CN1738823A - Porphyrin derivatives - Google Patents

Porphyrin derivatives Download PDF

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Publication number
CN1738823A
CN1738823A CNA2003801087820A CN200380108782A CN1738823A CN 1738823 A CN1738823 A CN 1738823A CN A2003801087820 A CNA2003801087820 A CN A2003801087820A CN 200380108782 A CN200380108782 A CN 200380108782A CN 1738823 A CN1738823 A CN 1738823A
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group
compound
cancer
general formula
pharmaceutical salts
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CN100439372C (en
Inventor
禹南台
姜旼锡
李元营
李昌凞
金容禄
李大云
元东勳
高时奂
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Kostarworld Co Ltd
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0036—Porphyrins

Abstract

The invention relates to a novel porphyrin photosensitive compound used as an anticancer or a photodynamic diagnostic reagent through reproducing the singlet oxygen free radical and medicine salt thereof. The compound of the invention has great advantages, such as the invention has outstanding photon yield to produce singlet oxygen, good physical stability and effective cytotoxicity compared to the conventional photosensitizer. The invention also provides a drug composition. The composition comprises a novel porphyrin photosensitive compound with the general formula being (I)-(VII), which is used as an active ingredient for preventing or treating various cancers, such as a stomach cancer, a liver cancer, a lung cancer, a cervical cancer and a breast cancer of a human being or a mammal, medicine salt and a medical carrier thereof.

Description

Derivatives of porphyrin
Technical field
The present invention relates to derivatives of porphyrin or its pharmaceutical salts and the pharmaceutical composition that is used for photodynamic therapy that comprises them.
Background technology
Photodynamic therapy (PDT) is by using cancer cells or various tumour to be had a kind of treatment technology that the photosensitizer pharmacological agent of selectivity and light enhanced activity can not cure diseases, the complication that it does not need surgical operation and does not have to occur in the chemotherapy.
The mechanism of action of photosensitizer medicine for example is, with medicine intravenously give the patient and with the light of optimal number to its radiation to form the excited state of photosensitizer.Medicine causes the activation oxygen molecule to be transformed into the singlet oxygen that excites, and cancer cells or various tumour are attacked and damaged to new free radical or new chemical substance selectivity.
Representational photosensitizer is from silk worm ight soil or mulberry leaf or green alga extraction and has suitable spectrophotometer measurement characteristic with the porphyrin compound as photosensitizer.Their most important properties is to cause transition of electron because its wavelength is the infrared light of 700-900nm, allows active and so the generation of triplet oxygen excited state of big relatively Premeabilisation of cells.
Not only can selective permeation or be accumulated in tumor locus as the derivatives of porphyrin of photosensitizer, and can also emitting fluorescence or phosphorescence, therefore can be used as the early diagnosis instrument.
In the prior art there are a large amount of reports in several derivatives of porphyrin.For example, the U.S. patent 5,633,275; 5,654,423; 5,675,001; 5,703,230; 5,705,622 and U.S. patent 4,882,234 several photofrin II compounds are disclosed.According to reports, wherein a kind ofly sell on market, other is carrying out clinical trial now, yet those porphyrins II is the mixtures that several oligopolymer that connected by haematoporphyrin (HpD) ether are formed.
PCT/WO97/29915 (A) discloses BPDMA (Visudyne), and it is a kind of known to skin carcinoma, and psoriasis and AMD represent the benzoporphyrin derivative of special effect.Be disclosed in PCT/WO97/48393, become known for treating the MTHPC of tracheae and lung cancer or be disclosed in the No.2121716 of CA registration and the No.09071531 of Japanese Patent registration, the known single bigcatkin willow acyl chlorides (Monoaspitylchlorine) that is used for photodynamic therapy as a kind of chlorine derivative with relevant several patents, be PCT/WO97/19081, PCT/WO 97/32885; EP 569113; U.S.Pat.Nos.5,587,394; 5,648,485 and 5,693,632 report together, and all documents are hereby incorporated by.
Yet the great majority of those porphyrin group compounds are meso-tetraphenylporphyrin derivatives, the chlorine group, the chlorophyll group, purpurine group (purpurin), alunite fourth (nerdine), Di Shi (Diels-Elder) reaction adducts etc. and the amino oxopentanoic acid of 5-, phthalocyanine and non-porphyrin group compound.
Because it is directly related with cytotoxic activity to produce the yield of singlet oxygen molecular, yield and cytotoxic activity are proportional, and in the photodynamic therapy of human body, it, still needs to improve as most important factor with retention time now.Yet above-mentioned to use porphyrin compound to have several shortcomings according to reports as the photosensitizer medicine clinically oversize so that discharge disadvantageous phototoxicity as the time that keeps in human body, still needs now to improve.
Therefore, the present inventor is devoted to find novel derivatives of porphyrin or their pharmaceutical salts, these derivatives or its pharmaceutical salts are new improved chlorine groups, the shortcoming of improving conventional photosensitizer medicine is promptly with respect to the physical stability of conventional derivatives of porphyrin, singlet oxygen free radical and higher cytotoxic activity are produced in the regeneration of high yield, finally finish the present invention.
Summary of the invention
The invention provides the new porphyrin compound and the pharmaceutical salts thereof that in photodynamic therapy, are used as photosensitizer.
The present invention also provides the pharmaceutical composition that comprises above-mentioned porphyrin compound, its as activeconstituents with its effective dose with pharmaceutical carrier, the treatment or the preventing cancer disease.
The present invention also provides above-mentioned porphyrin compound to be used for the treatment of or to prevent purposes in the medicine of the various cancers in the mankind or the Mammals in preparation.
The present invention also provides method for cancer in treatment or the prevention Mammals, and its method comprises above-claimed cpd or its pharmaceutical salts for the treatment of significant quantity.
Therefore, the object of the present invention is to provide new compound by following general formula (I) expression, and pharmaceutical salts:
Figure A20038010878200091
Wherein
R 1, R 2Be respectively straight chain or branching low alkyl group or alkoxyl group, polyethylene group or alkylsulfonyl with 1-6 carbon atom;
R 3Be hydrogen atom, have the alkoxyl group or a polyethylene group of 1-6 carbon atom;
R 4Be hydrogen atom, hydroxyl or alkoxyl group with 1-6 carbon atom,
A directly is connected or bridge joint with Sauerstoffatom, can with the transition metal ion chelating that comprises the Ni metal ion.
Embodiment preferred comprises the compound of general formula (I), wherein R 1, R 2Be selected from ethyl, propyl group, ethylene glycol group, diethylene glycol group, triglycol group, Tetraglycol 99 group, hexaethylene glycol group, seven glycol groups or methoxyl group ethylene glycol group; R 3Be selected from hydrogen atom, ethyl, propyl group, methoxyl group, oxyethyl group, ethylene glycol group, triglycol group, six ethylidene; R 4Be hydrogen atom, hydroxyl or methoxyl group; Directly be connected with A, condition is R 1And R 2Be identical group, and R 2Be different from R 1Or R 3
Preferred exemplary compounds of the present invention comprises the following compound by general formula (II)-(VII) expression.
Therefore, further aim of the present invention is to provide the new compound by following general formula (II) expression, and pharmaceutical salts:
Figure A20038010878200101
Wherein
R 1, R 2Be respectively straight chain or branching low alkyl group or alkoxyl group, polyethylene group or alkylsulfonyl with 1-6 carbon atom, it can with the transition metal ion chelating that comprises the Ni metal ion.
Therefore, still further aim of the present invention is to provide the new compound by following general formula (III) expression, and pharmaceutical salts:
Figure A20038010878200102
In the base
R 1It is polyethylene group;
R 4Be hydrogen atom or hydroxyl.
Therefore, still further aim of the present invention is to provide the new compound by following general formula (IV) expression, and pharmaceutical salts:
Figure A20038010878200111
Wherein
R 2Be bromopropyl or polyethylene group;
R 4Be hydrogen atom or hydroxyl.
Therefore, still further aim of the present invention is the new compound of being represented by following logical formula V is provided, and pharmaceutical salts:
Figure A20038010878200112
Wherein
R 1Be methyl, ethyl or ethylene glycol group.
Still, further aim of the present invention is to provide the new compound by following general formula (VI) expression, and pharmaceutical salts:
Figure A20038010878200121
Wherein
R 1, R 2It is respectively polyethylene group.
Still, further aim of the present invention is to provide the new compound by following general formula (VII) expression, and pharmaceutical salts:
Figure A20038010878200122
Wherein
R 1It is polyethylene group.
Can be transformed into their pharmaceutical salts with ordinary method well known in the art by the The compounds of this invention of general formula (I)-(VII) expression.For example, the acid salt that is formed by its medicinal free acid is useful and can be prepared by ordinary method, for example, in excess acid solution after the dissolved compound, salt is mixed with machine solvent such as methyl alcohol, ethanol, acetone or acetonitrile precipitation with the preparation acid salt mutually by water, further can be with the compound of equivalent and the mixture heating up of the acid of water or alcohol as the dilution of glycol monomethyl ether and the drying or under reduced pressure filter by evaporation subsequently with acquisition exsiccant salt.
As the free acid of aforesaid method, can use organic acid or mineral acid.For example, can use organic acid such as methylsulfonic acid, tosic acid, acetate, trifluoroacetic acid, citric acid, toxilic acid, succsinic acid, oxalic acid, phenylformic acid, lactic acid, oxyacetic acid, gluconic acid, galacturonic acid, L-glutamic acid, pentanedioic acid, glucuronic acid, Aspartic Acid, xitix, carbonylic acid, vanillic acid, hydroiodic acid HI etc. and mineral acid example hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartrate etc. at this.
In addition, can prepare the medicinal metal salt form of The compounds of this invention by using alkali.Its basic metal or alkaline earth salt can be prepared by ordinary method, for example, after compound being dissolved in excess base metal hydroxides or alkaline earth metal hydroxides solution, filtering insoluble salt and remaining filtrate is evaporated and dry the acquisition.As metal-salt of the present invention, sodium, potassium or calcium salt are that pharmacy is suitable, and its corresponding silver salt can prepare by an alkali metal salt or alkaline earth salt and suitable silver salt such as Silver Nitrate are reacted.
If do not specifically note, can comprise all acid-salts or the basic salt that can in compound, exist by the pharmaceutical salts of the compound of general formula (I)-(VII) expression at this.For example, pharmaceutical salts of the present invention comprises hydroxy salt such as its sodium, calcium and sylvite; Amide such as hydrobromate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, dihydrogen orthophosphate, acetate, succinate, Citrate trianion, tartrate, lactic acid salt, amygdalate, mesylate (mesylate) and tosilate (tosylate) etc., they can be by ordinary method preparation well known in the art.
Because the compound of general formula (I)-(VII) expression contains asymmetric center, can adopt the different diastereomer form of optics to exist, therefore, compound of the present invention comprises all optically active isomers, R or S steric isomer and composition thereof.The present invention also comprises racemic mixture, more than all application and all preparations of diastereomer well known in the art or the separation method of a kind of optically active isomer or its mixture.
Compound of the present invention can be by the method chemosynthesis in the following reaction scheme, and this method only is illustration and never limits the present invention.Reaction scheme represents to prepare the step of representative compounds of the present invention, also can follow following steps and produce other compound by suitable improvement reagent and original material, and these are faced by those skilled in the art.
General building-up process
For example, its pharmaceutical salts of porphyrin compound by general formula (I) expression can be prepared by following steps: phoeophytin α or 10-hydroxyl phoeophytin α are obtained by following mode: adopt water or organic solvent to contain the extract of porphyrin with acquisition as extractions such as alcohol, acetone or chloroforms in exsiccant silkworm worm ight soil or green alga; Extract is carried out multiple column chromatography and thin-layer chromatography to separate phoeophytin α (1) or 10-hydroxyl phoeophytin α; Then with isolated compound and alcohol (R 1OH) reacting under room temperature or reflux conditions in the presence of acid or the alkali to obtain ph(a)eophorbide α alkyl ester (2) or 10-hydroxyl ph(a)eophorbide α methyl ester, they are as the beginning material of the compound of being represented by general formula (II)-(VII).
Scheme 1
Figure A20038010878200141
Shown in above scheme 1, with phoeophytin α (1) and conventional alcohol (R 1OH) as 3-bromo-1-propyl alcohol or PEG such as ethylene glycol, triglycol in acid, preferably sulfuric acid exists down under nitrogen, reaction is 1 hour to 3 days in solvent such as toluene, oxazine, methylene dichloride, preferred 24 hours, adopt suitable washing soln washing, then remaining solvent is removed obtaining final product in a vacuum by vaporizer, ph(a)eophorbide α ester (2), and adopt column chromatography well known in the art or TLC further refining and separate it.
Detailed process described in the scheme 1 is explained in this paper embodiment 1-3.
Scheme 2
Figure A20038010878200142
(3) (4)
Shown in above scheme 2, with methylphaeophorbide α methyl ester (3) and alcohol (R 2OH) as 3-bromo-1-propyl alcohol or PEG such as ethylene glycol, triglycol in acid, preferably sulfuric acid or alkali, preferred pyridine exists down, under nitrogen, reaction is 1 hour to 3 days in inert solvent such as toluene, oxazine, methylene dichloride, preferred 24 hours, adopts suitable washing soln to wash, remaining solvent is removed obtaining final product ph(a)eophorbide α methyl ester (4) in a vacuum by vaporizer, adopted column chromatography well known in the art or TLC further refining and separate it.
Detailed process described in the scheme 2 is explained in this paper embodiment 4-5.
Scheme 3
Shown in above scheme 3, with methylphaeophorbide α methyl ester (5) Yu oxazine at alkali, preferred pyridine exists down, under nitrogen, reaction is 1 hour to 3 days in inert solvent such as toluene, oxazine, methylene dichloride, preferred 24 hours, adopt suitable washing soln such as ammonium sulfate to wash, then remaining solvent is removed obtaining end product oxazine class ph(a)eophorbide α methyl ester (6) in a vacuum by vaporizer, adopted column chromatography well known in the art or TLC further refining and separate it.
Detailed process described in the scheme 3 is explained in this paper embodiment 6.
Scheme 4
Shown in above scheme 4, with methylphaeophorbide α methyl ester (7) and triglycol in acid, preferably sulfuric acid exists down, under nitrogen, reaction is 1 hour to 3 days in inert solvent such as toluene, oxazine, methylene dichloride, preferred 24 hours, adopt suitable washing soln such as sodium bicarbonate to wash, remaining solvent is removed obtaining final product ph(a)eophorbide α methyl ester (8) in a vacuum by vaporizer, adopted column chromatography well known in the art or TLC further refining and separate it.
Detailed process described in the scheme 4 is explained in this paper embodiment 7 and 8.
Scheme 5
Figure A20038010878200162
Shown in above scheme 5, with phoeophytin α (9) and conventional alcohol (R 1OH) as 3-bromo-1-propyl alcohol or PEG such as ethylene glycol, triglycol in acid, there was down under nitrogen in solvent such as toluene, oxazine, methylene dichloride reaction in preferably sulfuric acid 1 hour to 3 days, preferred 24 hours, adopt the washing of suitable washing soln and remaining solvent is removed in a vacuum by vaporizer.Further compound is adopted oxygenant such as KMnO 4, NaIO 4Under alkaline condition, in nitrogen, in protonic solvent such as water, carry out oxidation obtaining final product ph(a)eophorbide α alcohol (10), adopt column chromatography well known in the art or TLC further refining and separate it.
Detailed process described in the scheme 5 is explained in this paper embodiment 9.
The present invention also provides and comprises that general formula is the compound or pharmaceutically acceptable salt thereof of (I)-(VII) is used for preventing or treat cancer of the stomach, liver cancer, lung cancer, cervical cancer and the mammary cancer of various cancers such as the mankind or Mammals as activeconstituents a pharmaceutical composition.
For can being provided as, the compound of (I)-(VII) comprises pharmaceutical carrier, the pharmaceutical composition of adjuvant or thinner according to general formula of the present invention.For example, compound of the present invention can be dissolved in oil, propylene glycol or other solvent commonly used and be used to produce injection liquid.The suitable example of carrier comprises physiological saline, polyoxyethylene glycol, ethanol, vegetables oil, isopropyl myristate etc., but is not limited to them.For topical, prepare with the form that adopts ointment and emulsion in the compound of the present invention.
Compound of the present invention has effective antitumour activity, and therefore, pharmaceutical composition of the present invention can be used for the treatment of or prevents various cancers by producing singlet oxygen free radical and excellent cytotoxic activity again.
The present invention also provides and is selected from general formula and is the compound of the compound or pharmaceutically acceptable salt thereof of (I)-(VII) purposes as photosensitizer in the photodynamic therapy.
According to a further aspect in the invention, also provide compound (I)-(VII) to be used for the treatment of or to prevent purposes in the medicine of cancer of the stomach, liver cancer, lung cancer, cervical cancer and mammary cancer in various cancers such as the mankind or the Mammals in manufacturing.
According to a further aspect in the invention, the method for the treatment of or preventing cancer of the stomach, liver cancer, lung cancer, cervical cancer and mammary cancer in various cancers such as the mankind or the Mammals also is provided, and it comprises that the general formula for the treatment of significant quantity is the compound or pharmaceutically acceptable salt thereof of (I)-(VII).
Following compound method and vehicle only are illustrations, never limit the present invention.
Compound of the present invention can adopt the form of their pharmaceutical salts to use on pharmaceutical dosage form, also can use separately or suitable being used in combination, and be used in combination with other medicinal activity compound.
By at water solvent such as physiological saline, 5% glucose, or dissolving in non-aqueous solvent such as vegetables oil, synthetic aliphatic acid glyceride, higher aliphatic acid esters or the propylene glycol, suspension or emulsification, compound of the present invention can be mixed with injection preparation.Preparaton can comprise conventional additives such as solubilizing agent, isotonic agent, suspension agent, emulsifying agent, stablizer and sanitas.
The required dosage of The compounds of this invention relies on the condition and the weight of object, severity, and medicament forms, can be selected by those skilled in the art route of administration and cycle and change.Yet for obtaining required effect, the dose of generally recommending of compound of the present invention is 0.0001-100mg/kg, preferably 0.001-100mg/kg/ days.The dosage of every day can be once or divide give several times with.Aspect composition, the amount of compound should be the 0.0001-10% of the gross weight of composition, preferred 0.0001-1%.
Pharmaceutical composition of the present invention can be administered to object animal such as Mammals (rat, mouse, the domestic animals or the mankind) by all means.For example imagine all mode of administration, administration can be oral, per rectum or undertaken by intravenous injection, intramuscularly, subcutaneous injection, intrathecal injection, epidural injection or intracerebral ventricle injection.
To those skilled in the art, obviously can be to composition of the present invention, purposes and preparation are carried out various improvement and variation and are not deviated from the spirit or scope of the present invention.
The present invention will more specifically be explained by following embodiment.Yet, be to be understood that the present invention is limited to these embodiment never in any form.
Description of drawings
More be expressly understood above and other purpose of the present invention in conjunction with the accompanying drawings from following detailed description, feature and other advantage, wherein:
Fig. 1 represents the UV spectrum of this photosensitization material (DH-1-180-3);
Fig. 2 is illustrated in the measurement result (λ excites) of oxygen singlet under the 508nm;
Fig. 3 represents to measure the cytotoxicity result who measures mouse EMT6 clone by MTT, wherein represent control group (contrast) separately, only optical radiation group (light), solvent treatment group (DMF) does not have the photosensitizer sample preparation group (only Ps (2)) of light and by this photosensitization mass treatment group (DH-1-180-3);
Fig. 4 is expressed as research apoptosis mechanism with the painted coloration result of AnnexinV/PI;
Fig. 5 represents to measure different PDT concentration PDT intake in cell by facs analysis;
Fig. 6 represents to measure according to time length PDT accumulation ratio in cell by facs analysis;
Fig. 7 represents the strength detection cytotoxicity degree according to irradiates light;
Fig. 8 represents to be determined at MMP in the EMT6 cell (mitochondrial membrane electromotive force) by facs analysis after PDT processing and JC-1 dyeing;
Fig. 9 represents the tumor suppression of the BALB/c mouse that caused by the EMT6 cell that DH-1-180-3 handles;
Figure 10 represents the survivorship curve by result's acquisition of Fig. 9.
Implement best mode of the present invention
More specifically explain the present invention by following embodiment.Yet, be to be understood that the present invention is limited to these embodiment never in any form.
Embodiment
Embodiment 1:(13-glycol ether-oxygen carbonyl)-and ph(a)eophorbide α, the preparation of methyl ester (2)
Methylene dichloride (3ml) the solution impouring 50ml flask that will contain phoeophytin α (60mg) is handled and is stirred with glycol ether (20ml).To wherein adding 1ml sulfuric acid, stirred 3 hours, then to wherein adding sodium bicarbonate aqueous solution.Solution is adopted chloroform extraction, and the chloroform layer of collection concentrates by removing organic solvent.Residuum is refining to isolate (13-glycol ether-oxygen carbonyl)-ph(a)eophorbide α methyl ester (2) of 39mg by column chromatography:
1H-NMR(500MHz，CDCl 3)δ：9.51(s，1H，meso-H)，9.37(s，1H，meso-H)，8.56(s，1H，meso-H)，7.99(dd，1H，J＝6.2，11.6Hz，CH 2＝CH)，6.29(d，1H，J＝17.8Hz，CH 2＝CH)，6.28(s.1H，CH)，6.18(d，1H，J＝11.6HzCH 2＝CH)，4.48-4.41(m，1H，CH)，4.24-4.22(m.1H.CH)，4.19-4.04(m，2H，OCH 2)，3.87(s，3H，OCH 3)，3.71-3.66(m，2H，CH 2)，3.68(s，3H，CH 3)，3.64-3.42(m，6H，CH 2OCH 2CH 2)，3.40(s，3H，CH 3)，3.22(s，3H，CH 3)，2.68-2.15(m，4H，CH 2CH 2)，1.82(d，3H，J＝7.3Hz，CH 3)，1.69(t，3H，J＝7.6Hz，CH 3)，0.56(br.S.，1H，N-H)，-1.61(br.s.，1H，N-H).
Embodiment 2:(13-methoxyl group triglycol-oxygen carbonyl) preparation of ph(a)eophorbide α methyl ester (3)
By the preparation of the identical process described in the above embodiment 1, difference is to use phoeophytin (60mg) and methoxyl group triglycol (30ml) with 29mg (13-methoxyl group triglycol-oxygen carbonyl) ph(a)eophorbide α methyl ester (3):
1H-NMR(500MHz，CDCl 3)δ：9.45(s，1H，meso-H)，9.30(s，1H，meso-H)，8.55(s，1H，meso-H)，7.93(dd，1H，J＝6.2，11.5Hz，CH 2＝CH)，6.26(s.1H，CH)，6.25(d，1H，J＝17.8Hz?CH＝CH 2)，6.14(d，1H，J＝11.3HzCH＝CH 2)，4.49-4.44(m，1H，CH)，4.22-4.20(m.1H.CH)，4.15-4.02(m，2H，OCH 2)，3.88(s，3H，OCH 3)，3.67(s，3H，CH 3)，3.60(q，2H，CH 3-CH 2)，3.51-3.45(m，8H，CH 2OCH 2CH 2OCH 2)，3.41-3.37(m，2H，CH 2)，3.38(s，3H，CH 3)，3.25(s，3H，OCH 3)，3.16(s，3H，CH 3)，2.65-2.18(m，4H，CH 2CH 2)，1.82(d，3H，J＝7.2Hz，CH 3)，1.68-1.64(m，，3H，CH 3)，0.51(br.s.，1H，N-H)，-1.61(br.s.，1H，N-H).
The preparation of embodiment 3:13-hydroxyl-(13-methoxyl group triglycol oxygen carbonyl) ph(a)eophorbide α methyl ester (4)
Use the step identical to prepare 13-hydroxyl-(13-methoxyl group triglycol oxygen carbonyl) ph(a)eophorbide α methyl ester (4) of 22mg, different 10-hydroxyl phoeophytin α (60mg) and the methoxyl group triglycols (20ml) of being to use with embodiment 1:
1H-NMR(500MHz，CDCl 3)δ：9.62(s，1H，meso-H)，9.49(s，1H，meso-H)，8.65(s，1H，meso-H)，8.03(dd，1H，J＝6.3，11.4Hz，CH 2＝CH)，6.31(d，1H，J＝17.8Hz，CH＝CH 2)，6.20(d，1H，J＝11.6Hz，CH＝CH 2)，5.78(s，1H，OH)，4.52-4.47(m，1H，CH)，4.30-4.14(m，3H，CH?and?OCH 2)，3.74(s，3H，OCH 3)，3.74-3.70(m，2H，CH 2)，3.63-3.57(m，8H，CH 2OCH 2CH 2OCH 2)，3.60(s，3H，CH 3)，3.47-3.46(m，2H，CH 2)，3.43(s，3H，CH 3)，3.29(s，3H，CH 3)，3.27(s，3H，OCH 3)，3.02-2.95，2.64-2.57and2.35-2.21(m，4H，CH 2CH 2)，1.71(t，3H，J＝7.5Hz，CH 3)，1.60(d，3H，J＝7.1Hz，CH 3)，0.30(br.s.，1H，N-H)，-1.83(br.s.，1H，N-H).
Embodiment 4:[13-(3-bromo-1-propoxycarbonyl)]-preparation of ph(a)eophorbide α methyl ester (5)
To contain methylphaeophorbide α methyl ester (4) pyridine (4ml) (20mg) and the solution impouring 50ml flask of toluene (8ml), adopt 3-bromo-1-propyl alcohol (0.003ml) stir process, heat 5 hours.Then solution is adopted the aqueous ammonium chloride solution washing and use dichloromethane extraction.The dichloromethane layer of collecting is concentrated by removing organic solvent, and residuum is refining by column chromatography, separates [13-(3-bromo-1-propoxycarbonyl)]-ph(a)eophorbide α methyl ester (5) of 11mg:
1H-NMR(500MHz，CDCl 3)δ：9.52(s，1H，meso-H)，9.38(s，1H，meso-H)，8.56(s，1H，meso-H)，7.99(dd，1H，J＝6.2，11.7Hz，CH 2＝CH)，6.28(d，1H，J＝19.3Hz，CH＝CH 2)，6.26(d，1H，CH)，J＝11.6Hz，CH＝CH 2)，6.18(d，1H，J＝11.6Hz，CH＝CH 2)，4.52-4.45(m，3H，CH?and?OCH 2)，4.24-4.22(m，1H，CH)，3.68(s，3H，CH 3)，3.67(m，2H，CH 2)，3.56(s，3H，OCH 3)，3.47-3.34(m，2H，CH 2)，3.40(s，3H，CH 3)，3.23(s，3H，CH 3)，2.68-2.17(m，6H，CH 2CH 2?and?CH 2)，1.83(d，3H，J＝7.3Hz，CH 3)，1.69(t，3H，J＝7.6Hz，CH 2-CH 3)，0.54(br.s.，1H，N-H)，-1.62(br.s.，1H，N-H).
Embodiment 5:(13-triglycol oxygen carbonyl) preparation of ph(a)eophorbide α methyl ester (6)
Adopt the similarity method among the embodiment 4, to contain methylphaeophorbide α methyl ester (4) pyridine (16ml) (100mg) and the solution impouring 50ml flask in the toluene (15ml), employing triglycol (0.033m) is handled under nitrogen and was heated 16 hours.Then solution is adopted the aqueous ammonium chloride solution washing and use dichloromethane extraction.The dichloromethane layer of collecting is concentrated by removing organic solvent, and residuum is refining by column chromatography, separates (13-triglycol oxygen carbonyl) ph(a)eophorbide α methyl ester (6) of 73mg:
1H-NMR(500MHz，CDCl 3)δ：9.53(s，1H，meso-H)，9.40(s，1H，meso-H)，8.57(s，1H，meso-H)，8.00(dd，1H，J＝6.3，11.5Hz，CH 2＝CH)，6.30(d，1H，J＝18.1Hz，CH＝CH 2)，6.27(s，1H，CH)，6.19(d，1H，J＝6.3，12.8Hz，CH＝CH 2)，4.49-4.45(m，3H，CH?and?OCH 2)，4.26-4.24(m，1H，CH)，3.72-3.66(m，4H，CH 2?and?OCH 2)，3.69(s，3H，CH 3)，3.55(s，3H，OCH 3)，3.49-3.39(m，4H，CH 2?OCH 2)，3.41(s，3H，CH 3)，3.31(t，2H，J＝4.6Hz，CH 2)，3.26-3.23(m，5H，CH 2?and?CH 3)，2.66-2.21(m，5H，CH 2CH 2and?OH)，1.82(d，3H，J＝7.3Hz，CH 3)，1.70(t，3H，J＝7.6Hz，CH 3)，0.54(br.s.，1H，N-H)，-1.62(br.s.，1H，N-H).
Embodiment 6:[13-hydroxyl-(13-triglycol oxygen carbonyl)] preparation of ph(a)eophorbide α methyl ester (7)
(8ml) heated 5 hours with oxazine (23ml) solution is dissolved in 10ml toluene will to contain methylphaeophorbide α methyl ester (4) pyridine (50mg).Then solution is adopted the aqueous ammonium chloride solution washing and use dichloromethane extraction.The dichloromethane layer of collecting is concentrated by removing organic solvent, and residuum is refining by column chromatography, separates [13-hydroxyl-(13-triglycol oxygen carbonyl)]-ph(a)eophorbide α methyl ester (7) of 21mg:
1H-NMR(500MHz，CDCl 3)δ：9.76(s，1H，meso-H)，9.54(s，1H，meso-H)，8.71(s，1H，meso-H)，8.01(dd，1H，J＝6.2，11.6Hz，CH 2＝CH)，6.34(d，1H，J＝17.9Hz，CH＝CH 2)，6.18(d，1H，J＝11.6Hz，CH＝CH 2)，6.09(s，1H，OH)，4.47-4.42(m，1H，CH)，4.07-4.05(m，1H，CH)，3.90(s，3H，OCH 3)，3.77(s，3H，CH 3)，3.74(q，2H，CH 3-CH 2)，3.54(s，3H，OCH 3)，3.44(s，3H，CH 3)，3.26(s，3H，CH 3)，2.61-1.78(m，4H，CH 2CH 2)，1.71(t，3H，J＝7.6Hz，CH 2-CH 3)，1.60(d，3H，J＝7.1Hz，CH 3)，-1.09(br.s.，1H，N-H)，-1.41(br.s.，1H，N-H).
Embodiment 7: the preparation of ph(a)eophorbide α triglycol methyl ester (8)
The solution that will contain methylphaeophorbide α methyl ester (30mg) is dissolved in the 20ml triglycol, stirs and adding 1ml sulfuric acid.Then solution is washed and uses ethyl acetate extraction with sodium bicarbonate aqueous solution.The ethyl acetate layer of collecting is concentrated by removing organic solvent, residuum is refining by column chromatography, the ph(a)eophorbide α triglycol methyl ester (8) of separating 32mg:
1H-NMR(500MHz，CDCl 3)δ：9.53(s，1H，meso-H)，9.40(s，1H，meso-H)，8.57(s，1H，meso-H)，8.00(dd，1H，J＝6.4，11.5Hz，CH 2＝CH)，6.30(d，1H，J＝17.9Hz，CH＝CH 2)，6.29(d，1H，CH)，6.19(d，1H，J＝12.5Hz，CH＝CH 2)，4.49-4.44(m，3H，CH?and?OCH 2)，4.26-4.24(m，1H，CH)，4.15-4.07(m，2H，OCH 2)，3.74-3.65(m，4H，CH 2?and?OCH 2)，3.69(s，3H，OCH 3)，3.58-3.43(m，14H，OCH 2)，3.41(s，3H，CH 3)，3.35(t，2H，J＝4.5Hz，CH 2)，3.30-3.28(m，2H，CH 2)，3.24(s，3H，CH 3)，2.66-2.02(m，6H，CH 2CH 2?and?OH)，1.82(d，3H，J＝7.3Hz，CH 3)，1.70(t，3H，J＝7.6Hz，CH 3)，0.55(br.s.，1H，N-H)，-1.62(br.s.，1H，N-H).
Embodiment 8: the preparation of methylphaeophorbide alpha deg ester (9)
The solution that will contain phoeophytin α (60mg) is dissolved in a small amount of methylene dichloride.20ml glycol ether and 1L sulfuric acid were joined wherein and stir 23 hours.Then solution is adopted the saturated sodium bicarbonate aqueous solution washing and use chloroform extraction.The chloroform layer of collecting is concentrated by removing organic solvent, and residuum is refining by column chromatography, separates 2mg methylphaeophorbide alpha deg ester (9):
1H-NMR(500MHz，CDCl 3)δ：9.26(s，1H，meso-H)，8.34(s，1H，meso-H)，7.92(dd，1H，J＝6.0，11.8Hz，CH 2＝CH)，6.33(s，1H，OH)，6.25(d，1H，J＝17.8Hz，CH＝CH 2)，6.17(d，1H，J＝11.6Hz，CH＝CH 2)，4.88(br.s，2H.OH)，4.76-4.60(m，4H，CH 2CH 2)，4.41-4.33(m，3H，CH?and?CH 2)，4.27-4.23(m，2H，CH?and?OCH 2)，3.96-3.94(m，2H，CH 2)，3.88-3.80(m，6H，CH 2)，3.75(s，3H，OCH 3)，3.75-3.69(m，2H，CH 2)，3.58(s，3H，CH 3)，3.31(s，3H，CH 3)，3.18(s，3H，CH 3)，2.75-2.00(m，4H，CH 2CH 2)，2.03(d，3H，J＝7.0Hz，CH 3)，1.64(t，3H，J＝7.3Hz，CH 3)，0.87(br.s.，1H，N-H)，-1.85(br.s.，1H，N-H).
Embodiment 9: the preparation of methylphaeophorbide α triethyleneglycol ester (10)
Methylphaeophorbide α methyl ester (100mg) solution that will be dissolved in the 16ml pyridine joins in the 15ml toluene.The 0.033ml triglycol is joined wherein, and heating is 16 hours under nitrogen.Then solution is adopted dichloromethane extraction.The dichloromethane layer of collecting is concentrated by removing organic solvent, and residuum is refining by column chromatography, separates the methylphaeophorbide α triethyleneglycol ester (10) of the following called after DH-1-180-3 of 73mg:
UV spectrum: referring to Fig. 1
1H-NMR(500MHz，CDCl 3)δ：9.53(s，1H，meso-H)，9.40(s，1H，meso-H)，8.57(s，1H，meso-H)，8.00(dd，1H，J＝6.3，11.5Hz，CH 2＝CH)，6.30(d，1H，J＝18.1Hz，CH＝CH 2)，6.27(s，1H.CH)，6.19(d，1H，J＝12.8Hz，CH＝CH 2)，4.49-4.45(m，3H，CH?and?OCH 2)，4.26-4.24(m，1H，CH)，3.72-3.66(m，4H，CH 2?and?CH 2)，3.69(s，3H，OCH 3)，3.55(s，3H，OCH 3)，3.49-3.39(m，4H，CH 2OCH 2)，3.41(s，3H，CH 3)，3.31(t，2H，，J＝4.6Hz，CH 2)，3.26-3.23(m，5H，CH 2?and?CH 3)，2.66-2.21(m，5H，CH 2CH 2?andOH)，1.82(d，3H，J＝7.3Hz，CH 3)，1.70(t，3H，J＝7.6Hz，CH 3)，0.54(br.s.，1H，N-H)，-1.62(br.s.，1H，N-H).
Test example 1: The compounds of this invention is to the active mensuration of the transformation of oxygen singlet
Target compound is measured by following method to the transformation activity of oxygen singlet.
Method
Use toluene (MerckCo.HPLC level) as solvent down in air saturation condition (99.999% high gas), the solution oxygen concn is 2.1 * 10 -3Under 21 ℃, carry out test determination during M.
The result
The measurement result of (λ excites) oxygen singlet under 508nm, as shown in Figure 2, the photon yield of transformation is 0.60 (5%).Therefore, confirm the transformation superior activity of DH-1-180-3 to the oxygen singlet, its physical stability is also good.
Test example 2: the mensuration of The compounds of this invention antitumour activity
The antitumour activity of target compound is by following test determination.
Measure in the body
As the DH-1-180-3 of test sample of the present invention and in contrast the group photofrin (photogem ) be used for the test.
Breast cancer cell line (EMT6; 1 * 10 6Individual cell/mouse) is transplanted to BALB/c mouse (12 every group), after 7 to 10 days, will be with the test sample of 1% tween 80 dilution with injecting water-reducible control drug respectively test sample group 0.4 and 0.8mg/kg/ mouse with under the dosage of control group 2mg/kg/ mouse, give every mouse.
After three hours,, under the intensity of 1.2J, it is shone by halogen lamp with mouse anesthesia.Under 2 or 3 days interval, measure the tumor size of each mouse by calipers, also measure the survival rate of mouse according to tumour.
External test
With breast cancer cell line (EMT6; 1 * 10 6Individual cell/mouse) in substratum (DMEM+10%FBS+100 unit's penicillin+100 μ g Streptomycin sulphates), cultivates, adopt 0.25% trypsinase-EDTA to handle, by the number of Trypan blue dyeing agent dyeing counting cell with collecting cell.
With every 3ml cell with 2 * 10 5The concentration of individual cell/ml joins the culture dish of 35mm, and 5%CO is being arranged 2Incubator in hatching made cell be arranged in individual layer in 24 hours.
The DH-1-180-3 that will be dissolved in the various concentration of DMF joins in the culture dish of 35mm, and the concentration of regulating the DMF solvent is no more than 0.5% to get rid of the influence of DMF.The photosensitization material joined in it and under the intensity of 1.2J it is shone by halogen lamp.Culture dish transferred in the incubator hatch.
The cytotoxicity that is caused by PDT is by the MTT determination and analysis, and the form of cell is by microscopic examination.
Conventional photosensitizer, promptly photogem  adjusts the concentration of several factors such as sample, the exposure intensity of light and the soak time of sample etc. as the contrast control group in this test.
The result
Fig. 3 represents the cytotoxicity result on mouse EMT6 clone by MTT mensuration.
As finding out among Fig. 3, only rayed group (light), only by DMF treatment group (DMF) and the group (only PS (2)) that do not have light by photosensitizer sample preparation showed cell toxicity not, the photosensitizer treatment group, particularly the group of being handled by 0.2 μ g photosensitizer of the present invention shows significant cytotoxicity, 100% of test group causes death and occurs in 0.4 μ g photosensitizer treatment group, and it is the most effective concentration.
Fig. 4 represents to adopt the painted coloration result of Annexin V/PI in order to study the apoptotic mechanism of action.
As can be Fig. 4 finds out, in control group greater than 90% cell survival, and in PDT treatment group (0.2 μ g/ hour) greater than 50 to 60% necrocytosis, these EMT6 cells are died from apoptosis.
Fig. 5 represents to measure different PDT concentration PDT intake in cell by facs analysis.
As can be finding out among Fig. 5, the intake of PDT increases with the concentration of PDT in the mode of dose-dependently and is closely related with cytotoxicity in cell.Confirmed that the strongest cytotoxicity is 208.92 at the numerical value of MFI (average fluorescent strength), the concentration of DH-I-180-3 is that at least 0.4 μ g place manifests.
Fig. 6 represents to measure according to time length PDT accumulation ratio in cell by facs analysis.
As among Fig. 6 as can be seen, the accumulation ratio of PDT increases with the time length and is closely related with cytotoxicity in cell.Confirmed that the strongest cytotoxicity reaches 208.92 at the numerical value of MFI (average fluorescent strength), the time length is to locate to manifest at least 60 minutes.
Fig. 7 represents the strength detection cytotoxicity degree according to irradiates light.
As can be finding out among Fig. 7, the irradiation light intensity presents the strongest cytotoxicity when reaching 1.2J, do not increase but surpass intensity effect.
Fig. 8 is illustrated in after PDT and the JC-1 dyeing, is determined at MMP in the EMT6 cell (mitochondrial membrane electromotive force) by facs analysis.
As can be finding out among Fig. 8, MMP significantly reduces with PDT, and this is consistent with the observations that adopts fluorescent microscope.
Fig. 9 represents the tumor suppression of the BALB/c mouse that caused by the EMT6 cell that DH-1-180-3 handles.
As comparing with photofrin (photogem ) treatment group with control group finding out among Fig. 9, the growth of tumor ratio significantly reduced with the processing time in the PDT treatment group.
Figure 10 represents the survivorship curve that the result by Fig. 9 draws.
As can finding out among Figure 10, comparing the survival ratio increase in the PDT treatment group with control group.
According to above-mentioned test-results, the optimal conditions of handling DH-1-180-3 of the present invention is: the photosensitizer concentration that is used for PDT is 0.4 μ g/ml, and the optimal absorption time is 1 hour, and exposure intensity is that 1.2J is 24 hours with measuring its active analysis time.Yet photofrin (photogem ) had not been effectively in 24 hours under the concentration of 50-100 μ g/ml, and its irradiates light intensity that satisfies same effect is greater than 10 to 100 times of DH-1-180-3.
Test 3: toxicity test
Method
(mean body weight 25 ± 5g) and Sprague-Dawley rat (carry out acute toxicity test on 235 ± 10g) the ICR mouse to use compound 1 and 10.To use test compound 20mg/kg respectively by every group that 3 mouse or rat are formed, 10mg/kg and 1mg/kg or solvent (0.2ml, intraperitoneal) intraperitoneal administration was observed 24 hours.
The result
Overall aspect does not all have the death relevant with treatment, clinical sign, the appearance of body weight change in any group or arbitrary sex.The compound for preparing among the present invention of these results suggest is effective and safe.
The kind of compound method and vehicle is described below, but the invention is not restricted to them.Representative preparation embodiment is described below.
Powder formulation
Compound 10 500mg
W-Gum 100mg
Lactose 100mg
Talcum 10mg
Prepare powder formulation by mixing above component and filling packages sealed.
Tablet formulation
Compound 10 100mg
W-Gum 100mg
Lactose 100mg
Magnesium Stearate 2mg
Prepare tablet formulation by mixing above component and compressing tablet.
Capsule preparations
Compound 1 50mg
Lactose 50mg
Magnesium Stearate 1mg
Prepare tablet formulation by mixing above component and filling gelatine capsule by the normal gelatin preparation method.
Injection formulations
Compound 1 100mg
The distilled water for injection optimal number
PH control agent optimal number
By the lytic activity component, control pH is to about 7.5 and fill all components then and the preparation injection formulations by conventional injection formulations method sterilization in the 2ml sample.
Describe the present invention like this, obviously can adopt many modes to change the present invention.Can not think that such variation deviates from the spirit and scope of the present invention, obviously all such improvement all comprise within the scope of the claims to those skilled in the art.
Industrial applicibility
Compound according to the present invention can be used for prevention or the treatment of various Cancerous diseases and has excellent In the advantage of conventional photosensitizer, as producing the excellent photon yield of singlet oxygen, good physics Stability and effective cytotoxicity.

Claims (13)

1. the compound of representing by following general formula (I), and pharmaceutical salts:
Figure A2003801087820002C1
Wherein
R 1, R 2Be respectively straight chain or branching low alkyl group or alkoxyl group, polyethylene group or alkylsulfonyl with 1-6 carbon atom;
R 3Be hydrogen atom, have the alkoxyl group or a polyethylene group of 1-6 carbon atom;
R 4Be hydrogen atom, hydroxyl or alkoxyl group with 1-6 carbon atom,
A directly is connected or bridge joint with Sauerstoffatom, can with the transition metal ion chelating that comprises the Ni metal ion.
2. compound according to claim 1, wherein R 1, R 2Be selected from ethyl, propyl group, ethylene glycol group, diethylene glycol group, triglycol group, Tetraglycol 99 group, hexaethylene glycol group, seven glycol groups or methoxyl group ethylene glycol group; R 3Be selected from hydrogen atom, ethyl, propyl group, methoxyl group, oxyethyl group, ethylene glycol group, triglycol group, six ethylidene; R 4Be hydrogen atom, hydroxyl or methoxyl group; A is direct connection, and condition is R 1And R 2Be identical group and R 2Be different from R 1Or R 3
3. the compound of representing by following general formula (II), and pharmaceutical salts:
Figure A2003801087820003C1
Wherein
R 1, R 2Be respectively straight chain or branching low alkyl group or alkoxyl group, polyethylene group or alkylsulfonyl with 1-6 carbon atom, can with the transition metal ion chelating that comprises the Ni metal ion;
Wherein X is a Sauerstoffatom; A is-CH 2-; R 1Be hydrogen atom or amino-ethyl; R2 is hydrogen or halogen atom or the alkyl with 1-6 carbon atom.
4. the compound of representing by following general formula (III), and pharmaceutical salts:
Figure A2003801087820003C2
In the base
R 1It is polyethylene group;
R 4Be hydrogen atom or hydroxyl.
5. the compound of representing by following general formula (IV), and pharmaceutical salts:
Figure A2003801087820004C1
Wherein
R 2Be bromopropyl or polyethylene group;
R 4Be hydrogen atom or hydroxyl.
6. the compound of representing by following logical formula V, and pharmaceutical salts:
Figure A2003801087820004C2
Wherein
R 1Be methyl, ethyl or ethylene glycol group.
7. the compound of representing by following general formula (VI), and pharmaceutical salts:
Figure A2003801087820004C3
Wherein
R 1, R 2It is respectively polyethylene group.
8. the compound of representing by following general formula (VII), and pharmaceutical salts:
Figure A2003801087820005C1
Wherein
R 1It is polyethylene group.
9. pharmaceutical composition, it comprise as activeconstituents be the compound or pharmaceutically acceptable salt thereof and the pharmaceutical carrier of (I)-(VII) by the described general formula of claim 1-8, treat or prevent various cancers by producing singlet oxygen free radical and excellent cytotoxic activity again.
10. according to the pharmaceutical composition of claim 9, wherein said cancer comprises cancer of the stomach, liver cancer, lung cancer, cervical cancer and the mammary cancer in the mankind or the Mammals.
11. light power diagnosis and therapeutical agent, it comprises compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier by the described general formula of claim 1-8 (I)-(VII) as activeconstituents, produces singlet oxygen free radical and the treatment of excellent cytotoxic activity or prevents various cancers by regeneration.
12. according to the described general formula of claim 1-8 is the compound or pharmaceutically acceptable salt thereof of (I)-(VII), in photodynamic therapy as the purposes of photosensitizer.
13. be used for the treatment of or prevent purposes in the medicine of cancer of the stomach, liver cancer, lung cancer, cervical cancer and mammary cancer in various cancers such as the mankind or the Mammals in preparation for the compound of (I)-(VII) according to the described general formula of claim 1-8.
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CN101948566A (en) * 2010-06-23 2011-01-19 中国科学院化学研究所 Multifunctional polymer for resisting fungi and cancers and performing cell imaging and preparation method thereof
CN102268004A (en) * 2011-06-21 2011-12-07 北京普瑞博思投资有限公司 Chlorophyllin salt compound and preparation method thereof

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JPS6058984A (en) * 1983-09-09 1985-04-05 Hidetoshi Tsuchida Terminal oligoethylene glycol type long-chain alkyl iron-tetraphenylporphyrin complex
EP0142732B1 (en) * 1983-10-24 1990-01-24 Toyo Hakka Kogyo Kabushiki Kaisha Pheophorbide derivatives and pharmaceutical preparations containing them
DE3687399T2 (en) * 1985-10-23 1993-04-29 Nihon Mediphysics Co Ltd PORPHYRINE DERIVATIVES, THEIR PRODUCTION AND USE.
JPS62249986A (en) * 1986-04-21 1987-10-30 Hamari Yakuhin Kogyo Kk Porphyrin derivative
JPH0786109B2 (en) * 1987-12-21 1995-09-20 浜理薬品工業株式会社 Pheophorbide derivative
US5591847A (en) * 1994-05-23 1997-01-07 Health Research, Inc. Long wavelength absorbing photosensitizers related to purpurin-18, bacteriopurpurin-18 and related compounds with imide linkages

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101948566A (en) * 2010-06-23 2011-01-19 中国科学院化学研究所 Multifunctional polymer for resisting fungi and cancers and performing cell imaging and preparation method thereof
CN102268004A (en) * 2011-06-21 2011-12-07 北京普瑞博思投资有限公司 Chlorophyllin salt compound and preparation method thereof

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