitizer still has certain disadvantages, and such as not pool, pheno is easily oxidized, stability is poor, solubility is weaker in water (Chem.Soc.Rev., 1995,24 (1)：19-33).It is swollen that Verteporfin was approved by the fda in the United States for clinical treatment in 2000 The diseases such as tumor and macular degeneration, synthesis material come from natural products protoporphyrin, belong to semi-synthetic product, synthesized Journey is complicated, has multiple isomers, isolates and purifies difficulty, total recovery is low.
Therefore, completely new dihydro porphin photosensitizer is developed to have very important significance.Horse metal and stone etc. develops a system Mono-substituted 5,15- diaryl porphines (formula A) and 5 on column phenyl ring, 15- diaryl -2,3 dihydroxy porphines (formula B) photosensitizer is (specially Sharp CN 1382493A), the structure of these compounds is：Wherein R=-H ,-OH ,-OCnH2n+1,-CnH2n+1,- COCnH2n+1,-COOH ,-COOCnH2n+1, N (CnH2n+1)2Deng n=1-7.But such compound remains unchanged there is some problems, Formula (A) class compound polarity is small, it is difficult to be absorbed and is distributed by tumor tissues, medicament is prepared also more difficult；Formula (B) class compound pole Though property has enhancing, needed in preparation process using deadly poisonous compound osmium tetroxide, there are problems, such as preparation process for this method It is required that it is stringent, be not suitable for amplification production；Harm is easily caused to personnel in preparation process, is polluted the environment；A small amount of four oxygen Toxic reaction can be caused to patient by changing the residual of osmium and its reaction product in drug；Transport, the management of violent in toxicity all easily occur Problem etc..
Summary of the invention
To overcome, complicated composition present in existing photosensitive drug, structural instability, preparation is difficult, has skin light poison work With, red light district absorb it is weak the defects of, the present invention is restored porphines compound, is prepared for new chlorin chemical combination Object makes compound in red light district influx and translocation；Polar group is introduced on the periphery of compound, water solubility is improved, increases Absorption and distribution of the photosensitizer in tumour reduce light toxic side effect so that light power effect is enhanced；Noval chemical compound knot Structure is stablized；Preparation is simple.New diphenyl chlorin compound has been synthesized after paying a large amount of creative works, Complete the present invention.
The present invention relates to a kind of diphenyl chlorin compounds and the preparation method and application thereof.
The present invention is summarized as follows：
A kind of diphenyl dihydro-compound has following structures (I)：
Wherein R1、R2Ortho position (o-) or meta position (m-) or contraposition (p-) in phenyl ring；
R1=-H or-OMe；R2=-OCH2COOH or-OCH2CH2CH2COOH。
The preparation method of a kind of diphenyl chlorin compound (I), includes the following steps：
Compound II and alkali are added in pyridine, stirred, is heated to flowing back under nitrogen protection；Then tolysulfonyl is added dropwise The pyridine solution of hydrazine.After reaction, reaction solution is cooled to room temperature, ethyl acetate and distilled water is added, is heated to reflux.It is cold But, it is neutralized with acid solution, stratification.By organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filters.It will The stirring of gained filtrate, is added portionwise tetrachloroquinone, until visible-ultraviolet characteristic absorption peak of isobacteriochlorin compound disappears；Instead Liquid solution of sodium bisulfite, sodium hydroxide solution and saturated common salt water washing are answered, anhydrous sodium sulfate is dry；It filters.By filtrate Evaporating solvent under reduced pressure carries out column chromatographic isolation and purification to gained residue and obtains diphenyl chlorin compound (III).
Diphenyl chlorin compound (III) is dissolved in organic solvent, aqueous slkali is added, is heated to reflux under nitrogen protection Stirring.Reaction solution is cooled to room temperature, evaporating solvent under reduced pressure.Residue adds water, adjusts pH to 3-4 with acid solution.It filters, to institute Solid is obtained to be dried in vacuo to obtain diphenyl chlorin compound (I).
Wherein R1、R2And R3Ortho position (o-) or meta position (m-) or contraposition (p-) in phenyl ring；
R1=-H or-OMe；R2=-OCH2COOH or-OCH2CH2CH2COOH；R3=-OCH2COOEt or- OCH2CH2CH2COOEt。
In the step, it is diisopropyl ethyl amine, triethylamine, pyridine, sodium that formula (II), which prepares alkali used when formula (III), Hydrogen, potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, potassium hydrogen phosphate, dibastic sodium phosphate, potassium hydroxide, sodium hydroxide, hydroxide Lithium, sodium formate, sodium acetate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, normal propyl alcohol sodium, normal propyl alcohol potassium, sodium isopropylate, isopropyl Any one in potassium alcoholate, potassium tert-butoxide, sodium tert-butoxide etc. or any a variety of mixture.The time being stirred to react is 1-10h.
In the step, it is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, third that formula (II), which prepares acid used when formula (III), Any one in acid, n-butyric acie, trifluoroacetic acid etc. or any a variety of mixture.
In the step, filler used in column chromatography for separation is silica gel when formula (II) prepares formula (III), and eluent is stone Oily ether: the mixed solution (1: 1-100) of methylene chloride.
In the step, it is methanol, ethyl alcohol, ethylene glycol, acetic acid second that formula (III), which prepares organic solvent used when formula (I), Ester, acetone, methylene chloride, acetonitrile, tetrahydrofuran, ether, glycol dimethyl ether, methyl tertiary butyl ether(MTBE), ethylene glycol diethyl ether, second Any one in glycol di-n-butyl ether etc. or any a variety of mixture.
In the step, it is potassium carbonate, sodium carbonate, saleratus, bicarbonate that formula (III), which prepares alkali used when formula (I), Sodium, potassium hydrogen phosphate, dibastic sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, sodium formate, sodium acetate, Sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, normal propyl alcohol sodium, normal propyl alcohol potassium, sodium isopropylate, potassium isopropoxide, potassium tert-butoxide, tertiary fourth Any one in sodium alkoxide etc. or any a variety of mixture.The time being stirred to react is 5-20h.
In the step, when formula (III) preparation formula (I) acid used be hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, Any one in n-butyric acie, trifluoroacetic acid etc. or any a variety of mixture.
It is yellow that one kind diphenyl chlorin compound (I) of the present invention can be used as light power diagnosis and treatment tumour, retina The drug of the diseases such as spot denaturation, actinic keratoma, nevus flammeus, condyloma acuminatum.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited Range.
[embodiment 1]
The preparation method of the synthesis of 5,15- bis- [(3- carboxymethoxyl) phenyl] chlorins (1)
Compound 2 (333mg, 0.5mmol) and potassium carbonate (828mg, 6mmol) are added in pyridine (23mL), stirred, nitrogen It is heated to flowing back under gas shielded；The pyridine solution (0.5mol/L) of unifor is added dropwise, thin-layer chromatography (TLC) monitors extremely Fully reacting.Reaction solution is cooling, ethyl acetate (100mL) and distilled water (50mL) is added, is heated to reflux 1h.It is cooling, use salt Acid solution (2mol/L) neutralizes, stratification.Organic phase is washed with saturated salt solution (50mL × 3), and anhydrous sodium sulfate is dry, is taken out Filter.Filtrate is stirred at normal temperature, tetrachloroquinone is added portionwise, until the ultraviolet-visible wave of diphenyl isobacteriochlorin compound Characteristic absorption peak in spectrum disappears；Reaction solution 5% solution of sodium bisulfite (50mL × 3), 2M sodium hydroxide solution (50mL × 3) it filters with saturated salt solution (50mL × 3) washing, anhydrous sodium sulfate drying, solvent is evaporated off in filtrate decompression.Gained is remained Object uses column chromatography purifying and obtains diphenyl chlorin compound 3 (121mg, 36.2%).
Compound 3 (334mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeOH=1/1) 25 mL, are added KOH solution (2mol/L) is heated to reflux stirring 12h under nitrogen protection.It is cooled to room temperature to reaction solution, evaporating solvent under reduced pressure is residual It stays object to add water (30mL), adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, obtained solid is dried in vacuo to obtain Dark green solid compound 1 (280.4mg, 91.6%).1H NMR (400MHz, DMSO-d6)：δ ppm 9.87 (s, 1H), 9.13 (d, J=4.6Hz, 1H), 9.02 (s, 1H), 8.99 (d, J=4.3Hz, 1H), 8.87 (d, J=4.7Hz, 1H), 8.82 (d, J =4.7Hz, 1H), 8.69 (d, J=4.2Hz, 1H), 8.43 (d, J=4.6Hz, 1H), 7.86 (d, J=7.4Hz, 1H), 7.77 (d, J=2.5Hz, 1H), 7.68 (q, J=8.4Hz, 2H), 7.57 (d, J=7.4Hz, 1H), 7.51 (d, J=2.6Hz, 1H), 7.37 (dd, J=8.3,2.4Hz, 1H), 7.30 (d, J=2.5Hz, 1H), 4.84 (d, J=8.4Hz, 4H), 4.68 (t, J= 7.9Hz, 2H), 4.35 (dqd, J=10.7,7.7,7.1,4.2Hz, 6H), 1.32 (t, J=7.1Hz, 6H), -1.41 (s, 1H), -1.94 (s, 1H)13C NMR (100MHz, DMSO-d6)：δ ppm 171.19,171.12,168.11,168.06, 158.08,157.31,152.58,150.37,142.95,142.1,140.53,139.33,135.38,133.71,133.60, 131.66,129.53,129.30,128.63,128.35,127.56,125.48,125.31,123.03,120.63, 118.84,114.76,114.49,111.67,108.85,97.63,65.67,65.61,35.71,35.32.HRMS (MALDI)：m/z calcd for C36H29N4O6[M+H]+, 613.2082；Found, 613.2079.
[embodiment 2]
The preparation method of 5,15- bis- [(3- carboxylic propoxyl group) phenyl] chlorins (4)
Compound 5 (361mg, 0.5mmol) and potassium carbonate (828mg, 6mmol) are added in pyridine (23mL), stirred, nitrogen It is heated to flowing back under gas shielded；The pyridine solution (0.5mol/L) of unifor is added dropwise, TLC is monitored to fully reacting.It will Reaction solution is cooling, and ethyl acetate (100mL) and distilled water (50mL) is added, is heated to reflux 1h.It is cooling, with hydrochloric acid solution (2mol/ L it) neutralizes, stratification.Organic phase is washed with saturated salt solution (50mL × 3), and anhydrous sodium sulfate is dry, is filtered.By filtrate normal The lower stirring of temperature, is added portionwise tetrachloroquinone, until the characteristic absorption in the UV-Vis spectra of diphenyl isobacteriochlorin compound Peak disappears；Reaction solution 5% solution of sodium bisulfite (50mL × 3), 2M sodium hydroxide solution (50mL × 3) and saturated common salt Water (50mL × 3) washing, anhydrous sodium sulfate is dry, filters, solvent is evaporated off in filtrate decompression.Gained residue is chromatographed with column and is divided Diphenyl chlorin compound 6 (200mg, 55.2%) is obtained from purifying.
Compound 6 (362mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeOH=1/1) 25 mL, are added KOH solution (2mol/L) is heated to reflux stirring 12h under nitrogen protection.It is cooled to room temperature to reaction solution, evaporating solvent under reduced pressure is residual It stays object to add water (30mL), adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, obtained solid is dried in vacuo to obtain Dark green solid compound 4 (325.8mg, 97.5%).1H NMR (400MHz, DMSO-d6)：δ ppm 12.28 (s, 2H), 10.13 (s, 1H), 9.43 (dd, J=4.8,1.8Hz, 1H), 9.26 (s, 1H), 9.13 (d, J=4.2Hz, 2H), 8.90 (d, J =4.7Hz, 1H), 8.63 (d, J=4.3Hz, 1H), 8.46 (dd, J=4.7,1.7Hz, 1H), 7.81-7.71 (m, 4H), 7.61 (d, J=2.3Hz, 1H), 7.56 (d, J=7.4Hz, 1H), 7.46 (dt, J=5.9,3.0Hz, 1H), 7.38 (dd, J= 8.4,2.5Hz, 1H), 4.71 (t, J=8.0Hz, 2H), 4.47-4.23 (m, 6H), 2.61-2.57 (m, 2H), 2.53 (d, J= 7.2Hz, 2H), 2.18-2.10 (m, 4H), -1.46 (s, 1H), -2.00 (s, 1H)13C NMR (100MHz, DMSO-d6)：δ Ppm 174.64,168.20,168.11,158.67,157.79,152.60,150.40,143.16,142.28,140.59, 139.42,135.39,133.76,133.59,131.64,129.66,129.34,128.66,128.41,127.15, 125.32,125.23,123.09,120.71,120.63,118.83,114.60,114.44,111.80,108.86,97.68, 67.36,67.27,35.80,35.44,30.70,30.67,24.36,24.83.HRMS (MALDI)：m/z calcd for C40H37N4O6[M+H]+, 669.2708；Found, 669.2709.
[embodiment 3]
The preparation method of 5,15- bis- [(3- carboxymethoxyl -4- methoxyl group) phenyl] chlorins (7)
Compound 8 (363mg, 0.5mmol) and potassium carbonate (828mg, 6mmol) are added in pyridine (23mL), stirred, nitrogen It is heated to flowing back under gas shielded；The pyridine solution (0.5mol/L) of unifor is added dropwise, TLC is monitored to fully reacting.It will Reaction solution is cooling, and ethyl acetate (100mL) and distilled water (50mL) is added, is heated to reflux 1h.It is cooling, with hydrochloric acid solution (2mol/ L it) neutralizes, stratification.Organic phase is washed with saturated salt solution (50mL × 3), and anhydrous sodium sulfate is dry, is filtered.By filtrate normal The lower stirring of temperature, is added portionwise tetrachloroquinone, until the characteristic absorption in the UV-Vis spectra of diphenyl isobacteriochlorin compound Peak disappears；Reaction solution 5% solution of sodium bisulfite (50mL × 3), 2M sodium hydroxide solution (50mL × 3) and saturated common salt Water (50mL × 3) washing, anhydrous sodium sulfate is dry, filters, solvent is evaporated off in filtrate decompression.Gained residue is chromatographed with column and is divided Diphenyl chlorin compound 9 (60.1mg, 16.5%) is obtained from purifying.
Compound 9 (364mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeOH=1/1) 25 mL, are added KOH solution (2mol/L) is heated to reflux stirring 12h under nitrogen protection.It is cooled to room temperature to reaction solution, evaporating solvent under reduced pressure is residual It stays object to add water (30mL), adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, obtained solid is dried in vacuo to obtain Dark green solid compound 7 (324mg, 96.4%).1H NMR (400MHz, DMSO-d6)：δ ppm 10.03 (s, 1H), 9.35 (s, 1H), 9.20 (s, 1H), 9.08-9.01 (m, 2H), 8.86 (d, J=3.7Hz, 1H), 8.59 (d, J=3.9Hz, 1H), 8.41 (d, J=3.7Hz, 1H), 7.68 (s, 2H), 7.48 (d, J=4.2Hz, 2H), 7.40 (d, J=24.2Hz, 2H), 4.81 (d, J=19.8Hz, 4H), 4.66 (t, J=7.5Hz, 2H), 4.37-4.28 (m, 2H), 4.05 (d, J=14.6Hz, 6H) ,- 1.48 (s, 1H), -2.07 (s, 1H)13C NMR (100MHz, DMSO-d6)：δ ppm 172.31,163.78,162.33, 153.61,153.05,148.83,148.79,146.09,144.54,143.78,133.80,133.40,132.73,132.10, 132.08,130.94,129.96,125.59,125.28,125.15,125.06,121.28,116.98,114.05, 113.75,113.53,113.24,113.13,105.56,101.44,65.12,59.91,33.45,31.80.HRMS (MALDI)：m/z calcd for C38H33N4O8 [M+H]+, 673.2293；Found, 673.2301.
[embodiment 4]
The preparation method of 5,15- bis- [(3- carboxylic propoxyl group) phenyl] chlorins (10)
Compound 11 (391mg, 0.5mmol) and potassium carbonate (828mg, 6mmol) are added in pyridine (23mL), stirred, It is heated to flowing back under nitrogen protection；The pyridine solution (0.5mol/L) of unifor is added dropwise, TLC is monitored to fully reacting. Reaction solution is cooling, ethyl acetate (100mL) and distilled water (50mL) is added, is heated to reflux 1h.It is cooling, use hydrochloric acid solution (2mol/L) is neutralized, stratification.Organic phase is washed with saturated salt solution (50mL × 3), and anhydrous sodium sulfate is dry, is filtered.It will filter Liquid stirs at normal temperature, and tetrachloroquinone is added portionwise, until the spy in the UV-Vis spectra of diphenyl isobacteriochlorin compound Absorption peak is levied to disappear；Reaction solution 5% solution of sodium bisulfite (50mL × 3), 2M sodium hydroxide solution (50mL × 3) and full It is washed with saline solution (50mL × 3), anhydrous sodium sulfate is dry, filters, solvent is evaporated off in filtrate decompression.To gained residue column Chromatography purifies to obtain diphenyl chlorin compound 12 (56.9mg, 14.5%).
Compound 12 (392mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeOH=1/1) it, is added 25mL KOH solution (2mol/L) is heated to reflux stirring 12h under nitrogen protection.It is cooled to room temperature, removes under reduced pressure molten to reaction solution Agent, residue add water (30mL), adjust pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, obtained solid is dried in vacuo Obtain dark green solid compound 10 (345.2mg, 94.7%).1H NMR (400MHz, DMSO-d6)：δ ppm 12.31 (s, 2H), 10.31 (s, 1H), 9.67 (s, 1H), 9.46 (s, 1H), 9.24 (d, J=4.2Hz, 2H), 9.01 (d, J=4.7Hz, 1H), 8.73 (d, J=4.3Hz, 1H), 8.51 (d, J=4.7Hz, 1H), 7.61 (s, 2H), 7.56 (d, J=2.4Hz, 1H), 7.46 (d, J=6.4Hz, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 4.67 (t, J=8.0Hz, 2H), 4.52-4.31 (m, 6H), 4.12 (d, J=5.8Hz, 6H), 2.64-2.58 (m, 4H), 2.23-2.16 (m, 4H), -1.53 (s, 1H), -2.07 (s, 1H).13C NMR (100MHz, DMSO-d6)：δ ppm 179.56,163.78,161.39,153.67,150.36,148.56, 148.29,146.39,144.57,142.88,133.78,133.45,132.76,132.10,132.04,130.98, 129.96,125.57,125.31,125.12,121.25,116.92,113.97,113.51,113.09,113.01, 112.54,105.56,101.44,67.91,55.91,55.85,33.45,31.80,30.83,24.61,24.57.HRMS (MaLDI)：m/z calcd for C42H39N4O8[M+H]+, 727.2762；Found, 727.2763.
[embodiment 5]
Photosensitizer tests the light power antiproliferative of human esophagus cancer Eca-109 cell
Subject cell：Human esophagus cancer cell Eca-109
Test medicine：5,15- bis- [(3- carboxymethoxyl) phenyl] chlorins (compound 1) (hereinafter referred to as photosensitizer 1)； 5,15- bis- [(3- carboxylic propoxyl group) phenyl] chlorins (compound 4) (hereinafter referred to as photosensitizer 2)；5,15- bis- [(3- carboxylic first Oxygroup -4- methoxyl group) phenyl] chlorin (compound 7) (hereinafter referred to as photosensitizer 3)；5,15- bis- [(3- carboxylic propoxyl group) benzene Base] chlorin (compound 10) (hereinafter referred to as photosensitizer 4)；Control compound 5,15- bis- (4- carboxyl phenyl) chlorin (abbreviation photosensitizer 5, the compound are compound described in the patent of horse metal and stone et al., are had purchased from Shanghai elder generation brightness medical sci-tech Limit company)；Control drug hemporfin (Shanghai Xian Hui Pharmaceutical Technology Co., Ltd provides, hereinafter referred to as photosensitizer 6)；
Light source：XD-650AB type laser；SD2490 type laser power measurement instrument.
The effect experiment of light power anti-tumour cell proliferative：
After cell in logarithmic growth phase is digested with pancreatin, complete medium is resuspended at cell suspension, therewith by it 96 orifice plates are inoculated in, every 100 μ L of hole is placed in 37 DEG C of 5%CO2Incubator culture, is added photosensitizer afterwards for 24 hours；12h changes into fresh Then culture medium carries out illumination (power 18mW/cm2, wavelength 650mm, light dosage 6J/cm2)；MTT detection is carried out when 72h.Training The MTT that 20 μ L 5mg/mL are added in 4h before terminating is supported, suction is abandoned after culture solution plus 150 μ L DMSO terminate reaction, and microplate reader 570nm is examined Survey OD value.Experiment is in triplicate.Experimental result is shown in Table 1, as a result, it has been found that photosensitizer 1, photosensitizer 2, photosensitizer 3, photosensitizer 4 are to people Esophageal cancer cell has antiproliferative effect, and bioactivity is better than control compound 5 and comparison medicine photosensitizer 6.
1 noval chemical compound of table is to Eca-109 human esophagus cancer cell inhibited proliferation
***P < 0.001 and comparison medicine photosensitizer 6
ΔΔΔP < 0.001 and blank control.

Claims (9)

1. a kind of diphenyl chlorin compound, it is characterized in that having following structures (I)：
Wherein R1、R2Ortho position (o-) or meta position (m-) or contraposition (p-) in phenyl ring；
R1=-H or-OMe；R2=-OCH2COOH or-OCH2CH2CH2COOH。
2. the preparation method of one kind diphenyl chlorin compound (I) according to claim 1, feature includes as follows Step：
Compound II and alkali are added in pyridine, stirred, is heated to flowing back under nitrogen protection；Then unifor is added dropwise Pyridine solution.After reaction, reaction solution is cooled to room temperature, ethyl acetate and distilled water is added, is heated to reflux.It is cooling, it uses Acid solution is neutralized, stratification.By organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filters.Gained is filtered Liquid stirring, is added portionwise tetrachloroquinone, until visible-ultraviolet characteristic absorption peak of isobacteriochlorin compound disappears；Reaction solution is used Solution of sodium bisulfite, sodium hydroxide solution and saturated common salt water washing, anhydrous sodium sulfate are dry；It filters.Filtrate decompression is steamed Except solvent, column chromatographic isolation and purification is carried out to gained residue and obtains diphenyl chlorin compound (III).
Diphenyl chlorin compound (III) is dissolved in organic solvent, aqueous slkali is added, is heated to reflux and stirs under nitrogen protection It mixes.Reaction solution is cooled to room temperature, evaporating solvent under reduced pressure.Residue adds water, adjusts pH to 3-4 with acid solution.It filters, to gained Solid is dried in vacuo to obtain diphenyl chlorin compound (I).
Wherein R1、R2And R3Ortho position (o-) or meta position (m-) or contraposition (p-) in phenyl ring；
R1=-H or-OMe；R2=-OCH2COOH or-OCH2CH2CH2COOH；R3=-OCH2COOEt or-OCH2CH2CH2COOEt。
3. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute State in step, when formula (II) preparation formula (III) alkali used be diisopropyl ethyl amine, triethylamine, pyridine, sodium hydrogen, potassium carbonate, Sodium carbonate, saleratus, sodium bicarbonate, potassium hydrogen phosphate, dibastic sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium formate, Sodium acetate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, normal propyl alcohol sodium, normal propyl alcohol potassium, sodium isopropylate, potassium isopropoxide, the tert-butyl alcohol Any one in potassium, sodium tert-butoxide etc. or any a variety of mixture.The time being stirred to react is 1-10h.
4. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute It states in step, it is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, n-butyric acie, three that formula (II), which prepares acid used when formula (III), Any one in fluoroacetic acid etc. or any a variety of mixture.
5. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute It states in step, filler used in column chromatography for separation is silica gel when formula (II) prepares formula (III), and eluent is petroleum ether: dichloro The mixed solution (1: 1-100) of methane.
6. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute It states in step, it is methanol, ethyl alcohol, ethylene glycol, ethyl acetate, acetone, two that formula (III), which prepares organic solvent used when formula (I), Chloromethanes, acetonitrile, tetrahydrofuran, ether, glycol dimethyl ether, methyl tertiary butyl ether(MTBE), ethylene glycol diethyl ether, the positive fourth of ethylene glycol two Any one in ether etc. or any a variety of mixture.
7. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute It states in step, it is potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, phosphoric acid hydrogen that formula (III), which prepares alkali used when formula (I), Potassium, dibastic sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, sodium formate, sodium acetate, sodium methoxide, first In potassium alcoholate, sodium ethoxide, potassium ethoxide, normal propyl alcohol sodium, normal propyl alcohol potassium, sodium isopropylate, potassium isopropoxide, potassium tert-butoxide, sodium tert-butoxide etc. Any one or any a variety of mixture.The time being stirred to react is 5-20h.
8. the preparation method of one kind diphenyl chlorin compound (I) according to claim 2, it is characterised in that：Institute It states in step, it is hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, n-butyric acie, three that formula (III), which prepares acid used when formula (I), Any one in fluoroacetic acid etc. or any a variety of mixture.
9. it is yellow that one kind diphenyl chlorin compound (I) described in claim 1 can be used as light power diagnosis and treatment tumour, retina The drug of the diseases such as spot denaturation, actinic keratoma, nevus flammeus, condyloma acuminatum.
CN201810491842.XA 2018-05-21 2018-05-21 A kind of diphenyl chlorin compound and the preparation method and application thereof Pending CN108864117A (en)

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CN113754672A (en) * 2021-10-27 2021-12-07 上海先辉医药科技有限公司 Novel tetrapyrrole compound and application thereof
CN113831351A (en) * 2021-10-11 2021-12-24 上海先辉医药科技有限公司 Novel tetrapyrrole derivatives and application thereof
CN114524822A (en) * 2022-02-28 2022-05-24 上海先辉医药科技有限公司 Novel intermediate diphenyl naphthoporphin derivative and application thereof in medical field

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Cited By (6)

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CN113831351A (en) * 2021-10-11 2021-12-24 上海先辉医药科技有限公司 Novel tetrapyrrole derivatives and application thereof
CN113831351B (en) * 2021-10-11 2024-05-03 上海先辉医药科技有限公司 Novel tetrapyrrole derivatives and application thereof
CN113754672A (en) * 2021-10-27 2021-12-07 上海先辉医药科技有限公司 Novel tetrapyrrole compound and application thereof
CN113754672B (en) * 2021-10-27 2024-05-03 上海先辉医药科技有限公司 Novel tetrapyrrole compounds and application thereof
CN114524822A (en) * 2022-02-28 2022-05-24 上海先辉医药科技有限公司 Novel intermediate diphenyl naphthoporphin derivative and application thereof in medical field
CN114524822B (en) * 2022-02-28 2024-05-03 上海先辉医药科技有限公司 Novel intermediate diphenyl naphthoporphin derivative and application thereof in medicine field

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