CN100369914C - 3-ene-8-ethyl-2,7,12,15,18-pentamethyl-13-carboxylic acid-17-propionic acid amino acid amide, its synthetic method and light power therapeutic medicine - Google Patents
3-ene-8-ethyl-2,7,12,15,18-pentamethyl-13-carboxylic acid-17-propionic acid amino acid amide, its synthetic method and light power therapeutic medicine Download PDFInfo
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Abstract
The present invention provides 3-vinyl-8-ethyl-2, 7, 12, 15, 18-pentamethyl-17H, 18H, 21H, 23H-13-carboxylic acid-17-amido aminate propionate and its synthesis process. Compound 3-vinyl-8-ethyl-2, 7, 12, 15, 18-pentamethyl-17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid and methyl amidate react in mixed solution in the presence of DDC and DAMP to produce 3-vinyl-8-ethyl-2, 7, 12, 15, 18-pentamethyl-17H, 18H, 21H, 23H-13-carboxylic acid-17-methyl amidate propionate, which is then hydrolyzed to produce 3-vinyl-8-ethyl-2, 7, 12, 15, 18-pentamethyl-17H, 18H, 21H, 23H-13-carboxylic acid-17-amido aminate propionate. The compound 3-vinyl-8-ethyl-2, 7, 12, 15, 18-pentamethyl-17H, 18H, 21H, 23H-13-carboxylic acid-17-amido aminate propionate and its medicine composition possess optical effect of deactivating human cancer cell.
Description
Technical field
The present invention relates to 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide, its synthetic method and optical dynamic therapy medicine belong to the pharmaceutical chemistry field.
Background technology
Photodynamic therapy (Photodynamic therapy, PDT) be a kind of novel diagnosis and treatment technology that reaches its maturity, its main mechanism of action be photosensitizers in the tissue under the condition of aerobic, after laser radiation, produce a large amount of toxicity oxygen species, the damaged tissue cell reaches the purpose of treatment.The end of the seventies in last century, PDT began to be used for the clinical treatment of tumour, because it can effect a radical cure in early days, tumor in situ, in the improvement, the symptom of late tumor, also can carry out prophylactic treatment to precancerous lesion, so PDT has been listed in one of clinical treatment method of tumour after operation, chemotherapy, radiotherapy.In recent years, photodynamic therapy has also shown immense value in the treatment of some benign diseases, as treat nevus flammeus (Gu Ying, Deng. the clinical study of photodynamic therapy selective therapy nevus flammeus. Chinese laser medical journal .1992,1 (1): the 1216 routine clinical analysiss of 6-10. photodynamic therapy treatment nevus flammeus. Chinese laser medical journal .2001,10 (2): 86-89.) and senile macular degeneration SMD (Treatment of Age-related MacularDegeneration with photodynamic therapy (TAP) study group.Photodynamictherapy of subfoveal choroidal neovascularization in age-related maculardegeneration with verteporfin.Arch Ophthalmol.1999,117:1329-1345.).In addition, to the treatment of multiple benign disease also in the middle of research, as restenosis, rheumatoid arthritis, intractable glaucoma, psoriasis and hyperplastic scar or the like after atherosclerosis, the angioplasty.Photosensitizers is the key of photodynamic therapy, and its character has determined the effect and the range of application of treatment.Domestic and international commercially available optical dynamic therapy drug main will mate mixing porphyrin preparation (Xu Deyu: history, present situation, progress, problem and the prospect of light power curing cancer drug not good and that chemical constitution is indefinite and effective constituent is not clear for action spectrum at present.Chinese laser medical journal 2001,10 (1): 44-46; 2001,10 (2): 115-118.Michael R.Detty，Scott L.Gibson and Stephen J.Wagner：Currentclinical and preclinical photosensitizers for use in photodynamic therapy.J MedChem 2004，47(16)：3897-3915；)。The size of known red light district uptake factor is a kind of key of photosensitizers photosensitization power.So seeking class formation optical dynamic therapy medicine stable, that effective constituent is determined has very important significance.
Summary of the invention
The size of known red light district uptake factor is a kind of key of photosensitizers photosensitization power.3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide are as the derivative of chlorin, and its uptake factor at red light district is approximately higher than order of magnitude of porphyrins, and being the clear and definite monomer of chemical structure, is the candidate compound of the good optical dynamic therapy new drug of a class.
Purpose of the present invention provides 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide.
Another object of the present invention provides 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, the preparation method of 23H-13-carboxylic acid-17-propionic acid amino acid amide.
Further aim of the present invention provides a kind of optical dynamic therapy pharmaceutical composition.
Another object of the present invention provides the application of above-claimed cpd in preparation optical dynamic therapy medicine.
Following general formula of the present invention (III) compound:
R wherein represents :-CH
2COOH;
Or
3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-18-propionic acid glycine acid amides (IV), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid aspartic acid acid amides (V), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid ala amide (VI), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid leucine amide (VII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid methionine amide (VIII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid tryptophane acid amides (IX), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid serine amides (X) etc.They have the following chemical structure respectively:
3-vinyl provided by the invention-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, the synthetic method of 23H-13-carboxylic acid-17-propionic acid amino acid amide:
(1) be to serve as base beginning raw material with tame silkworm faeces (silkworm excrement), through volume ratio is acetone-water mixed solution extraction in 20: 80～40: 60, the concentrated crude product chlorophyll that makes, crude product chlorophyll is earlier after the bronsted lowry acids and bases bronsted lowry degraded obtains chlorophyll alpha degraded product 3-vinyl-8-ethyl-2,7,12,18-tetramethyl--17H, 18H, 21H, 23H-13-carboxylic acid, 1-acetate, the reflux decarboxylation in pyridine of 17-propionic acid, chlorophyll alpha degraded product generates 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid;
(2) 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid drop into water-methanol-sodium hydroxide mixing solutions stirring reaction with amino acid methyl ester with 1: 80～1: 50 part by weight and generate 3-vinyl-8-ethyl-2,7 in the presence of DDC, DAMP, 12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid methyl esters, the part by weight of water, methyl alcohol and sodium hydroxide is 100: 25: 10～100: 10: 5;
(3) 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid methyl esters hydrolysis obtains 3-vinyl-8 ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide.
Potential optical dynamic therapy medicine provided by the invention is 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide and pharmaceutically acceptable carrier.
The pharmaceutical composition that is used for optical dynamic therapy contains general formula (III) compound of significant quantity and contains one or more pharmaceutically acceptable carriers.
Experimental results show that: as 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-18-propionic acid glycine acid amides (IV) measure the half of people's lung cancer A549 till death and are 44.26ng/ml, far below HMME (293.93ng/ml).In addition, it shows in the intravital distribution of tumor-bearing mice: do not contain this compound in heart and the brain, behind the 12h, except that liver, the content in its hetero-organization is all much smaller than tumor tissues.In the intravital transformation period of rabbit is 25.75h.Compound of the present invention and pharmaceutical composition far above Porphyrin-Based Sensitizer, can be used for preparing the optical dynamic therapy medicine to the photoinactivation of human cancer cell.
Above-mentioned 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide is blackish green or the class black solid, and is water insoluble, be dissolved in methyl alcohol, tetrahydrofuran (THF) isopolarity organic solvent, be soluble in non-polar organic solvents such as ether, chloroform.
The present invention's raw material of used base beginning and synthetic intermediate pheophorbide acid a, 3-vinyl-8-ethyl-2,7,12,18-tetramethyl--17H, 18H, 21H, the 23H-13-carboxylic acid, 15-acetate, 17-propionic acid and 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid all are that (Xu Deyu: Chinese invention patent: ZL99119878.6) listed method obtains with reference to national inventing patent.
Optical dynamic therapy pharmaceutical composition of the present invention comprises the 3-vinyl-8-ethyl-2,7 for the treatment of significant quantity, 12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-18-propionic acid glycine acid amides (IV), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid aspartic acid acid amides (V), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid ala amide (VI), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid leucine amide (VII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid methionine amide (VIII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid tryptophane acid amides (IX), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid serine amides (X) intravenous fluid.
" treatment significant quantity " of the present invention refers to the 0.5-2.0mg/kg body weight, is preferably 1.0-1.5mg/kg.
Pharmaceutically acceptable carrier of the present invention is the isotonic sodium chloride aqueous solution.
Description of drawings
Fig. 1 is general formula of the present invention (III) compound.
Embodiment
Below with embodiment the present invention is illustrated, these embodiment are intended to set forth optimum implementation of the present invention.Those skilled in the art are according to enlightenment of the present invention, and the various changes in conjunction with the general knowledge of this area is done all drop in the scope of the application's claim.
Embodiment 1:3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid glycine acid amides (IV) synthetic.
One, 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid glycinate amine synthetic:
3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid 55.2mg (0.1mmol) is dissolved in the 15ml anhydrous methylene chloride, add DCC (25mg respectively, 0.12mmol), DMAP (2.5mg), glycine methyl ester hydrochloride (15mg, 0.12mmol) and triethylamine (0.016ml), stirred overnight at room temperature.Thin plate detects no starting raw material, other adds the methylene dichloride of 35ml, washing with 50ml, water layer returns with the methylene dichloride of 20ml and carries, combined dichloromethane, the organic solvent evaporate to dryness is used the silica gel H purifying, developping agent is a chloroform: methyl alcohol: acetone: formic acid=10: 0.6: 0.6: 0.06, thin plate detect be one complete count qualified.Get 31mg black solid chlorin e4 glycinate acid amides, yield: 50%.
Two, 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid glycine acid amides synthetic:
3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid glycinate (62mg, 0.1mmol) methyl alcohol, the water of 3.5ml, the 1N NaOH aqueous solution 0.2～0.3ml of adding 20ml, 25 degree stirring reaction 48h.Thin plate detects no starting raw material, and reaction solution adds 0.02～0.03ml acetic acid, and reclaim under reduced pressure solution, raffinate add the citric acid of 30ml chloroform and 30ml10%, and fierce jolting divides and gets chloroform layer, and the citric acid water layer is used 20ml, 10ml chloroform extraction continuously.The combined chloroform layer, the organic solvent evaporate to dryness is used the silica gel H purifying, developping agent is a chloroform: methyl alcohol: acetone: formic acid=10: 1: 1: 0.1, thin plate detect be one complete count qualified.Get 48mg black solid 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid glycine acid amides, yield: 80%.Two step total recoverys: 40%.
MS(ESI+)m/z(C35H39N5O5)：610(M+1，100％)。1H-NMR(δppm，CDCl3+CD3OD)：10.02(s，1H，β-meso H)，9.90(s，1H，α-meso H)，9.25(s，1H，δ-meso H)，8.13(dd，1H，3a-H)，6.37(dd，2H，3b-H)，4.34～4.74(m，2H，17-Hand 18-H)，4.05(s，3H，15-CH3)，3.73～3.79(m，2H，8-CH2)，3.76～3.81(m，2H，NHCH2)，3.69(s，3H，12-CH3)，3.57(s，3H，2-CH3)，3.41(s，3H，7-CH3)，2.48～2.57(m，2H，17b-H)，2.24～2.29and 1.99～2.29(m，2H，17a-H)，1.88～1.95(m，3H，18-CH3)，1.66～1.69(m，3H，8b-CH3)。
Embodiment 2:3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid aspartic acid acid amides synthetic.
One, vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid Tianmen propylhomoserin esteramides synthetic:
Chlorin e4 (55.2mg, 0.1mmol) be dissolved in the 15ml anhydrous methylene chloride, add catalyzer DCC (Dicyclohexylcarbodiimide respectively, 25mg, 0.12mmol), DMAP (N, N-Dimethyl-4-pyridinamine, 2.5mg), aspartic acid methyl ester hydrochloride (40mg, 0.2mmol) and triethylamine (0.016ml), stirred overnight at room temperature.Thin plate detects no starting raw material, other adds the methylene dichloride of 35ml, washing with 50ml, water layer returns with the methylene dichloride of 20ml and carries, combined dichloromethane, the organic solvent evaporate to dryness is used the silica gel H purifying, developping agent is a chloroform: methyl alcohol: acetone: formic acid=10: 0.8: 0.8: 0.08, thin plate detect be one complete count qualified.Get 28mg black solid vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid aspartic acid esteramides, yield: 40%.
Two, 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid Tianmen propylhomoserin acid amides synthetic:
Vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid aspartic acid esteramides (70mg, 0.1mmol) methyl alcohol, the water of 3.5ml, the 1N NaOH aqueous solution 0.2～0.3ml of adding 20ml, 25 degree stirring reaction 72h.Thin plate detects no starting raw material, and reaction solution adds 0.04～0.05ml acetic acid, and reclaim under reduced pressure solution, raffinate add the citric acid of 30ml chloroform and 30ml 10%, and fierce jolting divides and gets chloroform layer, and the citric acid water layer is used 20ml, 10ml chloroform extraction continuously.The combined chloroform layer, the organic solvent evaporate to dryness is used the silica gel H purifying, developping agent is a chloroform: methyl alcohol: acetone: formic acid=10: 1.5: 1.5: 0.15, thin plate detect be one complete count qualified.Get 53mg black solid vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 24H-13-carboxylic acid-17-propionic acid aspartic acid acid amides, yield: 80%.Two step total recoverys: 30%.
MS(ESI+)m/z(C37H41N5O7)：668(M+1，100％)。1H-NMR(δppm，CDCl3+CD3OD)：9.85(s，1H，β-meso H)，9.73(s，1H，α-meso H)，9.09(s，1H，δ-meso H)，8.10(dd，1H，3a-H)，6.30(dd，2H，3b-H)，4.54～4.66(m，3H，17-H，18-H and NHCH)，4.00(s，3H，15-CH3)，3.81～3.787(m，2H，8-CH2)，3.64(s，3H，12-CH3)，3.55(s，3H，2-CH3)，3.34(s，3H，7-CH3)，2.68～2.81(m，2H，CH2COOH)，2.35～2.45(m，2H，17b-H)，1.99～2.10(m，2H，17a-H)，1.91～1.92(m，3H，18-CH3)，1.65～1.69(m，3H，8b-CH3)。
Embodiment 3-7: use L-Ala respectively, leucine, methionine(Met), glycine among tryptophane and the Serine replacement embodiment 1 or the aspartic acid among the embodiment 2, with the operation of embodiment 2, the synthetic respectively 3-vinyl-8-ethyl-2 that obtains, 7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid ala amide (VI), 3-vinyl-8-ethyl-2,7,12,15,18-five first-17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid leucine amide (VII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid methionine amide (VIII), 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid tryptophane acid amides (IX) and 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid serine amides (X).Mass spectroscopy is the result show, and is consistent shown in the molecular formula of their total mass number and above-mentioned target compound.
Table 1.The MS of target compound VI-X (ESI+) m/z measurement result among the embodiment 3-7
| The target compound numbering | Molecular formula | Molecular weight | MS(ESI+)m/z，100％ |
| VI | C36H41N5O6 | 639 | 640(M+1) |
| VII | C39H47N5O6 | 675 | 676(M+1) |
| VIII | C38H45N5O6S | 693 | 694(M+1) |
| IX | C44H45N5O6 | 733 | 734(M+1) |
| X | C36H41N5O6 | 633 | 634(M+1) |
MS(ESI+)m/z(C34H40N4O5)：585(M+1，100％)。1H-NMR(δppm，CDCl3+CD3OD)：9.88(s，1H，β-meso H)，9.76(s，1H，α-meso H)，8.87(s，1H，δ-meso H)，5.91～5.95(m，1H，3-CH)，4.50～4.58(m，2H，17-H and 18-H)，3.96(s，3H，15-CH3)，3.61～3.85(m，2H，8-CH2)，3.61(s，3H，3-OCH3)，3.55(s，3H，12-CH3)，3.48(s，3H，2-CH3)，3.33(s，3H，7-CH3)，2.42～2.57(m，2H，17b-H)，1.95～2.22(m，2H，17a-H)，2.11～2.13(m，3H，3-CH3)，1.76～1.77(m，3H，18-CH3)，1.70～1.72(m，3H，8b-CH3)。
Claims (4)
1. following general formula (III) compound:
R wherein represents :-CH
2COOH;
2. the preparation method of the described compound of claim 1 is characterized in that this method comprises the steps:
(1) 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid drop into water-methanol-sodium hydroxide mixing solutions stirring reaction with amino acid methyl ester with 1: 80～1: 50 part by weight and generate 3-vinyl-8-ethyl-2,7 in the presence of DDC, DAMP, 12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid methyl esters, the part by weight of water, methyl alcohol and sodium hydroxide is 100: 25: 10～100: 10: 5;
(2) 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid methyl esters hydrolysis obtains 3-vinyl-8-ethyl-2,7,12,15,18-pentamethyl--17H, 18H, 21H, 23H-13-carboxylic acid-17-propionic acid amino acid amide.
3. be used for the pharmaceutical composition of optical dynamic therapy, it is characterized in that: claim 1 compound and the pharmaceutically acceptable carrier that contain significant quantity.
4. the application of the described compound of claim 1 in preparation optical dynamic therapy medicine.
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| US4675338A (en) * | 1984-07-18 | 1987-06-23 | Nippon Petrochemicals Co., Ltd. | Tetrapyrrole therapeutic agents |
| CN1260347A (en) * | 1999-10-28 | 2000-07-19 | 许德余 | Chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4675338A (en) * | 1984-07-18 | 1987-06-23 | Nippon Petrochemicals Co., Ltd. | Tetrapyrrole therapeutic agents |
| CN1260347A (en) * | 1999-10-28 | 2000-07-19 | 许德余 | Chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer |
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| Title |
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| 光辐射肿瘤诊治新药血卟啉衍生物研究的进展. 许德余.第二军医大学学报，第4卷第1期. 1983 * |
| 锌二氢卟吩e4的合成及初步抗胃溃疡活性和对急性肝损伤的保护作用. 姚建忠等.药学学报，第36卷第3期. 2001 * |
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