CN104744482A - Novel chlorophyllin as well as preparation method and application thereof - Google Patents
Novel chlorophyllin as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a novel chlorophyllin compound for photodynamic therapy as well as a preparation method and application thereof. The preparation method comprises the following steps: (a) converting pheophorbide into acidic porphyrin; (b) derivatizing the acidic porphyrin; (c) reacting complex derivatized acidic porphyrin with selected alkali in a medium of water and aqueous organic solution to obtain the water-soluble chlorophyllin compound. The chlorophyllin compound can be used as a photo-sensitive medicine in photodynamic therapy for cancers, infections and other diseases requiring photoradiation therapy.
Description
Technical field
The present invention relates to bioactive compounds chemical field, namely photodynamic therapy (Photodynamic therapy is related to, PDT) novel photosensitive agent (Photosensitizer) in and preparation method thereof, particularly a kind of Novel leaf green acids salt and its preparation method and application.
Background technology
Photodynamic therapy (Photodynamic Therapy, PDT) is a kind of new technology utilizing photodynamic effect to carry out medical diagnosis on disease and treatment.Its exposure basis is photodynamic effect.This is a kind of Photosensitive reaction of the adjoint biological effect having oxygen molecule to participate in.Its process is, the laser radiation of specific wavelength makes the photosensitizers of tissue resorption be excited, and the photosensitizers of excited state transmission ofenergy to the oxygen of surrounding, generate active very strong singlet oxygen, singlet oxygen and adjacent biomacromolecule generation oxidizing reaction, produce cytotoxic effect, and then cause cell damage and even death.
Photodynamic therapy, as the new technology of oncotherapy, compared with the conventional meanses such as operation, chemotherapy, radiotherapy, has many important advantage, in the complex therapy of tumour, day by day demonstrates vital role.Up to now, this therapy is successfully in order to treat Several Kinds of Malignancy, the precancerous lesions such as esophagus squameous epithelial dysplasia and Barrett esophageal lesion, bronchiolar epithelium atypical hyperplasia, urinary bladder transitional epithelium atypical hyperplasia, and the nontumorous benign lesion such as senile fundus flavimaculatus pathology, skin nevus flammeus, curative effect is encouraging, has a extensive future.
Existing 3 kinds of photosensitive drugs obtain the approval of U.S. food and Drug Administration (FDA) at present, i.e. PHOTOFRIN (popular name porfimer sodium), Visudyne(popular name verteporfin, or chemical structure is called for short BPD-MA) and 5-ALA (5-aminolaevulinic acid, ALA).
Up to now, PHOTOFRIN has obtained unique photosensitive drug that U.S. FDA approval can be applicable to the treatment of multiple solid malignant.This kind ofly extracts from ox blood and carry out the porphyrin oligomer mixture of chemical modification.PHOTOFRIN is its trade(brand)name, this medicine now the U.S., Canada, etc. more than ten countries obtain the approval of Yao Jian departments of government, the conventional treatment of some tumor types patient in the esophageal carcinoma, lung cancer, bladder cancer, cervical cancer and skin carcinoma can be respectively used to.Another 2 kinds of photosensitive drugs and Visudyne and 5-aminolaevulinic acid are mainly used in the treatment of non-neoplastic disease (senile fundus flavimaculatus pathology, photochemistry property keratosis).
But show the analysis of PHOTOFRIN, its mesoporphyrin monomer: dimer: 22:23:55, the stratographic analysis carried out can obtain 60 peaks, so cannot effective quality control be carried out, so clinical effectiveness difference is huge.Photosensitizers is the key agents in photodynamic therapy, China was from 1986, You Jijia research institution just starts the research and development to anticancer photosensitizer, the main protoheme that extracts from ox blood obtains active drug (happiness pool point) by semi-synthetic again, then kills and wounds cancer cells with laser combined utilization.But due to completely unclear to the effective constituent of happiness pool point, therefore, happiness pool on applying, does not get a desired effect point as first-generation anticancer photosensitizer.
Object of the present invention, except overcoming above-mentioned shortcoming, it would also be desirable to provide the photosensitive drug stablized.
Clinically need the photosensitive drug with following characteristics: be first that absorbing wavelength is greater than 650 nanometers; Next is the quantum yield with higher triplet state quantum yield and single low heavy state oxygen; 3rd is have low dark toxicity; 4th selectivity is high; 5th is that structure is clear and definite, stable performance; Be exactly finally have good fat, water is compatible.
Summary of the invention
The object of the present invention is to provide a kind of novel chlorophyllin salt compound, and provide a kind of and to be easy to and effective means prepares this compound; CHLOROPHYLLINE salt compounds of the present invention can be used as photosensitizers in the photodynamic therapy of cancer, infection and other disease needing optical radiation to treat.
the object of the invention is to be achieved through the following technical solutions:
A kind of Novel leaf green acids salt, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl.
Further, described R
1independently selected from CH
2(CH
2)
4cH
3or CH
2(CH
2)
5cH
3, described R
2for NH
4 +or K
+, described R
3for H or carboxyl.
another object of the present invention is achieved through the following technical solutions:
A preparation method for Novel leaf green acids salt, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl;
Described preparation method comprises the following steps:
A) pheophorbide is converted into acidic porphyrin;
B) by acidic porphyrin derivatize, obtain complexing and derive acidic porphyrin;
C) described complexing is made to derive acidic porphyrin and selected alkali is obtained by reacting CHLOROPHYLLINE salt compounds in the medium being selected from water and aqueous organic solution.
Further, the described step solvent that a), b) the middle alkali aqueous solution adopted is miscible is: the mixture of one or more in lower alkane alcohols, polyalcohols, ring-type ethers, ketone, nitrile, amides, sulfoxide type, sulfone class, gylcol ether.
Further, described lower alkane alcohols is the mixture of one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol; Described polyalcohols is the mixture of one or more in ethylene glycol, 1,2-PD, glycerine; Described ring-type ethers is the mixture of one or more in tetrahydrofuran (THF), dioxane, morpholine; Described ketone is acetone; Described nitrile is the mixture of one or more in acetonitrile, succinonitrile; Described amides is the mixture of one or more in methane amide, DMF; Described sulfoxide type is methyl-sulphoxide; Described sulfone class is tetramethylene sulfone; Described gylcol ether is the mixture of one or more in methyl glycol, glycol monoethyl ether, glycol ether.
Further, the temperature of reaction in described step b) is 0 ~ 90 DEG C, is preferably 20 ~ 60 DEG C.
Further, the reaction times in described step b) is 4 ~ 24h.
Another object of the present invention is achieved through the following technical solutions:
For a photosensitive drug for photodynamic therapy, comprise described Novel leaf green acids salt in described photosensitive drug, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl.
the present invention's beneficial effect is compared to existing technology:
1, the novel photosensitive agent that Novel leaf green acids salt of the present invention is a class stable in properties, light is energetic, skin phototoxicity is little, quality controllable;
2, R in Novel leaf green acids salt of the present invention
2for NH
4 +or K
+, add the water-soluble of this photosensitizers, more effective in follow-up preparation and clinical application;
3, Novel leaf green acids salt of the present invention can be used for treatment or diagnosing malignant tumor, precancerous lesion, such as Ba Leiteshi oesophagus, oral leukoplakia etc.; Benign lesion, as senile fundus flavimaculatus pathology, atherosclerotic plaque, rheumatoid arthritis, Dermal microvessel deformity, psoriasis, Lupus erythematosus skin lesion etc.
Embodiment
embodiment 1
A kind of Novel leaf green acids salt, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl.
Further, described R
1independently selected from CH
2(CH
2)
4cH
3or CH
2(CH
2)
5cH
3, described R
2for NH
4 +or K
+, described R
3for H or carboxyl.
The preparation method of described Novel leaf green acids salt comprises the following steps:
A) pheophorbide is converted into acidic porphyrin;
B) by acidic porphyrin derivatize, obtain complexing and derive acidic porphyrin;
C) described complexing is made to derive acidic porphyrin and selected alkali is obtained by reacting CHLOROPHYLLINE salt compounds in the medium being selected from water and aqueous organic solution.
Further, the described step solvent that a), b) the middle alkali aqueous solution adopted is miscible is: the mixture of one or more in lower alkane alcohols, polyalcohols, ring-type ethers, ketone, nitrile, amides, sulfoxide type, sulfone class, gylcol ether.
Further, described lower alkane alcohols is the mixture of one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol; Described polyalcohols is the mixture of one or more in ethylene glycol, 1,2-PD, glycerine; Described ring-type ethers is the mixture of one or more in tetrahydrofuran (THF), dioxane, morpholine; Described ketone is acetone; Described nitrile is the mixture of one or more in acetonitrile, succinonitrile; Described amides is the mixture of one or more in methane amide, DMF; Described sulfoxide type is methyl-sulphoxide; Described sulfone class is tetramethylene sulfone; Described gylcol ether is the mixture of one or more in methyl glycol, glycol monoethyl ether, glycol ether.
Further, the temperature of reaction in described step b) is 0 ~ 90 DEG C, is preferably 10 ~ 65 DEG C, is more preferably 20 ~ 60 DEG C.
Further, the reaction times in described step b) is 4 ~ 24h, is preferably 12h.
On the other hand, the compound as photosensitive drug is present embodiments provided.
On the other hand, present embodiments provide a kind of photosensitive drug for photodynamic therapy, it comprises compound of the present invention or mixture of the present invention, and person comprise one or more pharmaceutically useful vehicle.
On the other hand, present embodiments provide the purposes of CHLOROPHYLLINE salt compounds, be namely used for the treatment of as photosensitive drug or diagnosing malignant tumor, precancerous lesion or benign lesion.
On the other hand, the present embodiment additionally provides the method for the treatment of malignant tumour, precancerous lesion or benign lesion, it comprises uses the compound of the present embodiment of significant quantity or the mixture of the present embodiment or its pharmaceutical composition to described individuality, and imposes the rayed of the specific wavelength of significant quantity.
embodiment 2
With silkworm excrement chlorophyll for raw material, preparation 2-removes vinyl-2-(the own hydroxyethyl of 1-)-pyropheophorbide-a ammonium (1), and preparation method comprises the following steps:
A) pheophorbide-a methyl esters is prepared
200g silkworm excrement chlorophyll is dissolved in 4000mL containing in the methanol solution of 5% sulfuric acid; under nitrogen protection, room temperature lucifuge stirs 12 hours; after filtration treatment; add water again and methylene dichloride carry out extraction treatment; organic phase washed with water; concentrating under reduced pressure after dry; the enriched material obtained is carried out silica gel column chromatography separation [eluent: V (sherwood oil): V (ethyl acetate)=3:1] again; obtain dark green solid A6.9g; namely obtain described Enfoliative cytologic, yield is 3.45%.UV-vis (CHCl3) λmax : 407(1.0), 503 (0.03), 532 (0.02), 610 (0.02), 667 (0.39) nm; IR ( KBr ) ν: 2946-2843 ( C-H ), 1736 ( C=C ), 1640 ( C=N ), 1624 ( C=C ) cm-1; 1H NMR (CDCl3) δ: -1.68 (1H, NH), 0.52( 1H, NH), 1.70 (d, J=7.5 Hz, 3H, 18-CH3), 1.82 (t, J=7.5Hz, 3H, 82-CH3), 2.17-2.40 (m, 2H 171-CH2),2.43-2.78 (m,2H, 172-H), 3.26, 3.40, 3.58, 3.67 (12H, CH3), 3.72 (q, J=7.5 Hz, 2H,81-CH2), 3.86 (s, 3H, 132-OCH3), 4.20-4.36 (m, 1H, 17-H), 4.38-4.50 (m, 1H, 18-H), 6.24 (s, 1H, 132-H),6.16 (d, J=11.5 Hz, 1H, 32b-H ), 6.29 (d, J=17.5 Hz, 1H, 32a-H), 8.03 (m, 1H, 31-H), 8.57, 9.41, 9.53( each s, 1H, meso-H )。
B) Methyl Pyropheophorbide is prepared
Get steps A) in the dark green solid A 2.0g (3.3mmol) that obtains, after dissolving with 200 mL glacial acetic acids, stirring and refluxing reacts 4 h, reaction terminates rear underpressure distillation, steam and add 200 mL water except after most of acetic acid, extraction treatment is carried out with methylene dichloride (3 × 60 ml), by concentrating under reduced pressure after organic phase drying, again gained enriched material is separated [eluent: V (sherwood oil): V (ethyl acetate)=3:1] by silica gel column chromatography, obtain dark green solid B (1.5g, 2.80mmol), i.e. Methyl Pyropheophorbide, productive rate is 85%.UV-vis (CHCl3) λmax: 411 (1.0), 669 (0.39) nm;IR( KBr ) ν: 2935-2846( C-H ), 1736 ( C=C ), 1643 ( C=N ), 1619 ( C=C ) cm-1; 1H NMR (CDCl3) δ: -1.68 (1H, NH), 0.49 (1H, NH),1.69 (d, J=7.5 Hz, 3H, 18-CH3), 1.80 (t, J=7.5 Hz, 3H, 82-CH3), 2.14-2.38 (m, 2H 171-CH2), 3.24,3.42, 3.66, 3.62(12H, CH3),2.41-2.82 (m,2H, 172-CH2), 3.70 (q, J=7.5 Hz, 2H, 81-CH2), 4.17-4.38 (m, 1H, 17-H) 4.40-4.53 (m, 1H, 18-H), 5.15 (d, J=20.0 Hz, 1H, 132-H), 5.26 (1H, 132-H), 6.19- 6.26 (m, 2H, 32-H), 8.00 (m, 1H, 31-H), 8.58, 9.45, 9.56 ( s, 1H, meso-H )。
C) 2-goes the preparation of vinyl-2-(the own hydroxyethyl of 1-)-Methyl Pyropheophorbide
Get 500mg (0.93mmol) dark green solid B with 30% Hydrogen bromide glacial acetic acid (12.5 milliliters) dissolve, then stirring at normal temperature reacts 3 h, vacuum decompression is except desolventizing, obtain the solid mainly removing vinyl-2-(1-bromotrifluoromethane)-Methyl Pyropheophorbide containing 2-, add 7.5 milliliters of n-hexyl alcohols, add 60 milliliters of anhydrous methylene chlorides and 200 milligrams of Anhydrous potassium carbonates, react under nitrogen protection after 1 hour, add methylene dichloride 500 milliliters, organic layer evaporate to dryness, take alumina column chromatography, [eluent: V (sherwood oil): V (acetone)=4:1], obtain target compound, productive rate is 55%, UV-vis (CHCl3) λ max:410 (1.00), 505 (0.10), 536 (0.10), 667 (0.45) nm, IR (KBr) v:2985-2870 (C-H), 1742,1708 (C=O), 1640 (C=N), 1620 (C=C) cm-1, 1H NMR (CDCl3) δ: 9.70, 9.53, 8.51 (each s, each 1H, meso-H), 6.25-6.43 (m, 1H, 31-H), 6.25 (s, 1H, 132-H), 4.45-4.49 (1H, 17-H), 4.15-4.26 (1H, 18-H), 3.88, 3.69, 3.55, 3.40, 3.23 (each s, each 3H, CH3), 3.70 (q, J=7.5 Hz, 81-CH2), 2.18 (d, J=7.0 Hz, 31-CH3), 2.00-2.70 (4H, 17-CH2), 1.81 (t, J=7.0 Hz, 8-CH3), 1.73 (d, J=7.5 Hz, 18-CH3), 0.50,-1.70 (each br s, each1H, NH).
D) 2-goes the preparation of vinyl-2-(the own hydroxyethyl of 1-)-pyropheophorbide-a ammonium salt
Get 100 milligrams of 2-to go vinyl-2-(the own hydroxyethyl of 1-)-Methyl Pyropheophorbide to add 20 ml tetrahydrofuran (THF)s to make whole dissolving, add 4 ml 4mol/L ammonia solns, placement is spent the night, removal of solvent under reduced pressure.Reaction product loads in apparatus,Soxhlet's, acetone reflux, and gained acetone reflux liquid evaporate to dryness, obtains target compound (1):
。
In the present embodiment, each raw material, reagent and equipment are market conventional products.
embodiment 3
With silkworm excrement chlorophyll for raw material 2-removes vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a two ammonium (2), preparation method comprises the following steps:
A) pheophorbide-a methyl esters is prepared
100g silkworm excrement chlorophyll is dissolved in 2000mL containing in the methanol solution of 5% sulfuric acid; under nitrogen protection, room temperature lucifuge stirs 12 hours; add water after filtration and dichloromethane extraction; organic phase washed with water; concentrating under reduced pressure after dry, silica gel column chromatography is separated [eluent: V (sherwood oil): V (ethyl acetate)=3:1], obtains dark green solid A 3.50g; be pheophorbide-a methyl esters, yield is 3.5%.UV-vis (CHCl
3) λmax : 407(1.0), 503 (0.03), 532 (0.02), 610 (0.02), 667 (0.39) nm; IR ( KBr ) ν: 2946-2843 ( C-H ), 1736 ( C=C ), 1640 ( C=N ), 1624 ( C=C ) cm
-1;
1H NMR (CDCl
3) δ: -1.68 (1H, NH), 0.52( 1H, NH), 1.70 (d, J=7.5 Hz, 3H, 18-CH
3), 1.82 (t, J=7.5Hz, 3H, 8
2-CH
3), 2.17-2.40 (m, 2H 17
1-CH
2),2.43-2.78 (m,2H, 17
2-H), 3.26, 3.40, 3.58, 3.67 (12H, CH
3), 3.72 (q, J=7.5 Hz, 2H,8
1-CH
2), 3.86 (s, 3H, 13
2-OCH
3), 4.20-4.36 (m, 1H, 17-H), 4.38-4.50 (m, 1H, 18-H), 6.24 (s, 1H, 13
2-H),6.16 (d, J=11.5 Hz, 1H, 3
2b-H ), 6.29 (d, J=17.5 Hz, 1H, 32a-H), 8.03 (m, 1H, 3
1-H), 8.57, 9.41, 9.53( each s, 1H, meso-H )。
B) 2-goes the preparation of vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a dimethyl ester
Dark green solid A described in 1.0 g (0.93mmol) the Hydrogen bromide glacial acetic acid of 25ml 30% is dissolved, then stirring at normal temperature reacts 3 h, vacuum decompression is except desolventizing, obtain the solid mainly removing vinyl-2-(1-bromotrifluoromethane)-pheophorbide-a dimethyl ester containing 2-, add 15 milliliters of n-hexyl alcohols, add 100 milliliters of anhydrous methylene chlorides and 500 milligrams of Anhydrous potassium carbonates, react under nitrogen protection after 1 hour, add methylene dichloride 1000 milliliters, organic layer evaporate to dryness, take alumina column chromatography, [eluent: V (sherwood oil): V (acetone)=4:1] namely obtains target compound, wherein remove vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a dimethyl ester containing described 2-, productive rate is 60%.UV-vis (CHCl
3)λmax: 410 (1.00), 505 (0.10), 536 (0.10), 667 (0.45) nm; IR (KBr) v: 2985-2870 (C-H), 1742,1708 (C=O), 1640 (C=N), 1620 (C=C) cm
-1；
1H NMR (CDCl
3) δ: 9.70, 9.53, 8.51 (each s, each 1H, meso-H), 6.25-6.43 (m, 1H,3
1-H), 6.25 (s,1H, 13
2-H), 4.45-4.49 ( 1H, 17-H), 4.15-4.26 (1H, 18-H), 3.88（s, 6 H, CH
3）, 3.69, 3.55, 3.40, 3.23(each s, each 3H, CH
3), 3.70 (q, J=7.5 Hz, 8
1-CH
2), 2.18 (d, J = 7.0 Hz, 3
1-CH3), 2.00-2.70 (4H, 17-CH
2), 1.81 (t, J=7.0 Hz, 8-CH
3), 1.73 (d, J=7.5 Hz, 18-CH
3), 0.50, -1.70 (each br s, each1H, NH)。
C) 2-goes the preparation of vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a two ammonium (2)
200 milligrams of 2-go that vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a dimethyl ester adds 40 ml tetrahydrofuran (THF)s makes whole dissolving, and add 10 ml 4mol/L ammonia solns, placement is spent the night, removal of solvent under reduced pressure.Reaction product loads in apparatus,Soxhlet's, acetone reflux, gained acetone reflux liquid evaporate to dryness, obtain target compound (
2):
。
In the present embodiment, each raw material, reagent and equipment are market conventional products.
embodiment 4
The present embodiment is the detected result of embodiment 2 and embodiment 3, and 2-goes vinyl-2-(the own hydroxyethyl of 1-)-pyropheophorbide-a ammonium (1) and 2-to go vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a two ammonium (2) photosensitization in cell-free system.
In heavy water, the photosensitization of compound judges the possibility of this compound as photo-dynamical medicine, reference [Xu Deyu etc., The 2nd Army Medical College journal, 1988,9(5): 435 and Li Yixin etc., Acta Biophysica Sinica, 1985,1(4): 257] described method, compare 2-go vinyl-2-(the own hydroxyethyl of 1-)-pyropheophorbide-a ammonium (
1) and 2-go vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a two ammonium (
2) in heavy water to the sensitization effect of NADPH photooxidation, the results are shown in following table.
According to the above results, 2-go vinyl-2-(the own hydroxyethyl of 1-)-pyropheophorbide-a ammonium (
1) and 2-go vinyl-2-(the own hydroxyethyl of 1-)-pheophorbide-a two ammonium (
2) photooxidation be all better than HpD.
Claims (10)
1. a Novel leaf green acids salt, is characterized in that, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl.
2. Novel leaf green acids salt according to claim 1, is characterized in that, described R
1independently selected from CH
2(CH
2)
4cH
3or CH
2(CH
2)
5cH
3, described R
2for NH
4 +or K
+, described R
3for H or carboxyl.
3. Novel leaf green acids salt according to claim 2, it is characterized in that, structural formula is:
。
4. Novel leaf green acids salt according to claim 2, it is characterized in that, structural formula is:
。
5. a preparation method for Novel leaf green acids salt, is characterized in that, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl;
Described preparation method comprises the following steps:
A) pheophorbide is converted into acidic porphyrin;
B) by acidic porphyrin derivatize, obtain complexing and derive acidic porphyrin;
C) described complexing is made to derive acidic porphyrin and selected alkali is obtained by reacting CHLOROPHYLLINE salt compounds in the medium being selected from water and aqueous organic solution.
6. the preparation method of Novel leaf green acids salt according to claim 5, is characterized in that,
The described step solvent that a), b) the middle alkali aqueous solution adopted is miscible is: the mixture of one or more in lower alkane alcohols, polyalcohols, ring-type ethers, ketone, nitrile, amides, sulfoxide type, sulfone class, gylcol ether.
7. the preparation method of Novel leaf green acids salt according to claim 6, is characterized in that,
Described lower alkane alcohols is the mixture of one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol;
Described polyalcohols is the mixture of one or more in ethylene glycol, 1,2-PD, glycerine;
Described ring-type ethers is the mixture of one or more in tetrahydrofuran (THF), dioxane, morpholine;
Described ketone is acetone;
Described nitrile is the mixture of one or more in acetonitrile, succinonitrile;
Described amides is the mixture of one or more in methane amide, DMF;
Described sulfoxide type is methyl-sulphoxide;
Described sulfone class is tetramethylene sulfone;
Described gylcol ether is the mixture of one or more in methyl glycol, glycol monoethyl ether, glycol ether.
8. the preparation method of the Novel leaf green acids salt according to any one of claim 5-7, is characterized in that, the temperature of reaction in described step b) is 0 ~ 90 DEG C, is preferably 20 ~ 60 DEG C.
9. the preparation method of the Novel leaf green acids salt according to any one of claim 5-7, is characterized in that, the reaction times in described step b) is 4 ~ 24h.
10. for a photosensitive drug for photodynamic therapy, it is characterized in that, comprise Novel leaf green acids salt as claimed in claim 1 or 2 in described photosensitive drug, the general formula of described CHLOROPHYLLINE salt is as follows:
Wherein, R
1independently selected from C
1-18alkyl, C
1-18alkenyl, C
1-8alkoxyl group and C
1-18acyl group, it is optionally replaced by one or more substituting group being selected from halogen and hydroxyl; R
2for NH
4 +or K
+; R
3for H or carboxyl.
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|---|---|---|---|---|
| CN106083872A (en) * | 2016-05-25 | 2016-11-09 | 中国人民解放军第二军医大学 | C.I. Natural Red 8 18 ether derivative and its production and use |
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