CN109265465B - Novel pyropheophorbide a derivatives and preparation method and application thereof - Google Patents
Novel pyropheophorbide a derivatives and preparation method and application thereof Download PDFInfo
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- CN109265465B CN109265465B CN201811316296.2A CN201811316296A CN109265465B CN 109265465 B CN109265465 B CN 109265465B CN 201811316296 A CN201811316296 A CN 201811316296A CN 109265465 B CN109265465 B CN 109265465B
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a novel pyropheophorbide a derivative, a preparation method and medical application thereof. More particularly, the invention relates to compounds of formula I as shown in the following structures, the definitions of which are described in the specification. The pyropheophorbide a derivatives which are single in structure, stable and simple and convenient in preparation method are designed and prepared, have strong photodynamic activity and can be used as photodynamic medicaments for diagnosing and treating diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus flammeus, condyloma acuminatum and the like.
Description
Technical Field
The invention belongs to the field of photosensitive drugs and photodynamic therapy, and particularly relates to a novel pyropheophorbide a derivative, a preparation method thereof and application thereof in the field of photodynamic therapy and diagnosis.
Background
As early as the 30 s in the 20 th century, it was found that when the liver of a cat or a mouse fed with abalone was exposed to sunlight, symptoms such as erythema, ulcer, and local necrosis appeared. This series of phenomena was later confirmed by Hedgeon (Japanese Journal of Medical Science & biology.1962,15,136-140) et al to be skin-photo-toxic by the abalone toxins present in the liver of abalone. The abalone toxin is derived from abalone bait seaweed, and is a pyropheophorbide a produced by degrading chlorophyll in the seaweed after the seaweed is swallowed by abalone. The active free radicals generated by the abalone toxins and oxygen under the action of light have strong photooxidation damage effect on biological molecules. This phototoxic injury is used to treat tumors, macular degeneration, condyloma acuminatum, actinic keratosis, and other diseases, also known as Photodynamic Therapy (PDT).
The action principle Of the photodynamic therapy is that after the photosensitizer is absorbed by target cells, the photosensitizer is transited from a ground state (S0) to an excited state (S1) under the irradiation Of laser with certain wavelength, And further transited to a triplet excited state (T1) through intersystem crossing, the photosensitizer in the triplet state reacts with surrounding molecules (mainly type I And type II), generates free radicals with high oxidation activity, kills the target cells (Journal Of Photochemistry And Photobiology B-biology 1990,6, 343-) 347) And destroys blood vessels in an irradiation area, And blocks nutrition And oxygen supply Of the target cells (Jpn.J. cancer Res.2000,91(5), 560-) 565-; simultaneously, the immune regulation of the body is stimulated, resulting in tumor necrosis (H.B. Van den Bergh et al, Lasers Opthalmol, 2003, 183-195).
With the approval of the first photosensitizer, photosensitizer II (Photofrin II) (M.A. biel et al, Photochem.Photobiol.,2007,83: 1063-1068), in 1993 in Canada for clinical bladder cancer treatment, Photofrin II was continuously approved in major countries of the world for marketing for the treatment of tumors in different sites such as esophageal cancer, lung cancer, bladder cancer, cervical cancer and skin cancer. In addition, the clinical application and the indications of the medicine are continuously developed and extended, wherein the medicine has very obvious curative effect on non-tumor diseases such as psoriasis, port wine stains, condyloma acuminatum and the like. Because the porphyrin ether polymer is a mixture of a plurality of porphyrin ether polymers, the porphyrin ether polymer has a plurality of defects, such as complex components, unstable components, long-time light shielding and difficult tolerance of patients; the absorption in a red light area is weaker, the penetration depth of tissues is shallow, and the curative effect on deep tumors is limited.
To overcome the disadvantages of photosensitizer II, two new chlorin monomer drugs were developed, namely Temoporfin (Int J Oral Maxillofac Surg.2001,30(6),504 and 509) approved by European Union and Talaporfin (Lung cancer.2007,58, 317) approved by Japan, wherein Talaporfin is a chlorophyll derivative and Temoporfin is an artificially synthesized chlorin compound, both of which have higher antitumor activity, significantly enhanced absorption in red region and significantly reduced light shielding time. However, these drugs have some disadvantages, such as the easy oxidation and poor stability of temoporfin; talaporfin is too fast in metabolism speed, difficult to prepare and the like.
In view of the strong photosensitive action of the abalone toxin (namely pyropheophorbide a), if the structure of the abalone toxin is modified to reduce the skin phototoxicity, a photosensitive new candidate drug with high-efficiency and low skin phototoxicity can be discovered.
5-Aminolevulinic acid (5-ALA) is an endogenous small molecule compound which has no photosensitive activity per se. It is an intermediate in the process of synthesizing heme in human body, and can be used for producing protoporphyrin IX (Photochem Photobiol.2000,72(1),128-134) with strong photosensitization under the catalysis of related enzyme after entering into the body, so that it is a prodrug of protoporphyrin. Experiments prove that 5-ALA is converted into endogenous protoporphyrin IX in vivo, the distribution of the protoporphyrin IX has high selectivity, the transformation rate of tumor cells and certain cells with rapid proliferation is high, so that the content of the protoporphyrin IX in diseased cells is higher than that of other cells, and a large amount of singlet oxygen and free radicals are generated by irradiation of light with specific wavelength, so that cells in diseased regions undergo apoptosis and necrosis, but the cells do not damage surrounding normal tissues and cells (Skin Therapy Lett.2001,6(10),1-2 and 5), and the defect that a patient with photosensitizer II needs to be protected from light for 4-6 weeks and the like after the medicine is taken is overcome. 5-aminolevulinic acid contains amino, carboxyl and carbonyl groups, can be used for adjusting the hydrophilicity and lipophilicity of the compound, and is a suitable group for carrying out structural modification of the medicine.
In order to solve the problems of the photosensitizer, endogenous small molecule 5-aminolevulinic acid (5-ALA) and derivatives thereof are introduced into the carboxyl terminal of pyropheophorbide a and ether derivatives thereof, and a series of pyropheophorbide a derivatives are prepared. The introduction of 5-ALA and its derivatives leads to improved water solubility of the compounds. Pharmacological experiments show that the compounds have obviously improved selectivity on tumor tissues, obviously enhanced anti-tumor effect and obviously reduced skin phototoxicity, can be used as photodynamic medicaments for diagnosing and treating diseases such as tumors, actinic keratosis, macular degeneration of retina, condyloma acuminatum, nevus flammeus and the like, and is worthy of further research and development.
Disclosure of Invention
In order to find a new photodynamic medicament with high activity, convenient preparation and low skin phototoxicity, pyropheophorbide a is taken as an initial raw material, a class of pyropheophorbide a derivatives (I) is designed and synthesized after a large amount of creative work is paid, and a preparation method of the class of compounds is provided.
The structure of the compound provided by the invention is as follows:
wherein R ═ H, straight or branched C1-C6 alkyl; r1Vinyl or 1-CH (CH)3)OR2;
R2=-H;
-(CH2)nCH3,n=0-7;
-CH(CH3)(CH2)n CH3,n=0-5;
-(CH2)nOH,n=2-5;
-(CH2CH2O)nCH3,n=1-3;
-CH2CH2O(CH2)nCH3,n=1-3;
-(CH2CH2CH2O)n CH3,n=1-3;
-(CH2)n F,n=2-5。
The compounds of formula I above include the following:
173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-1);
173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-2);
173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-3);
173- [ N-N-propyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-4);
173- [ N-isopropyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-5);
173- [ N-N-butyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-6);
3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-1);
3- (1-ethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-2);
3- (1-n-propoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-3);
3- (1-Isopropoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-4);
3- (1-n-butoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-5);
3- (1-n-pentyloxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-6);
3- (1-n-hexyloxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-7);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-8);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-9);
3- (1-ethoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-10);
3- (1-n-propoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-11);
3- [1- (2-Fluoroethoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-12);
3- [1- (3-Fluoropropoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-13);
3- [1- (4-Fluorobutoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-14);
3- (1-methoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-15);
3- (1-methoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-16);
3- (1-ethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-17);
3- (1-ethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-18);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-19);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-20);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-21);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-22).
The invention discloses a method for preparing a compound shown in a formula I, which comprises the following steps:
compound Ia can be prepared by the following method:
the pyropheophorbide a (compound II) and 5-aminolevulinic acid ester (compound III) are condensed to generate a compound IV, and then the compound IV is hydrolyzed to obtain a compound Ia.
R is H, straight chain or branched chain C1-C6 alkyl; r' is substituted or unsubstituted straight chain or branched chain C1-C10 alkyl and substituted or unsubstituted aryl.
Compound Ib can be prepared by the following two methods:
the preparation method comprises the following steps: and adding HBr-AcOH into the compound IV for addition reaction, then adding alcohol to obtain a compound V, and hydrolyzing the compound V to obtain a compound Ib.
Wherein R is H, straight chain or branched chain C1-C6 alkyl; r' is substituted or unsubstituted straight chain or branched chain C1-C10 alkyl and substituted or unsubstituted aryl. R2=H;-(CH2)nCH3,n=0-7;-CH(CH3)(CH2)nCH3,n=0-5; -(CH2)nOH,n=2-5;-(CH2CH2O)nCH3,n=1-3;-CH2CH2O(CH2)nCH3,n=1-3; -(CH2CH2CH2O)nCH3,n=1-3;-(CH2)n F,n=2-5。
The second preparation method comprises the following steps: the pyropheophorbide a ether derivative (compound VI) and 5-aminoketone valerate (compound III) are condensed to obtain a compound VII. Then hydrolyzing the compound VII to obtain a compound Ib.
Wherein R is H, straight chain or branched chain C1-C6 alkyl; r' is substituted or unsubstituted straight chain or branched chain C1-C10 alkyl and substituted or unsubstituted aryl. R2=H;-(CH2)nCH3,n=0-7;-CH(CH3)(CH2)nCH3,n=0-5; -(CH2)nOH,n=2-5;-(CH2CH2O)nCH3,n=1-3;-CH2CH2O(CH2)nCH3,n=1-3; -(CH2CH2CH2O)nCH3,n=1-3;-(CH2)n F,n=2-5。
The synthesis of such compounds can be carried out by those skilled in the art according to the methods described above.
In the step, when the compound (II) is used for preparing the compound (IV) and the compound (VI) is used for preparing the compound (VII), the amide condensing agent is Dicyclohexylcarbodiimide (DCC)/4-Dimethylaminopyridine (DMAP), N, N-Diisopropylcarbodiimide (DIC)/4-Dimethylaminopyridine (DMAP), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -di (dimethylamino) carbenium Hexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate (TBTU), benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), Diphenylphosphorylazide (DPPA), and the like, but is not limited to these condensing agents; the reaction time for preparing the compound (IV) from the compound (II) and the compound (VII) from the compound (VI) is 1-10h, and the reaction temperature is 0-100 ℃.
In the step, the compound (II) is used for preparing a compound (IV), the compound (IV) is used for preparing a compound (Ia), the compound (V) is used for preparing a compound (Ib), and the compound (VI) is used for preparing a compound (Ib), wherein the alkali is any one or a mixture of any more of triethylamine, diisopropylethylamine, pyridine, sodium hydrogen, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide and the like. The concentration of the alkali used for preparing the compound (Ia) from the compound (IV), the compound (Ib) from the compound (V) and the compound (Ib) from the compound (VII) is 1-20mol/L, the reaction time is 1-10h, and the reaction temperature is 0-100 ℃.
In the step, the compound (II) is used for preparing the compound (IV), the compound (IV) is used for preparing the compound (Ia), the compound (V) is used for preparing the compound (Ib), the compound (VI) is used for preparing the compound (VII), and the organic solvent is 1, 4-dioxane, Tetrahydrofuran (THF), toluene, xylene, N-hexane, cyclohexane, ethyl acetate and N when the compound (VII) is used for preparing the compound (Ib), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2-methyltetrahydrofuran, dichloromethane, chloroform, dichloroethane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dipropyl ether, ethylene glycol dibutyl ether, methyl tert-butyl ether, or the like, or a mixture of any of them.
In the step, the alcohol used in the preparation of compound (V) from compound (IV) is methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, isopropanol, 2-butanol, isobutanol, sec-pentanol, isopentanol, cyclohexanol, benzyl alcohol, 2-fluoroethanol, 3-fluoropropanol, 4-fluorobutanol, etc., but is not limited thereto. When the compound (IV) is used for preparing the compound (V), the reaction temperature is 25-100 ℃ after the alcohol is added, and the reaction time is 2-10 h.
In the step, the HBr-HOAc solution used in the preparation of compound (V) from compound (IV) has a content of 5-35 wt%. The filler in the column chromatographic separation is silica gel, and the eluent is a mixed solvent of petroleum ether and ethyl acetate, petroleum ether and dichloromethane, dichloromethane and methanol or dichloromethane and acetone, and the mixing ratio range is 1:1-100: 1.
The synthesis of such compounds can be carried out by those skilled in the art according to the methods described above.
Advantageous effects
The compound has stable chemical property, single structure, simple preparation, obviously reduced skin phototoxicity and strong photodynamic activity, can obviously inhibit the proliferation of human esophageal cancer cells under the excitation of laser with certain wavelength, and can be used as a photodynamic medicament for diagnosing and treating diseases such as tumor, actinic keratosis, macular degeneration of retina, condyloma acuminatum, nevus flammeus and the like.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The compounds not listed below can also be prepared by selecting appropriate starting materials and adjusting reaction conditions slightly appropriately and universally as necessary, using the same synthetic route and synthetic method as those described below. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the description of the invention, and equivalents fall within the scope of the invention defined by the claims appended to the application.
[ example 1]
173- [ N- (2-oxo-4-carboxybutyl)]The preparation method of pyropheophorbide (compound Ia-1) specifically comprises the following steps:
step 1): 173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Synthesis of pyropheophorbide
Pyrophorbide a (2.0g,3.75mmol), methyl 5-aminolevulinic acid hydrochloride (1.0g,5.5mmol) and HBTU (1.7g,4.49mmol) were dissolved in dichloromethane (100mL) in a 50mL round-bottomed flask, followed by addition of DIPEA (2.0mL) and stirring at room temperature for 6 hours. Washed three times with water (100 mL. times.3), combined organic phases, anhydrous MgSO4Drying, filtering, and vacuum concentratingRemoving solvent, purifying by silica gel column chromatography, eluting with dichloromethane and acetone (v/v ═ 50:1), to obtain 173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyrophorbide (2.35g) in 94.9% yield.1H NMR(400MHz, CDCl3)δppm:9.48(s,1H),9.40(s,1H),8.62(s,1H),8.01(dd,J=18.2,11.7Hz,1H),6.31(d,J= 17.8Hz,1H),6.20(d,J=11.6Hz,1H),5.61(s,1H),5.33(d,J=2.3Hz,1H),5.27(s,1H),5.13(d, J=19.3Hz,1H),4.53(d,J=8.4Hz,1H),4.38(s,1H),3.82(s,1H),3.73–3.65(m,3H),3.64(s, 3H),3.60(d,J=2.1Hz,4H),3.44(s,3H),3.25(s,3H),2.68(s,1H),2.47(s,2H),2.37(t,J=6.6 Hz,2H),2.24(d,J=18.4Hz,2H),2.01(s,1H),1.84(d,J=7.4Hz,3H),-1.77(s,1H);ESI-MS m/z:662.3[M+1]+。
Step 2): 173- [ N- (2-oxo-4-carboxybutyl)]Synthesis of pyropheophorbide
Will 173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyrophorbide (100mg,0.15mmol) was dissolved in tetrahydrofuran (10mL), 1M LiOH (0.5mL) was added, and the mixture was stirred at room temperature for about 3 h. The solvent was removed under reduced pressure, dissolved in 50mL of dichloromethane, washed three times with water, the organic phase was collected and over anhydrous MgSO4And (5) drying. Filtering, collecting filtrate, removing solvent under reduced pressure to obtain 173- [ N- (2-oxo-4-carboxybutyl)]Pyrophorbide (85mg) in 86.8% yield.1H NMR(400MHz, DMSO-d6)δppm:9.57(s,1H),9.30(s,1H),8.88(s,1H),8.25(t,J=5.5Hz,1H),8.15(dd,J= 18.1,11.7Hz,1H),6.34(d,J=17.8Hz,1H),6.17(d,J=11.6Hz,1H),5.12(s,1H),4.58(d,J= 7.6Hz,1H),4.30(d,J=9.1Hz,1H),3.96(q,J=10.9,7.4Hz,2H),3.57(d,J=12.0Hz,6H),3.50 (s,1H),3.41(s,4H),3.12(s,3H),1.81(d,J=7.2Hz,3H),1.57(t,J=7.5Hz,3H),0.95(t,J=7.2 Hz,2H),0.10(s,1H),-2.10(s,1H);ESI-MS m/z:648.3[M+1]+。
[ example 2]
3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]The preparation method of pyropheophorbide (compound Ib-1) specifically comprises the following steps:
step 1): 3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Synthesis of pyropheophorbide
To 173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyrophorbide (132mg,0.2mmol) was added to 5mL of 30% HBr-AcOH solution and stirred for 2 h. 50mL of methanol was added slowly and stirred at room temperature for 4 h. 100mL of methylene chloride was added to the reaction solution, and the organic phase was washed with water 3 times. Collecting the organic phase, anhydrous MgSO4Drying, filtering, collecting filtrate, removing solvent under reduced pressure, purifying with silica gel column chromatography, eluting with dichloromethane and acetone (v/v ═ 50:1) to obtain 3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyrophorbide (91mg) in 65.7% yield.1H NMR(400MHz,CDCl3)δppm:9.75(s,1H),9.58(s,1H),8.61(s,1H),5.90(d,J=7.1 Hz,1H),5.31(d,J=20.0Hz,1H),5.15(d,J=19.8Hz,1H),4.55(s,1H),3.76(s,2H),3.71(s, 3H),3.64–3.55(m,5H),3.44(s,3H),3.31(s,3H),2.70(s,1H),2.40(s,3H),2.20–2.11(m,3H), 1.85(d,J=7.1Hz,3H),1.73(t,J=7.7Hz,3H),0.88(s,1H),-1.76(s,1H);ESI-MS m/z:694.4 [M+1]+。
Step 2): 3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Synthesis of pyropheophorbide
Reacting 3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyrophorbide (100mg, 0.144mmol) was dissolved in 10mL of tetrahydrofuran, 1M LiOH (0.5mL) was added, and the mixture was stirred at room temperature for about 3 h. The solvent was removed under reduced pressure, the residue was dissolved in 50mL of dichloromethane, washed three times with water, the organic phase was collected and washed with anhydrous MgSO4And (5) drying. Filtering, collecting filtrate, removing solvent under reduced pressure to obtain 3- (1-methoxyethyl) -3-dethyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyrophorbide (83mg) was obtained in 84.7% yield.1H NMR(400MHz,DMSO-d6)δppm:9.77(s,1H), 9.73(s,1H),8.87(s,1H),5.98(s,1H),4.59(d,J=8.0Hz,1H),4.33(s,1H),3.94(d,J=7.3Hz, 2H),3.74(s,3H),3.64(s,3H),3.49(s,4H),3.46(s,3H),3.24(s,3H),2.61(d,J=7.8Hz,3H), 2.38(d,J=6.8Hz,2H),2.04(d,J=6.3Hz,3H),1.79(d,J=7.5Hz,3H),1.64(t,J=7.0Hz,3H), 1.24(d,J=12.5Hz,4H),0.29(s,1H),-1.96(s,1H);ESI-MS m/z:680.4[M+1]+。
[ example 3]
173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ia-2)
The starting materials were pyropheophorbide-a and methyl 5-methylamino-4-oxopentanoate according to the procedure of example 1:
173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR(400MHz,DMSO-d6):δ ppm 12.33(s,1H),9.70(d,J=3.9Hz,1H),9.62(d,J=1.4Hz,1H),8.84(s,1H),5.98(dt,J=6.8, 3.9Hz,1H),5.19(s,1H),5.13(s,1H),4.57(dd,J=16.3,7.9Hz,1H),4.33-4.21(m,1H),3.66(q, J=7.6Hz,3H),3.54(s,4H),3.49(d,J=1.8Hz,3H),3.44(s,2H),3.21(s,3H),2.92-2.73(m, 8H),2.69(s,4H),2.47-2.39(m,6H),2.18(s,1H),2.04(dd,J=6.6,2.2Hz,3H),1.76(d,J=7.3 Hz,3H),1.60(t,J=7.5Hz,3H),1.36(s,4H),0.19(s,1H),-1.99(d,J=2.4Hz,1H);ESI-MS m/z:662.4[M+1]+。
[ example 4]
173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ia-3)
The starting materials were pyropheophorbide-a and methyl 5-ethylamino-4-oxopentanoate according to the procedure of example 1:
173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR(400MHz,DMSO-d6):δ ppm 11.33(s,1H),9.44(d,J=10.2Hz,1H),9.19(s,1H),8.41(d,J=5.7Hz,1H),8.05(d,J= 14.6Hz,1H),6.29(d,J=17.6Hz,1H),6.14(d,J=11.7Hz,1H),5.09(s,1H),4.56(q,J=15.4, 11.4Hz,1H),4.29(d,J=9.6Hz,1H),4.08(q,J=7.1Hz,2H),3.84(t,J=5.4Hz,1H),3.56–3.45 (m,4H),3.04(d,J=6.5Hz,2H),2.23(dt,J=14.0,6.5Hz,1H),2.09(s,1H),1.80(d,J=7.3Hz, 2H),1.64–1.38(m,3H),0.94–0.69(m,3H),-2.18(s,1H);ESI-MS m/z:676.4[M+1]+。
[ example 5]
3- (1-ethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ib-2)
At 17 with3- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyropheophorbide and ethanol were used as starting materials and obtained according to the method of example 2:
3- (1-ethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR(400 MHz,DMSO-d6)δppm:12.10(s,1H),9.83(s,1H),8.86(d,J=2.3Hz,1H),6.05(s,1H),5.24(d, J=19.7Hz,2H),4.33(s,1H),3.93(s,2H),3.75(s,4H),3.40(s,5H),3.24(s,3H),2.62(s,6H), 2.38(s,2H),2.16(s,2H),2.03(s,3H),1.79(d,J=7.1Hz,3H),1.65(s,3H),1.30(s,6H),0.32(s, 1H),-1.96(s,1H);ESI-MS m/z:694.4[M+1]+。
[ example 6]
3- (1-n-propoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ib-3)
At 17 with3- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyropheophorbide and n-propanol as raw materials, according to the method of example 2To:
3- (1-n-propoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR (400MHz,DMSO-d6):δppm 12.09(s,1H),9.80(d,J=3.5Hz,1H),9.67(d,J=2.5Hz,1H),8.85 (s,1H),8.19(dt,J=6.5,3.1Hz,1H),6.01(q,J=6.6Hz,1H),5.22(d,J=20.0Hz,2H),4.58(dt,J =7.4,4.0Hz,1H),4.32(d,J=8.8Hz,1H),4.00-3.85(m,2H),3.76-3.63(m,3H),3.58(d,J= 2.4Hz,3H),3.40(d,J=1.4Hz,3H),3.22(s,3H),2.62(t,J=6.5Hz,3H),2.48(s,5H),2.39(t,J= 6.5Hz,2H),2.04(dd,J=6.6,3.7Hz,3H),1.79(d,J=7.2Hz,3H),1.62(t,J=7.5Hz,4H),1.31- 1.11(m,9H),0.92(td,J=7.4,3.0Hz,4H),0.26(d,J=4.3Hz,1H),-1.97(d,J=3.0Hz,1H);ESI -MS m/z:708.3[M+1]+。
[ example 7]
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ib-9)
At 17 with3- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyropheophorbide and ethylene glycol monomethyl ether were obtained by the method of example 2:
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR (400MHz,DMSO-d6)δppm:9.76(d,J=15.4Hz,1H),9.30(s,1H),8.54(s,1H),6.03–5.88(m, 1H),5.02(d,J=19.9Hz,1H),4.47(s,1H),4.28(s,1H),3.88–3.70(m,4H),3.71–3.55(m,6H), 3.25(d,J=3.0Hz,4H),2.45–2.26(m,7H),2.17–2.04(m,5H),1.77(d,J=6.8Hz,4H),1.63(s, 7H),1.33(s,5H),1.28(s,8H),-1.94(s,1H);ESI-MS m/z:724.5[M+1]+。
[ example 8]
3- [1- (2-Fluoroethoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Preparation of pyropheophorbide (Compound Ib-12)
At 17 with3- [ N- (2-oxo-4-methoxycarbonylbutyl)]Pyropheophorbide and 2-fluoroethanol were obtained according to the method of example 2, starting from:
3- [1- (2-Fluoroethoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR(400MHz,DMSO-d6)δppm:12.08(s,1H),9.84–9.77(m,1H),9.71(dd,J=12.7,2.2Hz, 1H),8.85(s,1H),8.19(d,J=6.2Hz,1H),6.01(q,J=6.7Hz,1H),5.23(dd,J=20.2,6.4Hz,1H), 5.11(dd,J=20.1,7.5Hz,1H),4.59(t,J=7.8Hz,1H),4.41–4.28(m,1H),4.01–3.85(m,2H), 3.69(p,J=6.9,5.7Hz,3H),3.59(t,J=2.5Hz,3H),3.48(d,J=18.4Hz,2H),3.40(s,2H),3.23 (d,J=9.1Hz,3H),2.62(t,J=6.6Hz,3H),2.38(t,J=6.5Hz,2H),2.17(tdd,J=13.6,8.4,4.3Hz, 2H),2.04(dd,J=6.7,3.6Hz,2H),1.79(d,J=6.9Hz,3H),1.76–1.67(m,2H),1.63(t,J=7.5Hz, 4H),0.94(dtd,J=14.6,7.4,3.0Hz,4H),0.84(t,J=6.7Hz,2H),0.27(d,J=3.9Hz,1H),-1.96(d, J=2.9Hz,1H);ESI-MS m/z:712.4[M+1]+。
[ example 9]
3- (1-methoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]The preparation method of the pyropheophorbide (compound Ib-15) specifically comprises the following steps:
at 17 with3- [ N-methyl-N- (2-oxo-4-methoxycarbonylbutyl)]Pyropheophorbide, methyl 5-methylamino-4-oxopentanoate and methanol as starting materials, obtained according to the procedure of example 2:
3- (1-methoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide.1H NMR(400MHz,DMSO-d6)δppm:11.08(s,1H),9.12(s,1H),8.71(s,1H),6.95(s,1H),6.64(s, 1H),5.87(d,J=1.1Hz,1H),5.57(d,J=12.4Hz,1H),5.05(q,J=6.9Hz,1H),4.37–4.25(m, 2H),3.83(td,J=12.5,2.9Hz,1H),3.39(s,3H),3.29(q,J=7.4Hz,1H),2.98–2.58(m,9H),2.39 (s,3H),2.38–2.27(m,1H),2.17(s,3H),1.98–1.87(m,1H),1.86–1.74(m,5H),1.54(d,J=6.8 Hz,3H),1.27–1.19(m,6H),1.11(t,J=8.0Hz,3H),0.27(d,J=3.9Hz,1H),-1.96(d,J=2.9Hz, 1H);ESI-MS m/z:694.2[M+1]+。
EXAMPLE 10 photodynamic therapy experiment for human esophageal carcinoma cell (Eca-109) transplantation tumor in nude mouse
The test animals were: BABL/c nude mice, average weight 20 ~ 22g (Shanghai Si Laike laboratory animals LLC)
The tested drugs are: 173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-1); 3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-1); 173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-3); 3- (1-ethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-2); 3- (1-n-propoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-3); 3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-9); 3- [1- (2-Fluoroethoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-12); 3- (1-methoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-15); a control compound, temoporfin (supplied by shanghai pioneer pharmaceutical science co.
Light source: XD-650AB laser; model SD2490 laser power measuring instrument.
Photodynamic injury experiments of transplanted tumors of human esophageal cancer cells (Eca-109):
inoculating Eca-109 cells into the chest of a mouse under the aseptic condition, and selecting when the tumor grows to 6-7mm in diameterThe nude mice with good growth, no ulcer and hemispherical single tumor are randomly grouped according to the same sex in the same nest, 6 mice in each group are injected and dosed by tail vein, the drug solvent is used as a blank control, the temoporfin is prepared into solution with the same concentration as a positive control, and the power density is 180mW/cm after dosing2Laser (wavelength 650nm, light dose 120J/cm)2) Irradiating the tumor; 14 days after the light irradiation, the mice were sacrificed, tumors were exfoliated, weighed, and the inhibition rate was calculated.
The tumor inhibition rate is (C-T)/C × 100%
In the formula, T: mean tumor weight of the administered group; c: control group mean tumor weight.
The experimental results are shown in the table 2, Ia-1, Ib-1, Ia-2, Ia-3, Ib-2, Ib-3, Ib-9, Ib-12 and Ib-15 have obvious photodynamic inhibition effect on tumors, and no obvious skin phototoxic effect exists under the treatment dosage.
TABLE 2 tumor-inhibiting effect of Ia-1, Ib-1, Ia-2, Ia-3, Ib-2, Ib-3, Ib-9, Ib-12, Ib-15
P <0.001 and control drug temoporfin
ΔΔΔP<0.001 vs blank.
Claims (9)
1. A novel pyropheophorbide a derivative (I), the structural formula of which is as follows:
wherein R ═ H, straight or branched C1-C6 alkyl; r1Vinyl or-CH (CH)3)OR2;
R2=-H;
-(CH2)nCH3,n=0-7;
-CH(CH3)(CH2)nCH3,n=0-5;
-(CH2)nOH,n=2-5;
-(CH2CH2O)nCH3,n=1-3;
-CH2CH2O(CH2)nCH3,n=1-3;
-(CH2CH2CH2O)nCH3,n=1-3;
-(CH2)nF,n=2-5。
2. The novel pyropheophorbide a derivative according to claim 1, wherein said compound is:
173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia);
173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-1);
173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-2);
173- [ N-N-propyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-3);
173- [ N-isopropyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-4);
173- [ N-N-butyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ia-5);
3- (1-methoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-1);
3- (1-ethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-2);
3- (1-n-propoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl))]Pyropheophorbide (compound Ib-3);
3- (1-Isopropoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-4);
3- (1-n-butoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-5);
3- (1-n-pentyloxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-6);
3- (1-n-hexyloxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-7);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-8);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-9);
3- (1-ethoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-10);
3- (1-n-propoxyethoxyethyl) -3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-11);
3- [1- (2-Fluoroethoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-12);
3- [1- (3-Fluoropropoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-13);
3- [1- (4-Fluorobutoxy) ethyl]-3-devinyl-173- [ N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-14);
3- (1-methoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-15);
3- (1-methoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-16);
3- (1-ethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-17);
3- (1-ethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-18);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-19);
3- (1-hydroxyethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-20);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N-methyl-N- (2-oxo-4-carboxybutyl)]Pyropheophorbide (compound Ib-21);
3- (1-methoxyethoxyethyl) -3-devinyl-173- [ N-Ethyl-N- (2-oxo-4-carboxybutyl)]Pyrophorbide (compound Ib-22).
3. The process for the preparation of a new class of pyropheophorbide a derivatives (I) according to claim 1, comprising the following steps:
compound Ia can be prepared by the following method:
the method comprises the following steps: dissolving pyropheophorbide a (compound II), compound III and a condensing agent in an organic solvent, adding alkali, and stirring; washing with water, and collecting an organic phase; drying, filtering, concentrating under reduced pressure to remove solvent, and performing column chromatography to obtain dark green solid compound IV; dissolving a compound IV in an organic solvent, adding an alkali solution, and stirring at room temperature; adjusting pH to 3-5 with hydrochloric acid, extracting with dichloromethane, mixing organic phases, drying, filtering, concentrating under reduced pressure to remove solvent, and separating and purifying by column chromatography to obtain compound Ia;
r is H, straight chain or branched chain C1-C6 alkyl; r' is substituted or unsubstituted straight-chain or branched-chain C1-C10 alkyl and substituted or unsubstituted aromatic group;
compound Ib can be prepared by the following method:
the method comprises the following steps:
the preparation method comprises the following steps: dissolving the compound IV in HBr-AcOH solution, stirring, slowly adding alcohol, heating and stirring; adding water into the reaction solution, extracting with dichloromethane, collecting an organic phase, drying, filtering, concentrating under reduced pressure to remove the solvent, and performing column chromatography to obtain a compound V; dissolving the compound V in an organic solvent, adding alkali, and stirring; adjusting pH to 3-5 with hydrochloric acid, extracting with dichloromethane, mixing organic phases, drying, filtering, concentrating under reduced pressure to remove solvent, and separating and purifying by column chromatography to obtain compound Ib;
wherein R is H, straight chain or branched chain C1-C6 alkyl; r' is substituted or unsubstituted straight chain or branched chain C1-C10 alkyl, substituted or unsubstituted aryl; r2=-H;-(CH2)nCH3,n=0-7;-CH(CH3)(CH2)nCH3,n=0-5;-(CH2)nOH,n=2-5;-(CH2CH2O)nCH3,n=1-3;-CH2CH2O(CH2)nCH3,n=1-3;-(CH2CH2CH2O)nCH3,n=1-3;-(CH2)nF,n=2–5;
The second preparation method comprises the following steps: dissolving a compound VI, a compound III and a condensing agent in an organic solvent, adding alkali, and stirring; washing with water, collecting organic phase, drying, filtering, concentrating under reduced pressure to remove solvent, and performing column chromatography to obtain compound VII; dissolving a compound VII in an organic solvent, adding an alkali solution, and stirring; adjusting pH to 3-5 with hydrochloric acid, extracting with dichloromethane, mixing organic phases, drying, filtering, concentrating under reduced pressure to remove solvent, and separating and purifying by column chromatography to obtain compound Ib;
wherein R is a linear or branched C1-C6 alkyl group; r' is substituted or unsubstituted straight chain or branched chain C1-C10 alkyl, substituted or unsubstituted aryl; r2=H;-(CH2)nCH3,n=0-7;-CH(CH3)(CH2)nCH3,n=0-5;-(CH2)nOH,n=2-5;-(CH2CH2O)nCH3,n=1-3;-CH2CH2O(CH2)nCH3,n=1-3;-(CH2CH2CH2O)nCH3,n=1-3;-(CH2)nF,n=2-5。
4. The process for the preparation of the novel pyropheophorbide a derivative (I) according to claim 3, characterized in that: when the compound (II) is used for preparing the compound (IV) and the compound (VI) is used for preparing the compound (VII), the condensing agent is Dicyclohexylcarbodiimide (DCC)/4-Dimethylaminopyridine (DMAP), N, N-Diisopropylcarbodiimide (DIC)/4-Dimethylaminopyridine (DMAP), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -di (dimethylamino) carbenium Hexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate (TBTU), benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP) or diphenylphosphoryl azide (DPPA); the reaction time for preparing the compound (IV) from the compound (II) and the compound (VII) from the compound (VI) is 1-10h, and the reaction temperature is 0-100 ℃.
5. The process for the preparation of the novel pyropheophorbide a derivative (I) according to claim 3, characterized in that: when the compound (VII) is used for preparing the compound (Ib), the base is any one or a mixture of any more of triethylamine, diisopropylethylamine, pyridine, sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide and potassium tert-butoxide; the concentration of the alkali used for preparing the compound (Ia) from the compound (IV), the compound (Ib) from the compound (V) and the compound (Ib) from the compound (VII) is 1-20mol/L, the reaction time is 1-10h, and the reaction temperature is 0-100 ℃.
6. The process for the preparation of the novel pyropheophorbide a derivative (I) according to claim 3, characterized in that: when the compound (VI) is used for preparing the compound (VII) and the compound (VII) is used for preparing the compound (Ib), the organic solvent is any one or a mixture of any more of 1, 4-dioxane, Tetrahydrofuran (THF), toluene, xylene, N-hexane, cyclohexane, ethyl acetate, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), carbon tetrachloride, acetone, benzene, chlorobenzene, 2-methyltetrahydrofuran, dichloromethane, trichloromethane, dichloroethane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dipropylene ether, ethylene glycol dibutyl ether and methyl tert-butyl ether.
7. The process for the preparation of the novel pyropheophorbide a derivative (I) according to claim 3, characterized in that: the alcohol used for preparing the compound (V) from the compound (IV) is methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, isopropanol, 2-butanol, isobutanol, sec-pentanol, isoamyl alcohol, cyclohexanol, benzyl alcohol, 2-fluoroethanol, 3-fluoropropanol and 4-fluorobutanol; when the compound (IV) is used for preparing the compound (V), the reaction temperature is 25-100 ℃ after the alcohol is added, and the reaction time is 2-10 h.
8. The process for the preparation of the novel pyropheophorbide a derivative (I) according to claim 3, characterized in that: the HBr-HOAc solution used for preparing the compound (V) from the compound (IV) has the content of 5-35 percent by weight; the filler in the column chromatographic separation is silica gel, and the eluent is a mixed solvent of petroleum ether and ethyl acetate, petroleum ether and dichloromethane, dichloromethane and methanol or dichloromethane and acetone, and the mixing ratio range is 1:1-100: 1.
9. The use of the novel pyropheophorbide a derivatives (I) according to claim 1 for the preparation of photodynamic medicaments for the diagnosis and treatment of tumors, actinic keratosis, macular degeneration, condyloma acuminatum, port's disease.
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