CN108864118A - A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof - Google Patents
A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof Download PDFInfo
- Publication number
- CN108864118A CN108864118A CN201810491890.9A CN201810491890A CN108864118A CN 108864118 A CN108864118 A CN 108864118A CN 201810491890 A CN201810491890 A CN 201810491890A CN 108864118 A CN108864118 A CN 108864118A
- Authority
- CN
- China
- Prior art keywords
- sodium
- potassium
- diphenyl
- acid
- compound
- 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.)
- Pending
Links
- AMIZNWFJPUYCOH-XBEUCGDOSA-N C(C1)C(/C=C(/C=C2)\N/C2=C(\C(CC2)=N/C2=C\c2ccc3[nH]2)/c2ccccc2)=N/C1=C3/c1ccccc1 Chemical compound C(C1)C(/C=C(/C=C2)\N/C2=C(\C(CC2)=N/C2=C\c2ccc3[nH]2)/c2ccccc2)=N/C1=C3/c1ccccc1 AMIZNWFJPUYCOH-XBEUCGDOSA-N 0.000 description 1
- HCTBNNQHJIDJQC-GFOJACCOSA-N CCOC(CCCOc1cc(C(C(CC2)CC2/C(/C)=C(/C=C2)\N/C2=C(\C(CC2)=N/C2=C2)/c3cc(OCCCC(OCC)=O)ccc3)c3ccc2[nH]3)ccc1)=O Chemical compound CCOC(CCCOc1cc(C(C(CC2)CC2/C(/C)=C(/C=C2)\N/C2=C(\C(CC2)=N/C2=C2)/c3cc(OCCCC(OCC)=O)ccc3)c3ccc2[nH]3)ccc1)=O HCTBNNQHJIDJQC-GFOJACCOSA-N 0.000 description 1
- IPTGCHLNLMHRSV-JJKHNKQHSA-N CCOC(CCCOc1cccc(C(C(C=C2)N/C2=C\C(C=C2)=N/C2=C2/c3cccc(OCCCC(OCC)=O)c3)C(C=C3)=N/C3=C\c3ccc2[nH]3)c1)=O Chemical compound CCOC(CCCOc1cccc(C(C(C=C2)N/C2=C\C(C=C2)=N/C2=C2/c3cccc(OCCCC(OCC)=O)c3)C(C=C3)=N/C3=C\c3ccc2[nH]3)c1)=O IPTGCHLNLMHRSV-JJKHNKQHSA-N 0.000 description 1
- UKCWSHZEYCOBTR-OQFCWDSVSA-N OC(CCCOc1cc(C(C(CC2)N=C2CC(C=C2)N/C2=C(\C(CC2)=N/C2=C2)/c3cc(OCCCC(O)=O)ccc3)c3ccc2[nH]3)ccc1)=O Chemical compound OC(CCCOc1cc(C(C(CC2)N=C2CC(C=C2)N/C2=C(\C(CC2)=N/C2=C2)/c3cc(OCCCC(O)=O)ccc3)c3ccc2[nH]3)ccc1)=O UKCWSHZEYCOBTR-OQFCWDSVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to a kind of diphenyl isobacteriochlorin 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 isobacteriochlorin photosensitizer and preparation method thereof and in the application of field of medicaments.Diphenyl isobacteriochlorin 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
Technical field
The present invention relates to photosensitive drugs and photodynamic therapy field, more particularly to a kind of diphenyl isobacteriochlorin 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, unstable excitation state is become by ground state after sensitiser absorption photon energy, the photosensitizer in excitation state and surrounding point
Son reacts, and generates the free radical (such as singlet oxygen) of high oxidation activity, acts on target cell, cause cell metabolism disorder,
Kill target cell.The innovation of photosensitizer is always the core and difficult point of Trends in Photodynamic Therapy.Although PDT has been developed 100
For many years, but only a small number of photosensitive drugs can list.Porfimer Sodium (phytochrome II) is to be applied to clinical photosensitive medicine earliest
Object (photosensitizer), achieves significant therapeutic effect, but that there are still very important disadvantage such as constituents is complicated, there have to be relatively strong
Skin light toxic action and absorption in red light district are weaker.What is listed replaces not pool pheno phenolic hydroxyl group containing there are four, is easily oxidized, surely
Qualitative poor, solubility weaker (Chem.Soc.Rev., 1995,24 (1) in water：19-33).Verteporfin is beautiful in 2000
For diseases such as clinical treatment tumour and macular degenerations, synthesis process is complicated for state FDA approval, there is multiple isomers,
Difficulty is isolated and purified, total recovery is low.
Isobacteriochlorin class compound is gathered around there are two the pyrrole ring being reduced, and such carbon backbone structure is present in nature
In photosynthetic bacteria (Rhodospirillales and Rhizobiales).In the structure of such compound, two are reduced
Pyrrole ring for compound in uv-visible absorption spectra long wavelength region absorption play an important role.Isobacteriochlorin
Photosensitizer has outstanding ultraviolet absorption peak (740-780nm), therefore such photosensitizer has deeper penetration into tissue
(J.Med.Chem.2014,57,223-237).There is pa benefit pool fragrant into the isobacteriochlorin class photosensitizer of clinical test at present
(Padeliporfin), mainly pass through culture bacterium acquisition due to preparing the raw material of the compound, low yield is at high cost.Therefore,
The isobacteriochlorin class photosensitizer and preparation method thereof of exploitation new construction is of great significance.
Horse metal and stone etc. develops mono-substituted isobacteriochlorin photosensitizer (patent CN 1382493A) on a series of phenyl ring,
Shown in its general structure such as formula (A),Wherein R=-H ,-OH ,-OCnH2n+1,-CnH2n+1,-COCnH2n+1,
- COOH ,-COOCnH2n+1, N (CnH2n+1)2Deng n=1-7.But such compound water soluble is poor, it is difficult to be inhaled by tumor tissues
It receives and distribution, medicament is prepared also more difficult.
Summary of the invention
For overcome complicated composition present in existing photosensitive drug, have certain skin light toxic action, preparation it is more difficult, red
Light area absorbs the defects of weaker, and the present invention is restored porphines compound, is prepared for isobacteriochlorin compound, is made compound
In red light district influx and translocation；Polar group is introduced on the periphery of compound, water solubility is improved, increases photosensitizer in tumour
It absorbs and is distributed in tissue, reduce skin light toxic side effect；New compound structure is stablized；Preparation is simple.It is paying
New diphenyl isobacteriochlorin compound has been synthesized after a large amount of creative works out, has completed the present invention.
The present invention relates to a kind of diphenyl isobacteriochlorin compounds and the preparation method and application thereof.
The present invention is summarized as follows：
A kind of diphenyl tetrahydro-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 isobacteriochlorin 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, it is cooled to room temperature to reaction solution, 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
Solvent is evaporated off in gained filtrate decompression, carries out column chromatographic isolation and purification to gained residue and obtains diphenyl isobacteriochlorin compound
(III)。
Diphenyl isobacteriochlorin 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,
Obtained solid is dried in vacuo to obtain diphenyl isobacteriochlorin compound (I).
Wherein R1、R2、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: 1-1.00) 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 acid be hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid,
Any one in propionic acid, n-butyric acie, trifluoroacetic acid etc. or any a variety of mixture.
It is yellow that one kind diphenyl isobacteriochlorin 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] isobacteriochlorins (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.It is cooling to reaction solution, 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, is evaporated off solvent for filtrate decompression.Purifying is used column chromatography to gained residue and obtains diphenyl isobacteriochlorin compound 3
(95.2mg, 28.4%).
Compound 3 (335mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeoH=1/1) 25mL, is 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 (299.7mg, 97.6%).1H NMR (400MHz, DMSO-d6)：δ ppm 13.08 (s, 2H),
8.91 (s, 2H), 8.74 (d, J=4.5Hz, 2H), 8.10 (d, J=4.5Hz, 2H), 7.64 (t, J=7.8Hz, 2H), 7.52-
7.40 (m, 4H), 7.24 (d, J=8.4Hz, 2H), 4.85 (s, 4H), 4.45 (t, J=8.4Hz, 4H), 4.12 (qt, J=
16.9,8.0Hz, 4H), -1.65 (s, 2H)13C NMR (100MHz, DMSO-d6)：δ ppm 170.81,162.65,162.15,
157.83,143.29,136.39,135.12,129.45,125.35,122.96,121.81,118.46,114.38,
113.70,100.03,65.21,34.97,34.75.HRMS (MALDI)：m/z calcd for C36H30N4O6[M]+,
614.2160；Found, 614.2163.
[embodiment 2]
The preparation method of 5,15- bis- [(3- carboxylic propoxyl group) phenyl] isobacteriochlorins (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 monitors raw material fully reacting.
Reaction solution is cooling, ethyl acetate (100mL) is added and distilled water (50mL) 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, will
Solvent is evaporated off in filtrate decompression.Purifying is used column chromatography to gained residue and obtains diphenyl isobacteriochlorin compound 6
(125.3mg, 34.5%).
Compound 6 (363mg, 0.5mmol) is dissolved in 100mL THF/MeOH (VTHF/VMeOH=1/1) 25 mL, are added
KOH solution (2mol/L) is heated to reflux under nitrogen protection and is stirred to react 12h.It is cooled to room temperature, removes under reduced pressure molten to reaction solution
Water (30mL) is added in agent, residue, adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, it is dry to carry out vacuum to obtained solid
It is dry to obtain 4 compound of dark green solid (297mg, 88.6%).1H NMR (400MHz, DMSO-d6)：δ ppm 12.16 (s,
2H), 8.90 (s, 2H), 8.73. (d, J=4.5Hz, 2H), 8.10 (d, J=4.5Hz, 2H), 7.62 (t, J=7.8 Hz, 2H),
7.42 (d, J=9.2Hz, 4H), 7.30-7.21 (m, 2H), 4.44 (t, J=8.4Hz, 4H), 4.24-4.02 (m, 8H), 2.44
(t, J=7.3Hz, 4H), 2.02 (p, J=6.9Hz, 4H), -1.66 (s, 2H)13C NMR (100MHz, DMSO-d6)：δ ppm
174.64,162.62,162.14,158.56,143.41,136.42,135.11,129.48,124.90,122.92,121.83,
118.50,114.25,113.81,99.99,67.26,34.96,34.77,30.69,24.85.HRMS (MALDI)：m/z
calcd for C40H38N4O6[M]+, 670.2786；Found, 670.2780.
[embodiment 3]
The preparation method of 5,15- bis- [(3- carboxymethoxyl -4- methoxyl group) phenyl] isobacteriochlorins (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 monitors raw material fully reacting.
Reaction solution is cooling, ethyl acetate (100mL) and distilled water (50mL) is added, is heated to reflux 1h.It is cooling, use HCl solution
(2mol/L) is neutralized, stratification.Organic phase is washed with saturated salt solution (50mL × 3), and anhydrous sodium sulfate is dry, is filtered, will
Solvent is evaporated off in filtrate decompression.To gained residue column chromatographic isolation and purification obtain diphenyl isobacteriochlorin compound 9 (96.8mg,
26.5%).
Compound 9 (365mg, 0.5mmol) is dissolved in 100mL, THF/MeOH (VTHF/VMeOH=1/1) 25mL, is added
KOH solution (2mol/L) is heated to reflux under nitrogen protection and is stirred to react 18h.It is cooled to room temperature, removes under reduced pressure molten to reaction solution
Water (30mL) is added in agent, residue, adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, it is dry to carry out vacuum to obtained solid
It is dry to obtain dark green solid compound 7 (312mg, 92.6%).1H NMR (400MHz, DMSO-d6)：δ ppm 10.61 (s, 2H),
9.64 (d, J=3.9Hz, 4H), 9.13 (d, J=3.7Hz, 4H), 7.86-7.75 (m, 4H), 7.46 (d, J=6.4 Hz, 2H),
4.92 (s, 4H), 4.09 (s, 6H), -3.21 (s, 2H)13C NMR (100MHz, DMSO-d6)：δ ppm 170.98,149.42,
147.24,146.34,145.09,132.97,131.36,128.95,120.89,120.64,118.99,111.65,106.13,
65.61,56.34.HRMS (MALDI)：m/z calcd for C38H34N4O8[M]+, 674.2371；Found, 674.2370.
[embodiment 4]
The preparation method of 5,15- bis- [(3- carboxylic propoxyl group) phenyl] isobacteriochlorins (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 monitoring raw material has reacted
Entirely.Reaction solution is cooling, ethyl acetate (100mL) is added and distilled water (50mL) 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, will
Solvent is evaporated off in filtrate decompression.Purifying is used column chromatography to gained residue and obtains diphenyl isobacteriochlorin compound 12
(72.5mg, 18.4%).
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 under nitrogen protection and is stirred to react 18h.It is cooled to room temperature to reaction solution, decompression is steamed
Except solvent, water (30mL) is added in residue, adjusts pH to 3-4 with hydrochloric acid solution (2mol/L).It filters, obtained solid is carried out true
Sky is dried to obtain dark green solid compound 10 (327.2mg, 89.6%).1H NMR (400MHz, DMSO-d6)：δppm
12.08 (s, 2H), 8.89 (s, 2H), 8.72 (d, J=4.6Hz, 2H), 8.13 (d, J=4.6Hz, 2H), 7.48 (s, 2H),
7.37 (d, J=7.7Hz, 2H), 7.29 (d, J=8.2Hz, 2H), 4.44 (t, J=8.4Hz, 4H), 4.22-4.05 (m, 8H),
3.99 (s, 6H), 2.42 (t, J=7.4Hz, 4H), 2.00 (q, J=7.0Hz, 4H), -1.65 (s, 2H)13C NMR
(100MHz, DMSO-d6)：δ ppm 180.36,163.88,162.37,161.41,154.61,152.35,148.29,
146.69,142.75,134.50,133.53,132.04,128.38,125.75,124.35,116.02,113.69,
112.77,102.92,67.91,55.91,33.45,32.90,30.93,24.87.HRMS (MALDI)：m/z calcd for
C42H42N4O8[M]+, 730.2997；Found, 730.2996.
[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] isobacteriochlorins (compound 1) (hereinafter referred to as photosensitizer 1)；
5,15- bis- [(3- carboxylic propoxyl group) phenyl] isobacteriochlorins (compound 4) (hereinafter referred to as photosensitizer 2)；5,15- bis- [(3- carboxylic first
Oxygroup -4- methoxyl group) phenyl] isobacteriochlorin (compound 7) (hereinafter referred to as photosensitizer 3)；5,15- bis- [(3- carboxylic propoxyl group) benzene
Base] isobacteriochlorin (compound 10) (hereinafter referred to as photosensitizer 4)；Control compound 5,15- bis- (4- carboxyl phenyl) isobacteriochlorin
(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-730AB 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 730nm, light dosage 4J/cm2)；MTT detection is carried out when 72h.Culture
The MTT of 20 μ L 5mg/mL is added in 4h before terminating, and suction is abandoned after culture solution plus 150 μ L DMSO terminate reaction, and microplate reader 570nm is detected
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 eat people
Pipe cancer cell has antiproliferative effect, and activity 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 isobacteriochlorin 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 isobacteriochlorin 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, it is cooled to room temperature to reaction solution, 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 evaporating solvent under reduced pressure carries out column chromatographic isolation and purification to gained residue and obtains diphenyl isobacteriochlorin compound (III).
Diphenyl isobacteriochlorin 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, it is right
Obtained solid is dried in vacuo to obtain diphenyl isobacteriochlorin compound (I).
Wherein R1、R2、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 isobacteriochlorin 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 5-20h.
4. the preparation method of one kind diphenyl isobacteriochlorin 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 isobacteriochlorin 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 isobacteriochlorin 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 isobacteriochlorin 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 isobacteriochlorin 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, positive fourth that it is acid that formula (III), which prepares acid used when formula (I),
Any one in acid, trifluoroacetic acid etc. or any a variety of mixture.
9. one kind diphenyl isobacteriochlorin compound (I) according to claim 1 can be used as light power diagnosis and treatment tumour, view
The drug of the diseases such as film macular degeneration, actinic keratoma, nevus flammeus, condyloma acuminatum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810491890.9A CN108864118A (en) | 2018-05-21 | 2018-05-21 | A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810491890.9A CN108864118A (en) | 2018-05-21 | 2018-05-21 | A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108864118A true CN108864118A (en) | 2018-11-23 |
Family
ID=64333048
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810491890.9A Pending CN108864118A (en) | 2018-05-21 | 2018-05-21 | A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108864118A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114516879A (en) * | 2022-02-28 | 2022-05-20 | 上海先辉医药科技有限公司 | Novel intermediate tetraphenyl naphthoporphin derivative and application thereof in medical field |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382493A (en) * | 2001-04-25 | 2002-12-04 | 中国科学院化学研究所 | Diarylprophin photosensitizer and its preparing process and usage |
| WO2005000854A2 (en) * | 2003-06-06 | 2005-01-06 | Eukarion, Inc. | Orally bioavailable low molecular weight metalloporphyrins as antioxidants |
| WO2007047925A2 (en) * | 2005-10-20 | 2007-04-26 | North Carolina State University | Swallowtail motifs for imparting water solubility to porphyrinic compounds |
| CN107001031A (en) * | 2014-10-14 | 2017-08-01 | 芝加哥大学 | Nano particle for photodynamic therapy, the photodynamic therapy of X ray induction, radiotherapy, chemotherapy, immunotherapy and its any combination |
-
2018
- 2018-05-21 CN CN201810491890.9A patent/CN108864118A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382493A (en) * | 2001-04-25 | 2002-12-04 | 中国科学院化学研究所 | Diarylprophin photosensitizer and its preparing process and usage |
| WO2005000854A2 (en) * | 2003-06-06 | 2005-01-06 | Eukarion, Inc. | Orally bioavailable low molecular weight metalloporphyrins as antioxidants |
| WO2007047925A2 (en) * | 2005-10-20 | 2007-04-26 | North Carolina State University | Swallowtail motifs for imparting water solubility to porphyrinic compounds |
| CN107001031A (en) * | 2014-10-14 | 2017-08-01 | 芝加哥大学 | Nano particle for photodynamic therapy, the photodynamic therapy of X ray induction, radiotherapy, chemotherapy, immunotherapy and its any combination |
Non-Patent Citations (2)
| Title |
|---|
| JAYEETA BHAUMIK，等: "Bioinspired nanophotosensitizers: synthesis and characterization of porphyrin–noble metal nanoparticle conjugates", 《NEW J. CHEM.》 * |
| PEDRO M. SANTOS，等: "Evaluation of a 99mTc-labelled meso-bisphenylporphyrin as a tumour image agent", 《J. LABEL COMPD. RADIOPHARM》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN114516879A (en) * | 2022-02-28 | 2022-05-20 | 上海先辉医药科技有限公司 | Novel intermediate tetraphenyl naphthoporphin derivative and application thereof in medical field |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108864118A (en) | A kind of diphenyl isobacteriochlorin compound and the preparation method and application thereof | |
| KR20190070925A (en) | Novel chlorin e6 derivatives and their pharmaceutically acceptable salts, their preparation and application | |
| EP2940021B1 (en) | Cyanine dye compound and preparation method therefor, and dual-function agent for photodynamic therapy and preparation method therefor | |
| CN108864117A (en) | A kind of diphenyl chlorin compound and the preparation method and application thereof | |
| CN103833762B (en) | Chlorin compounds, its preparation method, pharmaceutical composition and application | |
| CN104974182A (en) | Silicon phthalocyanine complex, and preparation method and pharmaceutical application thereof | |
| CN110698449B (en) | Preparation method and application of photosensitizer | |
| Pandey et al. | Regioselective syntheses of ether-linked porphyrin dimers and trimers related to photofrin-II® | |
| CN113527319B (en) | Novel chlorin e4 derivative and pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| CN104817568B (en) | 5, 6-bidehydronorcantharides alcohol derivative and application thereof to tumor resistance | |
| WO2018086241A1 (en) | Ph-sensitive 1,4-disubstituted zinc phthalocyanine coordination complex, preparation method therefore, and application thereof in medicine | |
| CN107344943A (en) | A kind of amido modified tetraphenylporphyrin compound and preparation method and application | |
| CN102268004B (en) | Chlorophyllin salt compound and preparation method thereof | |
| CN106083872B (en) | Purpurin 18 ether derivative and its preparation method and application | |
| CN103864877B (en) | A kind of preparation method of Abiraterone acetate | |
| CN100408581C (en) | 3-(1-alkoxy ethyl)-8-ethyl-2,7,12,15,18-pentamethyl-13-carboxylic acid-17-propionic acid, its synthetic method and light power therapeutic medicine | |
| CN106939003A (en) | Double carboxymethyl meso-tetrahenylchlorin compounds of one class and preparation method and application | |
| CN105198714B (en) | Red bayberry 01 derivatives and its preparation method and application | |
| CN108864116A (en) | A kind of novel chlorin e 6 derivative and the preparation method and application thereof | |
| CN102068428A (en) | Dihydroporphin photosensitizer and preparation and application thereof | |
| CN107226817A (en) | A kind of pyropheophorbide-a methyl ether compound and preparation method and application | |
| CN102125549B (en) | Dihydroporphin photosensitizer as well as preparation method and application thereof | |
| EP0322198A2 (en) | Pheophorbide derivatives | |
| CN101606933A (en) | Dihydro porphin photosensitizer and preparation thereof and application | |
| CN114426538B (en) | Berberine canagliflozin derivative and preparation method and 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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181123 |
|
| WD01 | Invention patent application deemed withdrawn after publication |