CN105384743A - Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof - Google Patents

Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof Download PDF

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CN105384743A
CN105384743A CN201510770434.4A CN201510770434A CN105384743A CN 105384743 A CN105384743 A CN 105384743A CN 201510770434 A CN201510770434 A CN 201510770434A CN 105384743 A CN105384743 A CN 105384743A
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pyropheophorbide
amino acid
acid derivative
ethers
compound
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姚建忠
单彬
张万年
盛春泉
缪震元
贾宁阳
孟志
杜红丽
韩贵焱
刘明辉
董国强
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Second Military Medical University SMMU
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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
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    • 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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Abstract

The invention relates to the technical field of medicines and in particular relates to a novel chlorine photosensitizer-pyropheophorbide-a ether amino acid derivative, a preparation method thereof and an application to preparation of antitumor medicines. A chemical structure of the pyropheophorbide-a ether amino acid derivative is shown in a general formula (I) in the specification. The pyropheophorbide-a ether amino acid derivative has the advantages of high efficiency, low toxicity and the like, and can be used for preparing new medicines for photodynamic therapy of cancers, medicines for photodynamic therapy of benign vascular diseases, such as age-related macular degeneration and nevus flammeus and medicines for photodynamic therapy of condyloma acuminate.

Description

Pyropheophorbide-a ethers amino acid derivative and its production and use
Technical field
The present invention relates to medical art, being specifically related to is a kind of novel dihydro porphin photosensitizer---pyropheophorbide-a ethers amino acid derivative and preparation method thereof, and preparing the purposes in antitumor drug.
Background technology
Photodynamic therapy (photodynamictherapy, PDT) be last century neoplasm targeted therapy new technology that the eighties grows up gradually and administration (photosensitizers) afterwards with laser orientation irradiation focus (tumour) tissue that wavelength and the intrinsic red light district maximum absorption wavelength of photosensitizers match, by the matrix oxygen (O in photosensitizers induce tissue 2) excite produce singlet oxygen ( 1o 2) isoreactivity oxygen species (ROS), cause apoptosis of tumor cells or downright bad and play neoplasm targeted therapy effect.Because PDT only implements target illumination to tumor tissues, optionally destruction tumour cell normal tissue or organ then almost do not damage or damage very little, clinically also there is good controlling, therefore, it is a kind for the treatment of technology non-invasive to human body, there is side effect little (wound that nothing operation produces is painful, vomiting, nauseating and immunosuppression without radiation and chemotherapy generation), the advantages such as other treatment means repeatedly uses separately or can be coordinated.
Oxygen in illumination, tissue and photosensitizers are the three large key elements of PDT, and wherein, photosensitizers is core.First-generation Porphyrin-Based Sensitizer such as porfimer sodium (porfimersodium) etc. is used successfully to clinical therapy of tumor, achieve the curative effect attracted people's attention, but also there is open defect: the laser penetration killing tumor cells degree of depth that (1) red light district maximum absorption wave length (630nm) makes wavelength match with it is inadequate; And molar absorption coefficient (ε) is little, causes photosensitive activity low; (2) be polycomponent porphyrin mixture; (3) in body, removing causes delay phototoxicity large slowly.Therefore, from late nineteen nineties in last century, carried out chlorin such as benzoporphyrin derivative (benzoporphyrinderivative, BPD) and chlorophyll a degraded derivative is the research and development of the s-generation photosensitizers of representative.This wavelength laser is caused to have the better tumor-killing degree of depth and molar absorption coefficient (ε) high order of magnitude, photosensitive activity strong, internal metabolism fast, delay phototoxicity little, become photosensitive new drug research focus compared with porphyrin red shift to 660-690nm because dihydro porphin photosensitizer has single clear and definite, red light district (> 600nm) maximum absorption wavelength of structure.Wherein, Visudyne (verteporfin), temoporfin (temoporfin) and talaporfin (talaporfin) respectively at 2000, calendar year 2001 and 2004 successfully go on the market.
The composition optimizes that pyropheophorbide-a is current, widely at its 3-vinyl, 13 1-one carbonyl and 17 3structure of modification is carried out at-carboxyl three positions respectively, and (Liu Chunlin waits .3-alkane (acyl group) to replace-13 1the synthesis of-deoxidation Methyl Pyropheophorbide. Journal of Yantai University: natural science and engineering version, 2008, (1): 23-28; Qiu Jun, waits .E/Z-O-to mix fragrant acyl methyl pyropheophorbide-α 13 1the synthesis of-one oxime. Jilin Institute of Chemical Technology journal, 2007,23 (4): 8-11; Rancan, F., etal.Fullerene-PyropheophorbideaComplexesasSensitizerfor PhotodynamicTherapy:UptakeandPhoto-InducedCytotoxicityon JurkatCells.JournalofPhotochemistryandPhotobiologyB:Biol ogy, 2005,80:1-7.).
Wherein, introduce water-soluble amino acids residue in bibliographical information porphyrin and chlorin molecular structure and can improve its drug effect and pharmacopedics character (Hitoshi, T., etal.Synthesisofchlorophyll-aminoacidconjugatesasmodelsf ormodificationofproteinswithchromo/fluorophores.Bioorg.M ed.Chem.2014,22,1421-1428.; Kwitniewski, M., etal.DiaminoacidderivativesofPpIXaspotentialphotosensiti zersforphotodynamictherapyofsquamouscellcarcinomaandpros tatecancer:invitrostudies.J.Photochem.Photobiol.B2009,94,214 – 222.; Serra, V.V., Newporphyrinaminoacidconjugates:synthesisandphotodynamic effectinhumanepithelialcells.Bioorg.Med.Chem.2010,18,6170 – 6178.; Wang, H.M.; Porphyrinwithaminoacidmoieties:atumorphotosensitizer.Che m.Biol.Interact.2008,172,154-158.); In addition, the ether derivative of the 2-position vinyl of chlorin has stronger photosensitive activity and tumour PDT curative effect (Yao Jianzhong etc. than its primer, the synthesis of chlorin f methyl ether and photosensitization power thereof and tumour photobiological activity. Acta Pharmaceutica Sinica, 2000,35 (1): 63-66; Yao Jianzhong etc., the synthesis of 2-(1-hydroxyl) ethyl chlorin f and ether derivative thereof and tumour photobiological activity. Chinese pharmaceutical chemistry magazine, 2001,39 (1): 1-4.), the present invention intends researching and developing a new class dihydro porphin photosensitizer on this basis.
There is no bibliographical information at present using pyropheophorbide-a as guide structure, introduce the etherificate structure design of amino-acid residue and 2-position vinyl simultaneously.
Summary of the invention
The object of this invention is to provide a class pyropheophorbide-a ethers amino acid derivative, another object of the present invention is to the preparation method providing such pyropheophorbide-a ethers amino acid derivative, the third object of the present invention is to provide such pyropheophorbide-a ethers amino acid derivative and is preparing in antitumor drug the purposes in particularly photosensitizers.
The present invention is with Stability Analysis of Structures and chlorophyll alpha degraded product pyropheophorbide-a easy to prepare is guide structure, introduce water-soluble amino acids residue at its 17-position third carboxyl and carry out etherificate to 2-position vinyl simultaneously, optimization design has synthesized the novel dihydro porphin photosensitizer of a class---pyropheophorbide-a ethers amino acid derivative.
A first aspect of the present invention, provides class pyropheophorbide-a ethers amino acid derivative and a pharmaceutical salts thereof, and the chemical structure of pyropheophorbide-a ethers amino acid derivative of the present invention is as shown in formula I:
In formula I,
R 1represent H, low alkyl group, senior alkyl, (CH 2) moR 3or (CH 2) mnR 4r 5; Preferred CH 3, n-C 3h 7, n-C 5h 11, n-C 6h 13, n-C 8h 17deng.
R 2represent various amino-acid residue; Preferred Methionin, L-glutamic acid, aspartic acid etc.
R 3represent H, low alkyl group;
R 4and R 5represent low alkyl group independently;
M represents the integer between 2-6;
Described low alkyl group, refers to the straight or branched alkyl containing 1-6 carbon atom;
Described senior alkyl, refers to the straight or branched alkyl containing 7-18 carbon atom.
Pyropheophorbide-a ethers amino acid derivative of the present invention, part preferred compound I 1~ I 15r 1and R 2combine as shown in table 1 respectively:
Table 1: part preferred compound I of the present invention 1~ I 15
Wherein n represents " n-".
Further, present invention also offers the pharmaceutical salts of above-mentioned pyropheophorbide-a ethers amino acid derivative and pharmaceutically acceptable preparation, described pharmaceutical salts can be the intravenous formulations such as an alkali metal salt, particular certain cancers etc., described preparation preferred liposome and high-fat emulsion.
A second aspect of the present invention, provides the preparation method of above-mentioned pyropheophorbide-a ethers amino acid derivative.
The invention provides the novel dihydro porphin photosensitizer that a kind of raw material sources are wide, preparation method is simple, toxicity is low---the preparation method of pyropheophorbide-a ethers amino acid derivative.
The present invention is raw materials used stablizes degraded product for chlorophyll a--pyropheophorbide-a (pyropheophorbidea), and its chemical structural formula is as follows:
3-vinyl in pyropheophorbide-a structure and 17-third carboxyl, respectively with alcohol and amino acid through etherificate and peptide formation, synthesis obtains dihydro porphin photosensitizer---the pyropheophorbide-a ethers amino acid derivative of the new structure type of the present invention.
Above-mentioned raw materials can with the chlorophyll a in silkworm excrement through soda acid degraded preparation.
China is silk big producing country of the world, and silkworm excrement (family's silkworm faeces) is one of Main By product of silkworm industry.The annual silk of China about can produce 1,000,000 tons of silkworm excrements in producing.Silkworm excrement Determination of Chlorophyll a content accounts for 0.75%, is very enrich and the chlorophyll resource of cheapness.Utilize silkworm excrement to prepare pyropheophorbide-a ethers amino acid derivative, the medical applications of silkworm industry waste resource can be expanded, final realization " turning waste into wealth ".
Pyropheophorbide-a also can directly be bought, or with literature method synthesis obtain (Yao Jianzhong, etc. the chemical research of silkworm excrement Determination of Chlorophyll a degradation process. herbal medicine, 1999,30 (8): 568-57.)
The preparation method of pyropheophorbide-a ethers amino acid derivative of the present invention, with silkworm excrement chlorophyll crude extract---commercially available chlorophyll paste is that the base beginning preparation method of raw material is as follows:
A, prepare pyropheophorbide-a (pyropheophorbidea, V) with chlorophyll a (chlorophylla, VII) for raw material, reaction process is:
B, prepare target compound pyropheophorbide-a ethers amino acid derivative I with compound V, reaction process is as follows:
Concrete synthesis step is:
A, with chlorophyll a (chlorophylla, VII) for pyropheophorbide-a (pyropheophorbidea, V) prepared by raw material:
(A1) method one
First, the diethyl ether solution of commercially available chlorophyll paste, generates pheophorbide acid a (pheophorbidea, VI) with equal volume amounts concentrated hydrochloric acid stirring reaction 0.5h under the cold condition of 0 ~ 5 DEG C; Then, compound VI back flow reaction 4h obtained V in glacial acetic acid solution;
(A2) method two
The diethyl ether solution of commercially available chlorophyll paste, at ambient temperature with equal volume amounts concentrated hydrochloric acid stirring reaction 2d obtained V;
B, prepare pyropheophorbide-a ethers amino acid target derivative (I) by compound V:
(B1) pyropheophorbide-a ether derivative (III) is prepared
First by compound V and excessive 33%HBr Glacial acetic acid liquid room temperature reaction 24h, obtained 3 1-bromo-3 1-remove vinyl pyropheophorbide-a (IV); Then compounds Ⅳ is at excessive K 2cO 3there is lower and various alcohol (R 1oH) react and obtain compound III;
(B2) pyropheophorbide-a ethers amino acid target derivative (I) is prepared:
By the dichloromethane solution of compound III 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), N-hydroxybenzotriazole (HOBt) and N, N-dimethyl isopropyl amine (DIPEA) exist under respectively with various protected amino acid hydrochloric acid (R 2nH 2hCl) the pyropheophorbide-a ethers amino acid derivative (II) of the obtained amino of reaction or carboxy protective, compound ii takes off the tertiary butyl or tertbutyloxycarbonyl and lithium hydroxide demethylation ester through trifluoracetic acid (TFA) and namely obtains pyropheophorbide-a ethers amino acid target compound I.
Part preferred compound I of the present invention 1~ I 15r 1and R 2combination is as follows respectively:
A third aspect of the present invention, provides the pharmaceutical applications of above-mentioned pyropheophorbide-a ethers amino acid derivative.
Pyropheophorbide-a ethers amino acid derivative of the present invention has excellent Photodynamic therapy effect to people's colon-cancer cell HCT116, gastric carcinoma cells MKN45 and human breast cancer cell MDA-MB-231, and has advantage that is efficient, low toxicity.
Compared with the photosensitizers Visudyne (verteporfin) of new generation of existing clinical application, the advantages such as pyropheophorbide-a ethers amino acid derivative of the present invention has efficiently, low toxicity, can be used for preparing antitumor drug, particularly new Photodynamic therapy of cancer medicine, optical dynamic therapy non-malignant vascular disease are as the medicine of senile macular degeneration SMD (a kind of retinal microvascular proliferative disease) and nevus flammeus (a kind of congenital cutaneous capillary blood vessel deformity pathology) and optical dynamic therapy pointed condyloma (human papilloma virus infection disease) medicine.
Embodiment
Now in conjunction with the embodiments, the present invention is described in detail, but enforcement of the present invention is not limited only to this.Agents useful for same of the present invention and raw material all commercially maybe can be prepared by literature method.
The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
Embodiment 1: the preparation of pyropheophorbide-a (V)
Silkworm excrement chlorophyll paste, purchased from Feng Ming chlorophyll company limited of Haining city.
Method one: silkworm excrement chlorophyll paste 100g, adds the ether of 500mL and isopyknic concentrated hydrochloric acid, logical N 2rear confined reaction 2d, reaction solution is poured in separating funnel to leave standstill and point is taken off a layer acid liquid, adds 2 times of water gagings dilutions, and it is 5-6 that the NaOH cooling lower 10mol/L is neutralized to pH, suction filtration, P 2o 5after drying, through silica gel H pillar layer separation, [moving phase is CH 2cl 2: CH 3cOCH 3: CH 3oH:HCO 2h=60:1:1:0.1 (v/v/v/v)] obtain compound V sterling 2g.
MS(ESI +)m/z:535.54(M+H,100％)；1068.98(2M+1,100％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.36 (1H, s, meso-H), 9.26 (1H, s, meso-H), 8.50 (1H, s, meso-H), 7.91 (1H, dd, J=18.0,9.0Hz, 3 1-H), 6.22 (1H, d, J=18.0Hz, 3 2-H b), 6.18 (1H, d, J=9.0Hz, 3 2-H a), 5.22 (1H, d, J=10.5Hz, 13 2-H b), 5.06 (1H, d, J=10.5Hz, 13 2-H a), 4.41-4.47 (1H, m, 17-H), 4.25-4.27 (1H, m, 18-H), 3.60 (2H, q, J=7.5Hz, 8 1-CH 2), 3.57 (3H, s, 12-CH 3), 3.36 (3H, s, 7-CH 3), 3.15 (3H, s, 2-CH 3), 2.56-2.69 (2H, m, 17 2-CH 2), 2.16-2.39 (2H, m, 17 1-CH 2), 1.79 (3H, d, J=7.5Hz, 18-CH 3), 1.63 (3H, t, J=7.8Hz, 8 2-CH 3) ,-1.75 (1H, s, NH in ring).
Method two: silkworm excrement chlorophyll paste (VII) 200g is dissolved in 500mL ether, adds isopyknic concentrated hydrochloric acid and stirring reaction 0.5h under 0 ~ 5 DEG C of condition, divides and takes off a layer acid solution, add 2 times of water gaging dilutions, it is 5-6 that the NaOH cooling lower 10mol/L is neutralized to pH, suction filtration, P 2o 5black powder pheophorbide acid a (VI) crude product 10g is obtained after drying.Get compound VI crude product 2g, be dissolved in glacial acetic acid 100mL, after back flow reaction 4h, stopped reaction.Reaction solution is poured in the cold water of 1L, with methylene dichloride (DCM) extraction (300mL × 3), merge organic phase, wash 3 times, anhydrous Na 2sO 4drying, reclaim under reduced pressure organic solvent, obtains compound V 1.5g through silica gel H pillar layer separation.MS(ESI +)m/z:535.54(M+H,100％)。
Embodiment 2:3 1-bromotrifluoromethane-3 1-go the preparation of vinyl pyropheophorbide-a (IV)
Compound V (1.0g), adds 33%HBr Glacial acetic acid liquid 100mL, and Room-temperature seal reaction 24h, removes Glacial acetic acid under reduced pressure, obtain dark green solid compounds Ⅳ, does not do purifying and is directly used in next step reaction.
Embodiment 3:3 1-methoxyl group-3 1-remove vinyl pyropheophorbide-a (III 1) preparation
Above-mentioned dark green solid compounds Ⅳ (0.5g), is dissolved in dry DCM50mL, adds 1gK 2cO 3methyl alcohol dry with 10mL, at N 2the lower room temperature reaction of protection, TLC monitors reaction process, reacts complete after about 2h, stopped reaction.Add 5 times of volume water gagings in reaction solution, with DCM (200mL × 3) extraction, divide and get merging organic layer, wash 3 times, saturated common salt washes 1 time, anhydrous Na 2sO 4dry 2h, silica gel H chromatographic separation after reclaim under reduced pressure organic solvent, moving phase DCM:CH 3cOCH 3: CH 3oH:CH 3cO 2h=80:1:1:0.1 (v/v/v/v), obtains 0.3g black powder III 1, fusing point 230 ~ 231 DEG C, productive rate 56.6%.
MS(ESI +)m/z:567.66(M+H,100％),1133.93(2M+1,35％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.63 (1H, s, meso-H), 9.50 (1H, s, meso-H), 8.52 (1H, s, meso-H), 5.85 (1H, q, J=6.8Hz, 3 1-H), 5.22 (1H, d, J=10.0Hz, 13 2-H b), 5.11 (1H, d, J=10.0Hz, 13 2-H a), 4.30-4.36 (1H, m, 17-H), 4.21-4.27 (1H, m, 18-H), 3.71 (2H, q, J=7.8Hz, 8 1-CH 2), 3.65 (3H, s, 12-CH 3), 3.51 (3H, s, 3 1-OCH 3), 3.36 (3H, s, 7-CH 3), 3.25 (3H, s, 2-CH 3), 2.56-2.75 (2H, m, 17 2-CH 2), 2.22-2.34 (2H, m, 17 1-CH 2), 2.08 (3H, d, J=6.8Hz, 3 2-CH 3), 1.79 (3H, d, J=7.5Hz, 18-CH 3), 1.68 (3H, t, J=7.8Hz, 8 2-CH 3) ,-1.73 (1H, s, NH in ring).
Embodiment 4:3 1-positive propoxy ethyl-3 1-remove vinyl pyropheophorbide-a (III 2) preparation
By the method for embodiment 3, compounds Ⅳ (0.5g) reacts 45min with the dry n-propyl alcohol of 10mL and obtains black solid III 20.35g, fusing point 168 ~ 170 DEG C, yield 62.5%.
MS(ESI +)m/z:595.62(M+H,100％),1189.11(2M+H,40％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.64 (1H, s, meso-H), 9.54 (1H, s, meso-H), 8.58 (1H, s, meso-H), 5.90 (1H, q, J=6.8Hz, 3 1-H), 5.31 (1H, d, J=11.5Hz, 13 2-H b), 5.13 (1H, d, J=11.5Hz, 13 2-H a), 4.48-4.51 (1H, m, 17-H), 4.32-4.34 (1H, m, 18-H), 3.71 (2H, q, J=7.5Hz, 8 1-CH 2), 3.67 (3H, s, 12-CH 3), 3.44 (3H, s, 2-CH 3), 3.56 (2H, t, J=6.5Hz, 3 1-O cH 2cH 2cH 3), 3.29 (3H, s, 7-CH 3), 2.67-2.79 (2H, m, 17 2-CH 2), 2.50-2.60 (2H, m, 17 1-CH 2), 2.28-2.31 (2H, m, 3 1-OCH 2 cH 2cH 3), 2.08 (3H, d, J=6.8Hz, 3 2-CH 3), 1.81 (3H, d, J=7.5Hz, 18-CH 3), 1.70 (3H, t, J=7.5Hz, 8 2-CH 3), 0.92 (3H, t, J=7.0Hz, 3 1-OCH 2cH 2 cH 3) ,-1.80 (1H, s, NH in ring).
Embodiment 5:3 1-n-pentyloxy ethyl-3 1-remove vinyl pyropheophorbide-a (III 3) preparation
By the method for embodiment 3, compounds Ⅳ (0.5g) reacts 45min with the dry Pentyl alcohol of 10mL and obtains black solid III 30.40g, fusing point 172 ~ 175 DEG C, yield 69.0%.
MS(ESI +)m/z:623.77(M+H,100％),1242.921(2M+1,40％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.75 (1H, splitteds, meso-H), 9.49 (1H, splitteds, meso-H), 8.55 (1H, splitteds, meso-H), 5.89 (1H, q, J=6.8Hz, 3 1-H), 5.26 (1H, d, J=10.5Hz, 13 2-H b), 5.10 (1H, d, J=10.5Hz, 13 2-H a), 4.46-4.50 (1H, m, 17-H), 4.29-4.31 (1H, m, 18-H), 3.67 (2H, q, J=8.2Hz, 8 1-CH 2), 3.63 (3H, s, 12-CH 3), 3.47 (2H, t, J=6.0Hz, 3 1-O cH 2cH 2cH 3), 3.36 (3H, s, 7-CH 3), 3.25 (3H, s, 2-CH 3), 2.57-2.70 (2H, m, 17 2-CH 2), 2.21-2.31 (2H, m, 17 1-CH 2), 2.09 (3H, d, J=6.8Hz, 3 2-CH 3), 1.80 (3H, d, J=6.8Hz, 18-CH 3), 1.68 (3H, t, J=6.8Hz, 8 2-CH 3), 1.19-1.26 (6H, m, 3 1-OCH 2 cH 2 cH 2 cH 2cH 3), 0.81 (3H, t, J=6.2Hz, 3 1-OCH 2cH 2cH 2cH 2 cH 3) ,-1.70 (1H, s, NH in ring) ,-1.79 (1H, s, NH in ring).
Embodiment 6:3 1-positive hexyloxyehtyl-3 1-remove vinyl pyropheophorbide-a (III 4) preparation
By the method for embodiment 3, compounds Ⅳ (0.5g) reacts 2h with the dry n-hexyl alcohol of 10mL and obtains black solid III 40.33g, fusing point 165 ~ 167 DEG C, yield 55.0%.
MS(ESI +)m/z:637.48(M+H,100％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.80 (1H, s, meso-H), 9.54 (1H, s, meso-H), 8.55 (1H, s, meso-H), 5.95 (1H, q, J=6.5Hz, 3 1-H), 5.30 (1H, d, J=10.5Hz, 13 2-H b), 5.15 (1H, d, J=10.5Hz, 13 2-H a), 4.51-4.55 (1H, m, 17-H), 4.34-4.43 (1H, m, 18-H), 3.77 (2H, q, J=7.8Hz, 8 1-CH 2), 3.70 (3H, s, 12-CH 3), 3.50 (2H, t, 3 1-O cH 2cH 2cH 2cH 2cH 2cH 3), 3.41 (3H, s, 7-CH 3), 3.30 (3H, s, 2-CH 3), 2.57-2.70 (2H, m, 17 2-CH 2), 2.21-2.31 (2H, m, 17 1-CH 2), 2.14 (3H, d, J=6.5Hz, 3 2-CH 3), 1.85 (3H, d, J=6.5Hz, 18-CH 3), 1.74 (3H, t, J=7.8Hz, 8 2-CH 3), 1.23-1.30 (8H, m, 3 1-OCH 2 cH 2 cH 2 cH 2 cH 2cH 3), 0.81 (3H, t, J=6.8Hz, 3 1-OCH 2cH 2cH 2cH 2cH 2 cH 3) ,-1.65 (1H, s, NH in ring).
Embodiment 7:3 1-n-octyloxy ethyl-3 1-remove vinyl pyropheophorbide-a (III 5) preparation
By the method for embodiment 3, compounds Ⅳ (0.5g) reacts 2h with the dry n-hexyl alcohol of 10mL and obtains black solid III 50.25g, yield 42.3%.
MS(ESI +)m/z:665.79(M+H,100％)。
Embodiment 8:N-(3 1-methoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid di tert butyl carbonate (II 1) preparation
Compound III 1(230mg, 0.41mmol) is dissolved in the DCM of 175mL drying, adds HOBt (65.81mg, 0.49mmol) and EDCHCl (93.37mg, 0.49mmol), reacts 30min under ice bath.Separately get L-Aspartic acid di-t-butyl ester hydrochloride (136.4mg, 0.49mmol), be dissolved in the DCM of 30mL, add N, N-diisopropylethylamine (DIPEA) (80 μ L, 0.49mmol) ultrasonic 10min, then slowly instills it in above-mentioned solution through constant pressure addition device, N 2protective reaction is spent the night.After completion of the reaction, reaction solution uses 5% citric acid, 5%NaHCO successively in TLC monitoring 3water and saturated aqueous common salt respectively wash 1 time, anhydrous Na 2sO 4drying, obtains black powder II through silica gel H chromatographic separation after decompression and solvent recovery 1150mg, productive rate 54.2%.
MS(ESI +)m/z:795.63(M+2,100％),817.65(M+Na+1,86％),1610.44(2M+Na+1,100％).
Embodiment 9:N-(3 1-positive propoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid di-t-butyl ester (II 2) preparation
By the method for embodiment 8, compound III 2(30mg, the dry DCM liquid of 50mL 0.05mmol), with HOBt (8.1mg, 0.06mmol) with EDCHCl (11.60mg, after 0.06mmol) reacting 30min under ice bath, obtained black powder II is reacted again with the DCM (5mL) of L-Aspartic acid di-t-butyl ester hydrochloride (17.10mg, 0.06mmol) and DIPEA (9.7 μ L, 0.06mmol) sonification fluid 220mg, fusing point is 114 ~ 115 DEG C, productive rate 55.8%.
MS(ESI +)m/z:822.64(M+H,100％)。
Embodiment 10:N-(3 1-n-pentyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid di tert butyl carbonate (II 3) preparation
By the method for embodiment 8, compound III 3(110mg, the dry DCM liquid of 50mL 0.18mmol), with HOBt (28.62mg, 0.21mmol) with EDCHCl (40.63mg, after 0.21mmol) reacting 30min under ice bath, obtained black powder II is reacted again with the DCM (5mL) of L-Aspartic acid di-t-butyl ester hydrochloride (59.72mg, 0.21mmol) and DIPEA (34.04 μ L, 0.21mmol) sonification fluid 390mg, productive rate 60.1%.
MS(ESI +)m/z:850.52(M+H,100％)。
Embodiment 11:N-(3 1-positive hexyloxyehtyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid di-t-butyl ester (II 4) preparation
By the method for embodiment 8, compound III 4(40mg, the dry DCM liquid of 50mL 0.06mmol), with HOBt (10.18mg, 0.08mmol) with EDCHCl (14.45mg, after 0.08mmol) reacting 30min under ice bath, obtained black powder II is reacted again with the DCM (5mL) of L-Aspartic acid di-t-butyl ester hydrochloride (17.75mg, 0.08mmol) and DIPEA (12.10 μ L, 0.08mmol) sonification fluid 428mg, productive rate 51.6%.
MS(ESI +)m/z:864.58(M+H,100％)。
Embodiment 12:N-(3 1-n-octyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid di tert butyl carbonate (II 5) preparation
By the method for embodiment 8, compound III 5(180mg, the dry DCM liquid of 50mL 0.27mmol), with HOBt (43.90mg, 0.32mmol) with EDCHCl (62.28mg, after 0.32mmol) reacting 30min under ice bath, obtained black powder II is reacted again with the DCM (5mL) of L-Aspartic acid di-t-butyl ester hydrochloride (91.54mg, 0.32mmol) and DIPEA (52.17 μ L, 0.32mmol) sonification fluid 5128mg, fusing point is 80 ~ 81 DEG C.Productive rate 53.0%.
MS(ESI +)m/z:892.71(M+H,100％)。
Embodiment 13:N-(3 1-methoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone di tert butyl carbonate (II 6) preparation
By the method for embodiment 8, compound III 1(100mg, 174.46 μm ol) the dry DCM liquid of 50mL, with HOBt (34mg, 176.46 μm of ol) and EDCHCl (24mg, 211.76 μm ol) react 30min under ice bath after, obtained purple-brown powder II is reacted again with the DCM (5mL) of Pidolidone di-t-butyl ester hydrochloride (52.20mg, 176.46 μm of ol) and DIPEA (30.4 μ L, 176.46 μm of ol) sonification fluid 6104.1mg, fusing point is 120 ~ 121 DEG C.Productive rate 73.3%.
MS(ESI +)m/z:808.52(M+H,100％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.68 (1H, s, meso-H), 9.53 (1H, s, meso-H), 8.54 (1H, s, meso-H), 5.90 (1H, m, 3 1-H), 5.30 ~ 5.10 (2H, dd, 13 2-CH 2), 4.48 (1H, m, 17-H), 4.40 (1H, m, 18-H), 3.69 (2H, m, 8 1-CH 2), 3.56 (3H, s, 12-CH 3), 3.40 (3H, s, 3 1-OCH 3), 3.35 (3H, s, 7-CH 3), 3.27 (3H, s, 2-CH 3), 3.23 (1H, m, N-CH), 2.25-2.29 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CH 2cO 2-t-Bu), 2.08 (3H, d, J=6.8Hz, 3 2-CH 3), 1.72 (3H, d, J=7.5Hz, 18-CH 3), 1.66 (3H, t, J=7.8Hz, 8 2-CH 3), 1.43,1.40 (each9H, s, 2 × C (CH 3) 3) ,-0.20 ,-1.75 (each1H, s, NH × 2 in ring).
Embodiment 14:N-(3 1-positive propoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone di-t-butyl ester (II 7) preparation
By the method for embodiment 8, compound III 2(200mg, the dry DCM liquid of 30mL 0.34mmol), with HOBt (54.53mg, 0.41mmol) with EDCHCl (64.47mg, after 0.34mmol) reacting 10min under ice bath, obtained purple-brown powder II is reacted again with the DCM (5mL) of Pidolidone di-t-butyl ester hydrochloride (99.47mg, 0.34mmol) and DIPEA (59.0 μ L, 0.34mmol) sonification fluid 7140mg, fusing point is 85 ~ 86 DEG C.Productive rate 49.5%.
MS(ESI +)m/z:836.88(M+H,100％)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.79 (1H, splitteds, meso-H), 9.69 (1H, s, meso-H), 8.83 (1H, s, meso-H), 8.10 (1H, d, amide NHs), 6.01 (1H, q, J=6.0Hz, 3 1-H), 5.20 (1H, d, J=18.0Hz, 13 2-H b), 5.07 (1H, d, J=18.0Hz, 13 2-H a), 4.52 (1H, m, 17-H), 4.30 (1H, m, 18-H), 4.10 (2H, t, 3 1-O-CH 2), 3.68 (2H, q, 8 1-CH 2), 3.58 (3H, s, 12-CH 3), 3.39 (1H, m, N-CH), 3.35 (3H, s, 7-CH 3), 3.20 (3H, s, 2-CH 3), 2.58 (2H, m, 17 2-CH 2), 2.49 (3H, d, 3 2-CH 3), 2.42 (2H, m, 17 1-CH 2), 2.20 (2H, m, CH 2cO 2-t-Bu), 1.77 (3H, d, CH 2, 18-CH 3), 1.58-1.63 (5H, m, 3 1-OCH 2 cH 2 cH 3+ 8 2-CH 3), 1.34,1.29 (each9H, s, 2 × C (CH 3) 3), 0.88 (3H, t, 3 1-OCH 2cH 2 cH 3 ) ,-1.79 (1H, s, NH in ring).
Embodiment 15:N-(3 1-n-pentyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone di-t-butyl ester (II 8) preparation
By the method for embodiment 8, compound III 3(50mg, 80.28 μm ol) the dry DCM liquid of 20mL, with HOBt (13.02mg, 96.34 μm of ol) and EDCHCl (15.39mg, 80.28 μm ol) react 10min under ice bath after, obtained purple-brown powder II is reacted again with the DCM (5mL) of Pidolidone di-t-butyl ester hydrochloride (23.75mg, 80.28 μm of ol) and DIPEA (12.89 μ L, 80.28 μm of ol) sonification fluid 830mg, fusing point is 100 ~ 101 DEG C.Productive rate 43.5%.
MS(ESI +)m/z:864.65(M+H,100％)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.79 (1H, s, meso-H), 9.70 (1H, s, meso-H), 8.83 (1H, s, meso-H), 8.10 (1H, d, J=6.0Hz, amide NHs), 5.99 (1H, q, J=6.0Hz, 3 1-H), 5.20 (1H, d, J=18.0Hz, 13 2-H b), 5.07 (1H, d, J=18.0Hz, 13 2-H a), 4.55 (1H, m, 17-H), 4.30 (1H, m, 18-H), 4.12 (2H, q, 3 1-O-CH 2), 3.68 (2H, q, 8 1-CH 2), 3.59 (3H, s, 12-CH 3), 3.38 (1H, m, N-CH), 3.35 (3H, s, 7-CH 3), 3.20 (3H, s, 2-CH 3), 2.56 (2H, m, 17 2-CH 2), 2.49 (3H, d, 3 2-CH 3), 2.17 (4H, m, 17 1-CH 2+ CH 2cO 2-t-Bu), 1.77 (3H, d, 18-CH 3), 1.62 (9H, m, 3 1-OCH 2 cH 2 cH 2 cH 2cH 3+ 8 2-CH 3), 1.34,1.29 (each9H, s, 2 × C (CH 3) 3), 0.78 (3H, t, 3 1-OCH 2cH 2cH 2cH 2 cH 3 ) ,-1.97 (1H, s, NH in ring).
Embodiment 16:N-(3 1-positive hexyloxyehtyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone di-t-butyl ester (II 9) preparation
By the method for embodiment 8, compound III 4(104.8mg, 164.57 μm ol) the dry DCM liquid of 50mL, with HOBt (26.68mg, 197.48 μm of ol) and EDCHCl (31.55mg, 164.57 μm ol) react 10min under ice bath after, obtained purple-brown powder II is reacted again with the DCM (5mL) of Pidolidone di-t-butyl ester hydrochloride (39.45mg, 164.57 μm of ol) and DIPEA (28.66 μ L, 164.57 μm of ol) sonification fluid 9100mg, fusing point is 57 ~ 58 DEG C.Productive rate 69.3%.
MS(ESI +)m/z:878.79(M+H,100％)。
1hNMR (300MHz, CDCl 3, δ, ppm): 9.78 (1H, s, meso-H), 9.51 (1H, s, meso-H), 8.52 (1H, s, meso-H), 5.90 (1H, q, 3 1-H), 5.30 ~ 5.10 (2H, dd, 13 2-CH 2), 4.50 ~ 4.50 (2H, m, 17-H+18-H), 3.80 ~ 3.40 (9H, m, 8 1-CH 2+ N-CH+12-CH 3+ 3 1-OCH 2), 3.38 (3H, s, 7-CH 3), 3.27 (3H, s, 2-CH 3), 2.10-2.15 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CH 2cO 2-t-Bu), 2.03 (3H, d, J=6.8Hz, 3 2-CH 3), 1.73 (3H, d, J=7.5Hz, 18-CH 3), 1.62 (9H, m, 3 1-OCH 2 cH 2 cH 2 cH 2cH 2cH 3+ 8 2-CH 3), 1.45,1.40 (each9H, s, 2 × C (CH 3) 3), 1.25-0.90 (4H, m, 3 1-O (CH 2) 4 cH 2 cH 3+ cH 2 cH 2cO 2-t-Bu), 0.80 (3H, m, 3 1-O (CH 2) 5 cH 3 ) ,-0.19 (1H, s, NH in ring) ,-1.17 (1H, s, NH in ring).
Embodiment 17:N-(3 1-n-octyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone di-t-butyl ester (II 10) preparation
By the method for embodiment 8, compound III 5(122.30mg, 183.94 μm ol) the dry DCM liquid of 50mL, with HOBt (29.83mg, 220.73 μm of ol) and EDCHCl (35.26mg, 183.94 μm ol) react 10min under ice bath after, obtained purple-brown powder II is reacted again with the DCM (5mL) of Pidolidone di-t-butyl ester hydrochloride (77.09mg, 183.94 μm of ol) and DIPEA (32.04 μ L, 183.94 μm of ol) sonification fluid 10140mg, fusing point is 50 ~ 51 DEG C.Productive rate 83.9%.
MS(ESI +)m/z:906.74(M+H,100％)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.84 (1H, splitteds, meso-H), 9.76 (1H, s, meso-H), 8.87 (1H, s, meso-H), 8.16 (1H, d, J=9.0Hz, amide NH), 6.0 (1H, q, J=6.0Hz, 3 1-H), 5.25 (1H, d, J=21.0Hz, 13 2-H b), 5.13 (1H, d, J=21.0Hz, 13 2-H a), 4.61 (1H, m, 17-H), 4.35 (1H, m, 18-H), 4.16 (2H, q, 3 1-O-CH 2), 3.84 (2H, q, 8 1-CH 2), 3.74 (3H, s, 12-CH 3), 3.42 (1H, m, N-CH), 3.37 (3H, s, 7-CH 3), 3.25 (3H, s, 2-CH 3), 2.60 ~ 2.0 (9H, m, 17 2-CH 2+ 3 2-CH 3+ 17 1-CH 2+ CH 2cO 2-t-Bu), 1.82 (3H, d, 18-CH 3), 1.66 (5H, m, 3 1-OCH 2 cH 2 (CH 2) 5cH 3+ 8 2-CH 3), 1.39,1.34 (each9H, s, 2 × C (CH 3) 3), 1.30 ~ 0.90 (12H, m, 3 1-OCH 2cH 2 (CH 2 ) 5 cH 3+ cH 2 cH 2cO 2-t-Bu), 0.62 (3H, m, 3 1-O (CH 2) 7 cH 3 ) ,-1.79 (1H, s, NH in ring).
Embodiment 18:N α-(3 1-methoxyl group-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-N ε-tertbutyloxycarbonyl-1B methyl esters (II 11) preparation
By the method for embodiment 8, compound III 1the dry DCM liquid of the 30mL of (100mg, 176.46 μm of ol), after reacting 30min under HOBt (28.61mg, 211.76 μm of ol) and EDCHCl (33.83mg, 176.46 μm of ol) ice bath, then with N εthe DCM (5mL) of-tertbutyloxycarbonyl-1B methyl ester hydrochloride (52.37mg, 176.46 μm of ol) and the obtained purple-brown powder II of DIPEA (30.74 μ L, 176.46 μm of ol) sonification fluid reaction 1180mg, productive rate 55.1%.
MS(ESI +)m/z:809.68(M+H,100％)。
Embodiment 19:N α-(3 1-positive propoxy-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-N ε-tertbutyloxycarbonyl-1B methyl esters (II 12) preparation
By the method for embodiment 8, compound III 2the dry DCM liquid of the 50mL of (135mg, 226.99 μm of ol), after reacting 30min under HOBt (36.81mg, 272.39 μm of ol) and EDCHCl (52.22mg, 272.39 μm of ol) ice bath, then with N εthe DCM (5mL) of-tertbutyloxycarbonyl-1B methyl ester hydrochloride (95.85mg, 323 μm of ol) and the obtained purple-brown powder II of DIPEA (56.34 μ L, 323 μm of ol) sonification fluid reaction 1230mg, productive rate 15.8%.
MS(ESI +)m/z:837.54(M+H,100％)。
Embodiment 20:N α-(3 1-n-pentyloxy-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-N ε-tertbutyloxycarbonyl-1B methyl esters (II 13) preparation
By the method for embodiment 8, compound III 3the dry DCM liquid of the 50mL of (140mg, 224.79 μm of ol), after reacting 30min under HOBt (36.45mg, 269.75 μm of ol) and EDCHCl (51.71mg, 269.75 μm of ol) ice bath, then with N εthe DCM (15mL) of-tertbutyloxycarbonyl-1B methyl ester hydrochloride (80.06mg, 269.75 μm of ol) and the obtained purple-brown powder II of DIPEA (48.0 μ L, 269.75 μm of ol) sonification fluid reaction 1385mg, productive rate 43.7%.
MS(ESI +)m/z:865.64(M+H,100％)。
Embodiment 21:N α-(3 1-positive hexyloxy-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-N ε-tertbutyloxycarbonyl-1B methyl esters (II 14) preparation
By the method for embodiment 8, compound III 4the dry DCM liquid of the 80mL of (240mg, 376.87 μm of ol), after reacting 30min under HOBt (61.11mg, 452.25 μm of ol) and EDCHCl (86.70mg, 452.25 μm of ol) ice bath, then with N εthe DCM (25mL) of-tertbutyloxycarbonyl-1B methyl ester hydrochloride (112mg, 377 μm of ol) and the obtained purple-brown powder II of DIPEA (67.0 μ L, 377 μm of ol) sonification fluid reaction 14120mg, productive rate 36.2%.
MS(ESI +)m/z:879.77(M+H,100％)。
Embodiment 22:N α-(3 1-n-octyloxy-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-N ε-tertbutyloxycarbonyl-1B methyl esters (II 15) preparation
By the method for embodiment 8, compound III 5the dry DCM liquid of the 80mL of (40mg, 60.2 μm of ol), after reacting 30min under HOBt (8.2mg, 60.7 μm of ol) and EDCHCl (11.7mg, 61.0 μm of ol) ice bath, then with N εthe DCM (15mL) of-tertbutyloxycarbonyl-1B methyl ester hydrochloride (17.87mg, 60.2 μm of ol) and the obtained black powder II of DIPEA (13.0 μ L, 73.1 μm of ol) sonification fluid reaction 1520mg, fusing point is 68 ~ 70 DEG C, productive rate 36.7%.
MS(ESI +)m/z:907.77(M+H,100％)。
Embodiment 23:N-(3 1-methoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid (I 1) preparation
Compound ii 1(50mg, 0.06mmol) is dissolved in the dry DCM of 10mL, adds 5mL trifluoroacetic acid (TFA), ice bath lower magnetic force stirring reaction, and TLC monitors reaction and carries out journey.After completion of the reaction, reaction solution adds 50mLDCM dilution, uses saturated NaHCO 3liquid regulates pH to 5 ~ 6, divides and gets organic layer, respectively wash 1 time, anhydrous Na with water and saturated aqueous common salt 2sO 4drying, through silica gel H purification by column chromatography after decompression and solvent recovery, moving phase is DCM:CH 3cOCH 3: CH 3oH:HCOOH=10:1:1:0.1 (v/v/v/v), obtains black powder I 135mg, fusing point 168 ~ 169 DEG C, yield 81.5%.
MS(ESI +)m/z:682.57(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):666(1.7×10 4),608(7.1×10 3),537(4.3×10 3),507(4.9×10 3)，413(4.8×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 12.10 (2H, s, 2 × CO 2h), 9.65 (1H, s, meso-H), 9.38 (1H, s, meso-H), 8.88 (1H, s, meso-H), 8.20 (1H, d, amide NHs), 6.02 (1H, q, J=6.8Hz, 3 1-H), 5.22 (1H, d, J=21.0Hz, 13 2-H b), 5.10 (1H, d, J=21.0Hz, 13 2-H a), 4.56-4.59 (1H, m, 17-H), 4.28-4.32 (1H, m, 18-H), 3.82 (1H, m, CONH cHcO), 3.69 (2H, q, J=7.2Hz, 8 1-CH 2), 3.62 (3H, s, 12-CH 3), 3.42 (3H, s, 3 1-OCH 3), 3.35 (3H, s, 7-CH 3), 3.17 (3H, s, 2-CH 3), 2.22-2.03 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH cH 2), 2.02 (3H, d, J=6.8Hz, 3 2-CH 3), 1.76 (3H, d, J=7.2Hz, 18-CH 3), 1.59 (3H, t, J=7.2Hz, 8 2-CH 3) ,-2.04 (1H, s, NH in ring).
Compound I 1chemical structural formula as follows:
Embodiment 24:N-(3 1-positive third oxygen ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid (I 2) preparation
By the method for embodiment 23, compound ii 2dry DCM liquid (15mL) and the TFA (15mL) of (60mg, 0.07mmol) react obtained black powder I 230mg, fusing point >300 DEG C, yield 57.7%.
MS(ESI +)m/z:710.56(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):651(1.7×10 4),602(4.4×10 3),536(4.1×10 3),415(6.3×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.80 (1H, splitteds, meso-H), 9.76 (1H, s, meso-H), 8.83 (1H, s, meso-H), 7.95 (1H, brs, amide NHs), 6.0 (1H, q, J=6.8Hz, 3 1-H), 5.23 (1H, d, J=21.0Hz, 13 2-H b), 5.09 (1H, d, J=21.0Hz, 13 2-H a), 4.51-4.58 (1H, m, 17-H), 4.28 (1H, m, 18-H), 3.74 (1H, m, CONH cHcO), 3.70 (2H, q, J=7.3Hz, 8 1-CH 2), 3.63 (3H, s, 12-CH 3), 3.49 (2H, m, 3 1-OCH 2), 3.39 (3H, s, 7-CH 3), 3.22 (3H, s, 2-CH 3), 2.12-2.30 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH cH 2), 2.02 (3H, d, J=6.8Hz, 3 2-CH 3), 1.76 (3H, d, J=7.6Hz, 18-CH 3), 1.63 (3H, t, J=7.3Hz, 8 2-CH 3), 0.82-0.93 (5H, m, 3 1-OCH 2 cH 2 cH 3) ,-1.98 (1H, s, NH).
Compound I 2chemical structural formula as follows:
Embodiment 25:N-(3 1-positive penta oxygen ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid (I 3) preparation
By the method for embodiment 23, compound ii 3dry DCM liquid (10mL) and the TFA (10mL) of (50mg, 0.059mmol) react obtained black powder I 333mg, fusing point >300 DEG C, yield 76.7%.
MS(ESI +)m/z:738.51(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):660(2.4×10 4),605(6.9×10 3),538(6.5×10 3),507(6.3×10 3),414(7.1×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.80 (1H, splitteds, meso-H), 9.75 (1H, s, meso-H), 8.83 (1H, s, meso-H), 7.95 (1H, brs, amide NHs), 5.98 (1H, q, J=6.8Hz, 3 1-H), 5.23 (1H, d, J=18.0Hz, 13 2-H b), 5.09 (1H, d, J=18.0Hz, 13 2-H a), 4.59-4.56 (1H, m, 17-H), 4.31-4.28 (1H, m, 18-H), 3.74 (1H, m, CONH cHcO), 3.71 (2H, q, J=7.7Hz, 8 1-CH 2), 3.62 (3H, s, 12-CH 3), 3.46-3.51 (2H, m, 3 1-OCH 2), 3.38 (3H, s, 7-CH 3), 3.22 (3H, s, 2-CH 3), 2.33-2.12 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH cH 2), 2.02 (3H, d, J=6.8Hz, 3 2-CH 3), 1.76 (3H, d, J=6.6Hz, 18-CH 3), 1.63 (3H, t, J=7.7Hz, 8 2-CH 3), 1.25 (4H, m, 3 1-OCH 2 cH 2 cH 2 ), 0.72-0.86 (5H, m, OCH 2cH 2cH 2 cH 2 cH 3) ,-1.98 (1H, s, NH).
Compound I 3chemical structural formula as follows:
Embodiment 26:N-(3 1-just own oxygen ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid (I 4) preparation
By the method for embodiment 23, compound ii 4dry DCM liquid (5mL) and the TFA (5mL) of (20mg, 0.02mmol) react obtained black powder I 410mg, fusing point >300 DEG C, yield 58.8%.
MS(ESI +)m/z:752.53(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):662(1.7×10 4),608(4.4×10 3),539(3.62×10 3),507(3.49×10 3),411(4.1×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.80 (1H, s, meso-H), 9.75 (1H, s, meso-H), 8.81 (1H, s, meso-H), 8.05 (1H, brs, amide NHs), 6.21 (1H, q, J=6.8Hz, 3 1-H), 5.20 (1H, d, J=18.0Hz, 13 2-H b), 5.05 (1H, d, J=18.0Hz, 13 2-H a), 4.55 (1H, m, 17-H), 4.26 (1H, m, 18-H), 4.12 (1H, m, CONH cHcO), 3.71 (2H, q, J=7.5Hz8 1-CH 2), 3.62 (3H, s, 12-CH 3), 3.49 (2H, m, 3 1-OCH 2), 3.39 (3H, s, 7-CH 3), 3.22 (3H, s, 2-CH 3), 2.12-2.33 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH cH 2), 2.02 (3H, d, J=6.8Hz, 3 2-CH 3), 1.76 (3H, d, J=6.6Hz18-CH 3), 1.63 (3H, t, J=7.5Hz, 8 2-CH 3), 1.27 (6H, m, 3 1-OCH 2(CH 2) 3), 0.80-0.90 (5H, m, 3 1-OCH 2cH 2cH 2cH 2 cH 2 cH 3).
Compound I 4chemical structural formula as follows:
Embodiment 27:N-(3 1-just pungent oxygen ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-L-Aspartic acid (I 5) preparation
By the method for embodiment 23, compound ii 5dry DCM liquid (8mL) and the TFA (8mL) of (30mg, 0.03mmol) react obtained black powder I 512mg, fusing point >300 DEG C, yield 46.2%.
MS(ESI +)m/z:780.62(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):651(3.1×10 4),603(8.1×10 3),537(7.1×10 3),415(1.1×10 5)(Soret)。
1hNMR (300MHz, (CD 3) 2cO, δ, ppm): 9.87 (1H, s, meso-H), 9.71 (1H, s, meso-H), 8.78 (1H, s, meso-H), 7.45 (1H, d, amide NHs), 6.02 (1H, q, J=6.8Hz, 3 1-H), 5.21 (1H, d, J=18.0Hz, 13 2-H b), 5.04 (1H, d, J=18.0Hz, 13 2-H a), 4.77 (1H, m, 17-H), 4.60 (1H, m, 18-H), 4.38 (1H, m, CONH cHcO), 3.69 (2H, q, J=7.5Hz8 1-CH 2), 3.58 (3H, s, 12-CH 3), 3.55 (2H, m, 3 1-OCH 2), 3.39 (3H, s, 7-CH 3), 3.22 (3H, s, 2-CH 3), 2.31-2.20 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH cH 2cO 2h), 2.06 (3H, d, J=6.8Hz, 3 2-CH 3), 1.78 (3H, d, J=6.6Hz, 18-CH 3), 1.64 (3H, t, J=7.5Hz, 8 2-CH 3), 1.20 (4H, m, 3 1-OCH 2( cH 2 ) 2 ), 0.81-0.82 (8H, m, 3 1-O (CH 2) 3( cH 2 ) 4 cH 3), 0.63 (3H, t, J=7.5Hz, 3 1-O (CH 2) 7 cH 3 ) ,-1.84 (1H, s, NH × 2 in ring).
Compound I 5chemical structural formula as follows:
Embodiment 27:N-(3 1-methoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone (I 6) preparation
By the method for embodiment 23, compound ii 6dry DCM liquid (8mL) and the TFA (8mL) of (50mg, 0.062mmol) react obtained black powder I 625mg, fusing point >300 DEG C, yield 58.1%.
MS(ESI +)m/z:696.55(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):665(1.9×10 4),614(5.3×10 3),508(6.0×10 3).412(8.6×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 9.70 (2H, s, 2 × meso-H), 8.85 (1H, s, meso-H), 8.15 (1H, d, amide NHs), 5.95 (1H, q, J=6.6Hz, 3 1-H), 5.20 (1H, d, J=18.0Hz, 13 2-H b), 5.07 (1H, d, J=18.0Hz, 13 2-H a), 4.56 (1H, m, 17-H), 4.30 (1H, m, 18-H), 4.10 (1H, m, CONH cHcO), 3.68 (2H, q, J=7.4Hz, 8 1-CH 2), 3.58 (3H, s, 12-CH 3), 3.47 (3H, s, 3 1-OCH 3), 3.40 (3H, s, 7-CH 3), 3.21 (3H, s, 2-CH 3), 2.25-2.03 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH (CO 2h) CH 2 cH 2cO 2h), 2.02 (3H, d, J=6.6Hz, 3 2-CH 3), 1.77 (3H, d, J=6.9Hz, 18-CH 3), 1.61 (3H, t, J=7.4Hz, 8 2-CH 3), 1.20-1.40 (2H, m, CONHCH (CO 2h) cH 2 cH 2cO 2h) ,-1.99 (1H, s, NH in ring).
Compound I 6chemical structural formula as follows:
Embodiment 28:N-(3 1-positive propoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone (I 7) preparation
By the method for embodiment 23, compound ii 7dry DCM liquid (15mL) and the TFA (15mL) of (50mg, 0.06mmol) react obtained black powder I 720mg, fusing point >300 DEG C, yield 45.5%.
MS(ESI +)m/z:724.54(M+H,40％)。
MS(ESI -)m/z:722.55(M-H,70％),1445.46(2M-1,100％)。
UV-Visλ max(CH 2Cl 2,nm):661(7.5×10 4),605(1.7×10 4),541(1.7×10 4),507(1.6×10 4),411(1.6×10 5)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 12.38 (2H, s, 2 × CO 2h), 9.80 (1H, splitteds, meso-H), 9.74 (1H, s, meso-H), 8.84 (1H, s, meso-H), 8.16 (1H, d, amide NHs), 6.0 (1H, q, J=6.3Hz, 3 1-H), 5.21 (1H, d, J=18.0Hz, 13 2-H b), 5.09 (1H, d, J=18.0Hz, 13 2-H a), 4.55 (1H, m, 17-CH), 4.31 (1H, m, 18-CH), 4.20 (1H, m, CONH cHcO), 3.71 (2H, q, J=7.7Hz, 8 1-CH 2), 3.62 (3H, s, 12-CH 3), 3.49 (2H, m, 3 1-OCH 2), 3.43 (3H, s, 7-CH 3), 3.21 (3H, s, 2-CH 3), 2.25-2.07 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CONHCH (CO 2h) CH 2 cH 2cO 2h), 2.02 (3H, d, J=6.3Hz, 3 2-CH 3), 1.76 (3H, d, J=6.8Hz, 18-CH 3), 1.63 (3H, t, J=7.7Hz, 8 2-CH 3), 1.13-1.38 (4H, m, CONHCH (CO 2h) cH 2 cH 2cO 2h+3 1-OCH 2 cH 2 cH 3), 0.90 (3H, t, J=7.5Hz, 3 1-OCH 2cH 2 cH 3) ,-1.98 (1H, s, NH in ring).
Compound I 7chemical structural formula as follows:
Embodiment 29:N-(3 1-n-pentyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone (I 8) preparation
By the method for embodiment 23, compound ii 8dry DCM liquid (15mL) and the TFA (15mL) of (100mg, 0.116mmol) react obtained black powder I 850mg, fusing point 180-182 DEG C, yield 57.5%.
MS(ESI +)m/z:752.99(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):651(9.8×10 4),602(2.4×10 4),538(2.1×10 4),411(3.4×10 5)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 12.53 (2H, s, 2 × CO 2h), 9.81 (1H, s, meso-H), 9.75 (1H, s, meso-H), 8.84 (1H, s, meso-H), 8.10 (1H, d, J=6.0Hz, amide NHs), 6.00 (1H, q, J=6.0Hz, 3 1-H), 5.22 (1H, d, J=18.0Hz, 13 2-H b), 5.09 (1H, d, J=18.0Hz, 13 2-H a), 4.56 (1H, m, 17-H), 4.32 (1H, m, 18-H), 4.18-4.20 (1H, m, CONH cHcO), 3.71 (2H, q, J=8.3Hz, 8 1-CH 2), 3.62 (3H, s, 12-CH 3), 3.48-3.50 (2H, m, 3 1-OCH 2), 3.39 (3H, s, 7-CH 3), 3.21 (3H, s, 2-CH 3), 2.33-2.10 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CH 2cO 2h), 2.01 (3H, d, J=6.0Hz, 3 2-CH 3), 1.76 (3H, d, J=6.8Hz, 18-CH 3), 1.63 (3H, t, J=8.3Hz, 8 2-CH 3), 1.20 (8H, m, CONHCH (CO 2h) cH 2 cH 2cO 2h+3 1-OCH 2( cH 2 ) 3 cH 3), 0.90 (3H, t, J=6.8Hz, O (CH 2) 4 cH 3 ) ,-1.98 (1H, s, NH in ring).
Compound I 8chemical structural formula as follows:
Embodiment 30:N-(3 1-positive hexyloxyehtyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone (I 9) preparation
By the method for embodiment 23, compound ii 9dry DCM liquid (8mL) and the TFA (8mL) of (55mg, 0.023mmol) react obtained black powder I 920mg, fusing point 184-185 DEG C, yield 41.7%.
MS(ESI +)m/z:766.26(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):662(5.2×10 4),606(1.2×10 4),541(1.2×10 4),507(1.2×10 4),410(1.1×10 5)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 12.29 (2H, s, 2 × CO 2h), 9.79 (1H, s, meso-H), 9.71 (1H, s, meso-H), 8.83 (1H, splitteds, meso-H), 8.14 (1H, d, J=6.0Hz, amide NHs), 5.95 (1H, q, J=5.7Hz, 3 1-H), 5.21 (1H, d, J=18.0Hz, 13 2-H b), 5.09 (1H, d, J=18.0Hz, 13 2-H a), 4.56 (1H, m, 17-H), 4.32 (1H, m, 18-H), 4.22 (1H, m, CONH cHcO), 3.69 (2H, q, J=7.3Hz, 8 1-CH 2), 3.60 (3H, s, 12-CH 3), 3.42 (2H, m, 3 1-OCH 2), 3.35 (3H, s, 7-CH 3), 3.20 (3H, s, 2-CH 3), 2.23-2.11 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CH 2cO 2h), 2.02 (3H, d, J=5.7Hz, 3 2-CH 3), 1.76 (3H, d, J=6.5Hz, 18-CH 3), 1.61 (3H, t, J=7.3Hz, 8 2-CH 3), 1.11-1.28 (10H, m, CONHCH (CO 2h) cH 2 cH 2cO 2h+3 1-OCH 2( cH 2 ) 4 cH 3), 0.81 (3H, t, J=5.4Hz, 3 1-O (CH 2) 5 cH 3) ,-1.97 (1H, s, NH in ring).
Compound I 9chemical structural formula as follows:
Embodiment 31:N-(3 1-n-octyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-Pidolidone (I 10) preparation
By the method for embodiment 23, compound ii 10dry DCM liquid (10mL) and the TFA (10mL) of (60mg, 0.066mmol) react obtained black powder I 1028mg, fusing point 180-182 DEG C, yield 52.8%.
MS(ESI -)m/z:792.63(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):661(1.7×10 4),605(4.4×10 3),540(4.3×10 3),507(4.2×10 3),411(3.8×10 4)(Soret)。
1hNMR (300MHz, DMSO-d 6, δ, ppm): 12.58 (2H, s, 2 × CO 2h), 9.79 (1H, s, meso-H), 9.72 (1H, s, meso-H), 8.82 (1H, s, meso-H), 7.90 (1H, d, J=6.0Hz, amide NHs), 5.95 (1H, q, J=6.8Hz, 3 1-H), 5.21 (1H, d, J=18.0Hz, 13 2-H b), 5.08 (1H, d, J=18.0Hz, 13 2-H a), 4.56 (1H, m, 17-H), 4.30 (1H, m, 18-H), 4.16 (1H, m, CONH cHcO), 3.69 (2H, q, J=7.8Hz, 8 1-CH 2), 3.60 (3H, s, 12-CH 3), 3.45 (2H, m, 3 1-OCH 2), 3.35 (3H, s, 7-CH 3), 3.20 (3H, s, 2-CH 3), 2.20-2.13 (6H, m, 17 2-CH 2+ 17 1-CH 2+ CH 2cO 2h), 2.02 (3H, d, J=6.8Hz, 3 2-CH 3), 1.75 (3H, d, J=6.8Hz, 18-CH 3), 1.62 (3H, t, J=7.8Hz, 8 2-CH 3), 0.82-1.37 (17H, m, CONHCH (CO 2h) cH 2 cH 2cO 2h+3 1-OCH 2( cH 2 ) 6 cH 3 ) ,-1.98 (1H, s, NH in ring).
Compound I 10chemical structural formula as follows:
Embodiment 32:N α-(3 1-methoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-1B (I 11) preparation
Compound ii 11(250.52mg, 0.31mmol) is dissolved in THF (15mL), adds LiOH (59.33mg, the 2.48mmol) aqueous solution (5mL) and methyl alcohol (10mL), and stirring at room temperature reaction 2h, reacts complete.Dilution that reaction solution adds water (50mL), uses saturated NH 4cl liquid regulates pH to 5-6, with DCM extraction (20mL × 3), merges organic phase, anhydrous Na 2sO 4drying, decompression removing organic solvent, P 2o 5vacuum-drying obtains black solid.Above-mentioned black solid is dissolved in dry DCM (10mL) again, adds TFA (5mL) and reacts 2h, react complete under ice bath.Reaction solution adds DCM (50mL) dilution, uses saturated NaHCO 3in and unreacted TFA be puce to reaction solution by green transition, point get organic layer, reclaim under reduced pressure organic solvent, through silica gel H pillar layer separation, gradient elution agent DCM:MeOH=4:1 ~ 2:1 (v/v), obtains black powder I 1130mg, fusing point 192-193 DEG C, yield 12.50%.
MS(ESI +)m/z:695.44(M+H,90％)。
MS(ESI -)m/z:693.38(M-H,100％)。
UV-Visλ max(CH 2Cl 2,nm):651(2.1×10 4),602(4.3×10 3),567(8.4×10 3),533(3.8×10 3),416(6.7×10 4)(Soret)。
1h-NMR (300MHz, DMSO-d 6, δ, ppm): 9.67 (1H, s, meso-H), 9.60 (1H, s, meso-H), 8.80 (1H, s, meso-H), 7.60 (1H, d, J=6.0Hz, amide NHs), 5.92 (1H, q, J=6.8Hz, 3 1-H), 5.14 (1H, d, J=18.0Hz, 13 2-H b), 5.02 (1H, d, J=18.0Hz, 13 2-H a), 4.52 (1H, m, 17-H), 4.21 (1H, m, 18-H), 4.10 (1H, m, CONH cHcO), 3.63 (2H, q, J=7.8Hz, 8 1-CH 2), 3.50 (3H, s, 12-CH 3), 3.40 (3H, m, 3 1-OCH 3), 3.25 (3H, s, 7-CH 3), 3.18 (3H, s, 2-CH 3), 2.65 (2H, 17 2-CH 2), 2.11 (2H, m, 17 1-CH 2), 1.99 (3H, d, J=6.8Hz, 3 2-CH 3), 1.72 (3H, d, J=7.8Hz, 18-CH 3), 1.58 (3H, t, J=7.8Hz, 8 2-CH 3), 1.18 (8H, m, ( cH 2) 4nH 2), 0.17 (1H, s, NH in ring) ,-2.03 (1H, s, NH in ring).
Compound I 11chemical structural formula as follows:
Embodiment 33:N α-(3 1-positive propoxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-1B (I 12) preparation
By the method for embodiment 32, compound ii 12(120mg, THF liquid (15mL) 0.14mmol) is first after the LiOH water (5mL) and methyl alcohol (10mL) mixed solution generation Ester hydrolysis of 8 times of molar equivalents, again through the de-tertbutyloxycarbonyl of TFA (5mL), obtained black powder I 1230mg, fusing point 252-253 DEG C, yield 34.7%.
MS(ESI +)m/z:723.46(M+H,90％)。
MS(ESI -)m/z:721.51(M-H,60％)。
UV-Visλ max(CH 2Cl 2,nm):661(1.8×10 4),605(4.3×10 3),537(4.8×10 3),505(4.8×10 3),410(5.9×10 4)(Soret)。
1h-NMR (300MHz, DMSO-d 6, δ, ppm): 9.82 (1H, s, meso-H), 9.75 (1H, s, meso-H), 8.80 (1H, s, meso-H), 8.15 (1H, d, J=6.0Hz, amide NHs), 6.0 (1H, q, J=7.8Hz, 3 1-H), 5.15 (1H, d, J=18.0Hz, 13 2-H b), 5.09 (1H, d, J=18.0Hz, 13 2-H a), 4.57-4.52 (1H, m, 17-H), 4.33-4.21 (1H, m, 18-CH), 4.10 (1H, m, CONH cHcO), 3.69 (2H, q, J=6.8Hz, 8 1-CH 2), 3.50 (3H, s, 12-CH 3), 3.40 (2H, m, 3 1-OCH 2), 3.25 (3H, s, 7-CH 3), 3.18 (3H, s, 2-CH 3), 2.58 (2H, m, 17 2-CH 2), 2.11 (2H, m, 17 1-CH 2), 1.99 (3H, d, J=7.8Hz, 3 2-CH 3), 1.71 (3H, d, J=7.8Hz, 18-CH 3), 1.58 (3H, t, J=6.8Hz, 8 2-CH 3), 0.80-1.15 (13H, m, ( cH 2 ) 4 nH 2, OCH 2 cH 2 cH 3), 0.20 (1H, s, NH in ring) ,-1.98 (1H, s, NH in ring).
Compound I 12chemical structural formula as follows:
Embodiment 34:N α-(3 1-n-pentyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-1B (I 13) preparation
By the method for embodiment 32, compound ii 13(135mg, THF liquid (10mL) 0.156mmol) is first after the LiOH water (3mL) and methyl alcohol (6mL) mixed solution generation Ester hydrolysis of 4 times of molar equivalents, again through the de-tertbutyloxycarbonyl of TFA (4mL), obtained black powder I 1330mg, fusing point 220-222 DEG C, yield 25.7%.
MS(ESI +)m/z:751.48(M+H,100％)。
MS(ESI -)m/z:749.56(M-H,70％)。
UV-Visλ max(CH 2Cl 2,nm):652(1.6×10 4),602(4.0×10 3),536(3.5×10 3),416(5.8×10 4)(Soret)。 1h-NMR (300MHz, DMSO-d 6, δ, ppm): 9.77 (1H, splitteds, meso-H), 9.63 (1H, splitteds, meso-H), 8.79 (1H, s, meso-H), 7.52 (1H, d, J=6.0Hz, amide NH), 5.93 (1H, q, J=6.8Hz, 3 1-H), 5.15 (1H, d, J=21.0Hz, 13 2-H b), 5.03 (1H, d, J=21.0Hz, 13 2-H a), 4.54-4.51 (1H, m, 17-H), 4.23-4.18 (1H, m, 18-H), 3.92 (1H, m, CONH cHcO), 3.66-3.30 (10H, m, 8 1-CH 2+ 12-CH 3+ 3 1-OCH 2+ 7-CH 3), 3.18 (3H, s, 2-CH 3), 2.62 (2H, m, 17 2-CH 2), 2.25-2.08 (2H, m, 17 1-CH 2), 2.48-2.07 (4H, m, 17 2-CH 2+ 17 1-CH 2), 1.99 (3H, d, J=6.8Hz, 3 2-CH 3), 1.71 (3H, d, J=7.8Hz, 18-CH 3), 1.58 (3H, t, J=7.8Hz, 8 2-CH 3), 1.18 (12H, m, NH 2( cH 2) 4, 3 1-OCH 2( cH 2 ) 2 ), 0.73 (2H, m, 3 1-O (CH 2) 3 cH 2), 0.70 (3H, t, J=7.8Hz, 3 1-O (CH 2) 4 cH 3), 0.22 (1H, s, NH in ring) ,-2.02 (1H, s, NH in ring).
Compound I 13chemical structural formula as follows:
Embodiment 35:N α-(3 1-positive hexyloxyehtyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-1B (I 14) preparation
By the method for embodiment 32, compound ii 14(50mg, THF liquid (6mL) 0.057mmol) is first after the LiOH water (2mL) and methyl alcohol (4mL) mixed solution generation Ester hydrolysis of 4 times of molar equivalents, again through the de-tertbutyloxycarbonyl of TFA (2.5mL), obtained black powder I 1410mg, fusing point 168-170 DEG C, yield 22.7%.
MS(ESI +)m/z:765.88(M+H,100％)。
UV-Visλ max(CH 2Cl 2,nm):660(8.1×10 3),605(2.3×10 3),537(2.5×10 3),505(2.6×10 3),409(1.9×10 4)(Soret)。
1h-NMR (300MHz, DMSO-d 6, δ, ppm): 9.80 (1H, s, meso-H), 9.74 (1H, s, meso-H), 8.82 (1H, s, meso-H), 7.70 (1H, d, J=6.0Hz, amide NHs), 5.97 (1H, q, J=6.6Hz, 3 1-H), 5.20 (1H, d, J=21.0Hz, 13 2-H b), 5.07 (1H, d, J=21.0Hz, 13 2-H a), 4.63-4.57 (1H, m, 17-H), 4.42-4.21 (1H, m, 18-H), 3.93-3.99 (1H, m, CONH cHcO), 3.70 (2H, q, J=7.5Hz, 8 1-CH 2), 3.60 (3H, s, 12-CH 3), 3.47 (2H, m, 3 1-OCH 2), 3.37 (3H, s, 7-CH 3), 3.18 (3H, s, 2-CH 3), 2.68 (2H, m, 17 2-CH 2), 2.19-2.09 (2H, m, 17 1-CH 2), 2.02 (3H, d, J=6.6Hz, 3 1-CH 3), 1.75 (3H, d, J=6.8Hz, 18-CH 3), 1.62 (3H, t, J=7.5Hz, 8 2-CH 3), 1.11-1.21 (14H, m, ( cH 2 ) 4 nH 2, 3 1-OCH 2( cH 2 ) 3 ), 0.82 (2H, m, 3 1-O (CH 2) 4 cH 2), 0.63 (3H, t, J=7.6Hz, 3 1-O (CH 2) 5 cH 3), 0.29 (1H, s, NH in ring) ,-1.98 (1H, s, NH in ring).
Compound I 14chemical structural formula as follows:
Embodiment 36:N α-(3 1-n-octyloxy ethyl-3 1-remove vinyl-17 3-decarboxylate pyropheophorbide-a-17 3-acyl group)-1B (I 15) preparation
By the method for embodiment 32, compound ii 15(37mg, THF liquid (9mL) 0.041mmol) is first after the LiOH water (3mL) and methyl alcohol (6mL) mixed solution generation Ester hydrolysis of 8 times of molar equivalents, again through the de-tertbutyloxycarbonyl of TFA (5mL), obtained black powder I 1515mg, fusing point 189-191 DEG C, yield 46.4%.
MS(ESI +)m/z:793.63(M+H,100％)。
MS(ESI -)m/z:791.71(M-H,100％)。
UV-Visλ max(CH 2Cl 2,nm):650(1.7×10 4),601(3.2×10 3),568(2.6×10 3),531(2.7×10 3),417(6.0×10 4)(Soret)。
1h-NMR (300MHz, DMSO-d 6, δ, ppm): 9.80 (1H, splittdes, meso-H), 9.74 (1H, s, meso-H), 8.83 (1H, s, meso-H), 7.70 (1H, d, J=6.0Hz, amide NH), 5.96 (1H, q, J=6.8Hz, 3 1-H), 5.21 (1H, d, J=21.0Hz, 13 2-H b), 5.08 (1H, d, J=21.0Hz, 13 2-H a), 4.58-4.52 (1H, m, 17-H), 4.32-4.29 (1H, m, 18-H), 4.11 (1H, m, CONH cHcO), 3.71 (2H, q, J=7.5Hz, 8 1-CH 2), 3.61 (3H, s, 12-CH 3), 3.48 (2H, m, 3 1-OCH 2), 3.38 (3H, s, 7-CH 3), 3.21 (3H, s, 2-CH 3), 2.75 (2H, m, 17 2-CH 2), 2.19-2.08 (2H, m, 17 1-CH 2), 2.02 (3H, d, J=6.8Hz, 3 1-CH 3), 1.77 (3H, d, J=7.8Hz, 18-CH 3), 1.62 (3H, t, J=7.5Hz, 8 2-CH 3), 1.11-1.21 (18H, m, ( cH 2 ) 4 nH 2, 3 1-OCH 2( cH 2) 5), 0.82 (2H, m, 3 1-O (CH 2) 6 cH 2), 0.63 (3H, t, J=7.8Hz, 3 1-O (CH 2) 7 cH 3) ,-1.97 (1H, s, NH in ring).
Compound I 15chemical structural formula as follows:
Embodiment 37: the external PDT anti-tumor activity test of part of the present invention preferred pyropheophorbide-a ethers amino acid derivative.
1. material
Cell strain selects people's colon-cancer cell (HCT116), gastric carcinoma cells (MKN45) and human breast cancer cell (MDA-MB-231), is provided by hemopathy institute of the Chinese Academy of Medical Sciences.
LASER Light Source adopts the 670nm semiconductor laser therapeutic instrument of Nankai University's contemporary optics Research Institute, and peak power output is 2W.
2. method
1) tumor cell line: people's colon-cancer cell (HCT116), gastric carcinoma cells (MKN45) and human breast cancer cell (MDA-MB-231) are cultivated: take out freeze-stored cell from liquid nitrogen, be placed in the nutrient solution (DMEM+10%FBS+ is dual anti-) changed after 42 DEG C of water-baths make cell rapid solution containing fresh calf serum immediately, be placed in 37 DEG C of CO 2cultivate in incubator, change a nutrient solution every other day.
2) drug solution preparing: get testing compound of the present invention and positive control medicine Visudyne (verteporfin, BCPDMA) and Zorubicin (DOX) be dissolved in DMSO, be made into the medicament storage liquid of 10mM concentration, solution or homogenous suspension that PBS (-) is made into 1000 μMs is added before experiment, then dilute with the PBS (-) containing DMSO, make sample final concentration be 100,10,1,0.1,0.01,0.001 μMs.
3) testing compound and positive control medicine measure the dark toxicity of 3 kinds of tumour cells and PDT lethal effect: it is 4 × 10 that the 96 every holes of orifice plate add concentration 4~ 5 × 10 4the cell suspension 100 μ L of individual/mL, puts 37 DEG C, 5%CO 2in incubator.After 24h, add sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C and 5%CO 2hatch 24h, accept illumination 2min, intensity of illumination is 10J/cm 2, continue to cultivate 24h.Every hole adds the MTT solution 20 μ L of 5mg/mL, lysate is added after effect 4h, 100 μ L/ holes, put in incubator, survey 570nmOD value after dissolving with the long multi-functional microplate reader (production firm: Thermoscientific) of VarioskanFlash-all-wave.
3. result
The dark toxicity of part selected objective target Compounds in vitro of the present invention 3 kinds of human tumor cells and PDT lethal effect result, in table 2.
Table 2 test compounds is to the half-inhibition concentration IC of 3 kinds of human tumor cells 50(μM)
Above-mentioned experimental result display:
Be 10J/cm at illumination dose 2under condition, all target compounds all have excellent PDT antitumour activity to 3 kinds of tumor cell lines, and its activity is all significantly better than positive control drug Zorubicin and similar listing photosensitive drug Visudyne (verteporfin, BPDMA).
Structure-activity Relationship shows:
(1) the PDT antitumour activity of target compound strengthens with ether chainpropagation, and with 6-8 carbon atom for the best, when ether chain length continues to increase, activity will decrease, and the lipotropy that prompting is suitable for is active required;
(2), in all tested target compounds, be good with the activity of the amino acid derivative of pyropheophorbide-a n-hexyl ether or n-octyl ether; Wherein, especially with I 4and I 10activity be best, they are 5.6 ~ 9.7 times of Visudyne to the PDT antitumour activity of 3 kinds of tumor cell lines, and dark toxicity ratio Visudyne is little 2.3 ~ 7.8 times.
Below the preferred embodiment of the invention is illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all equivalent modification or replacement under the prerequisite without prejudice to the invention spirit, and these equivalent modification or replacement are all included in the application's claim limited range.

Claims (10)

1. class pyropheophorbide-a ethers amino acid derivative and a pharmaceutical salts thereof, the chemical structure of described pyropheophorbide-a ethers amino acid derivative is as shown in formula I:
In formula I,
R 1represent H, low alkyl group, senior alkyl, (CH 2) moR 3or (CH 2) mnR 4r 5;
R 2represented amino acid residue;
R 3represent H, low alkyl group;
R 4and R 5represent low alkyl group independently;
M represents the integer between 2-6;
Described low alkyl group, refers to the straight or branched alkyl containing 1-6 carbon atom;
Described senior alkyl, refers to the straight or branched alkyl containing 7-18 carbon atom.
2. class pyropheophorbide-a ethers amino acid derivative and a pharmaceutical salts thereof according to claim 1, is characterized in that, in formula I,
R 1represent CH 3, n-C 3h 7, n-C 5h 11, n-C 6h 13or n-C 8h 17;
R 2represent Methionin, L-glutamic acid, or aspartic acid.
3. class pyropheophorbide-a ethers amino acid derivative and a pharmaceutical salts thereof according to claim 1, is characterized in that, R in described pyropheophorbide-a ethers amino acid derivative 1and R 2combination is as follows respectively:
4. class pyropheophorbide-a ethers amino acid derivative and the pharmaceutical salts thereof according to claim 1,2 or 3, it is characterized in that, described pharmaceutical salts is an alkali metal salt.
5. a preparation method for a class pyropheophorbide-a ethers amino acid derivative as claimed in claim 1 and pharmaceutical salts thereof, it is characterized in that, the method comprises the following steps:
Take pyropheophorbide-a as raw material, the 3-vinyl in pyropheophorbide-a structure and 17-third carboxyl, respectively with alcohol and amino acid through etherificate and peptide formation, synthesis pyropheophorbide-a ethers amino acid derivative.
6. the preparation method of a class pyropheophorbide-a ethers amino acid derivative according to claim 5 and pharmaceutical salts thereof, is characterized in that, described pyropheophorbide-a chlorophyll a prepares through soda acid degraded.
7. the preparation method of a class pyropheophorbide-a ethers amino acid derivative according to claim 5 and pharmaceutical salts thereof, it is characterized in that, the method comprises the following steps:
A, prepare pyropheophorbide-a (pyropheophorbidea, V) with chlorophyll a (chlorophylla, VII) for raw material, reaction process is as follows, and reaction method is selected from A1 or A2:
A1, first, the diethyl ether solution of commercially available chlorophyll paste, generates pheophorbide acid a (pheophorbidea, VI) with equal volume amounts concentrated hydrochloric acid stirring reaction 0.5h under the cold condition of 0 ~ 5 DEG C; Then, compound VI back flow reaction 4h obtained V in glacial acetic acid solution;
The diethyl ether solution of A2, commercially available chlorophyll paste, at ambient temperature with equal volume amounts concentrated hydrochloric acid stirring reaction 2d obtained V;
B, prepare target compound pyropheophorbide-a ethers amino acid derivative I with compound V, reaction process is as follows, and reaction method is B1 to B2:
B1, prepare pyropheophorbide-a ether derivative III
First by compound V and excessive 33%HBr Glacial acetic acid liquid room temperature reaction 24h, obtained 3 1-bromo-3 1-remove vinyl pyropheophorbide-a (IV); Then compounds Ⅳ is at excessive K 2cO 3there is lower and various alcohol (R 1oH) react and obtain compound III;
B2, prepare pyropheophorbide-a ethers amino acid target derivative I:
By the dichloromethane solution of compound III 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), N-hydroxybenzotriazole (HOBt) and N, N-dimethyl isopropyl amine (DIPEA) exist under respectively with various protected amino acid hydrochloric acid (R 2nH 2hCl) the pyropheophorbide-a ethers amino acid derivative II of the obtained amino of reaction or carboxy protective, compound ii takes off the tertiary butyl or tertbutyloxycarbonyl and lithium hydroxide demethylation ester through trifluoracetic acid (TFA) and namely obtains pyropheophorbide-a ethers amino acid target compound I.
8. a class pyropheophorbide-a ethers amino acid derivative as claimed in claim 1 and pharmaceutical salts thereof are preparing the application in antitumor drug.
9. a class pyropheophorbide-a ethers amino acid derivative according to claim 8 and pharmaceutical salts thereof are preparing the application in antitumor drug, and it is characterized in that, described antitumor drug is Photodynamic therapy of cancer medicine.
10. a class pyropheophorbide-a ethers amino acid derivative as claimed in claim 1 and pharmaceutical salts thereof are preparing optical dynamic therapy senile macular degeneration SMD, a nevus flammeus, or the application in pointed condyloma medicine.
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CN107987081A (en) * 2016-10-26 2018-05-04 刘辉 A kind of new chlorin e 6 derivative and its pharmaceutically acceptable salt, its preparation method and application
US9951081B1 (en) 2016-10-26 2018-04-24 Hui Liu Chlorin e6 derivative and pharmaceutically acceptable salt thereof and process for preparing and use of the same
JP2019533635A (en) * 2016-10-26 2019-11-21 リウ, フゥイLIU, Hui Novel dihydroporphine e6 derivative and pharmaceutically acceptable salt thereof, preparation method and use thereof
CN107987081B (en) * 2016-10-26 2019-12-06 刘辉 Chlorin e6 derivative and pharmaceutically acceptable salt thereof, and preparation method and application thereof
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CN109265465B (en) * 2018-11-07 2021-09-28 陈志龙 Novel pyropheophorbide a derivatives and preparation method and application thereof
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