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Targeted thymidine kinase photosensitizer, pharmaceutical composition thereof, and applications of targeted thymidine kinase photosensitizer in treating cancers

A technology of thymidine kinase and photosensitizer, which is applied in the field of targeted thymidine kinase photosensitizer and its pharmaceutical composition, can solve the problems of large limitations, single prostate cancer, and unsatisfactory effect, and achieve enhanced selectivity and tumor expansion Range of application, well tolerated effect

Inactive Publication Date: 2014-04-09
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, only a single photosensitizer-PDT therapy or chemotherapy is currently used for prostate cancer, which has great limitations and unsatisfactory effects.

Method used

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  • Targeted thymidine kinase photosensitizer, pharmaceutical composition thereof, and applications of targeted thymidine kinase photosensitizer in treating cancers
  • Targeted thymidine kinase photosensitizer, pharmaceutical composition thereof, and applications of targeted thymidine kinase photosensitizer in treating cancers
  • Targeted thymidine kinase photosensitizer, pharmaceutical composition thereof, and applications of targeted thymidine kinase photosensitizer in treating cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of HPPH-thymidine conjugates

[0057]

[0058] Wherein, the number of HPPH is compound 1, and the number of HPPH-thymidine conjugate is compound 3; the specific preparation method is as follows:

[0059] HPPH (300mg, 0.48mmol), benzotriazol-1-yl-oxytri(dimethylamino)phosphonium hexafluorophosphate (255mg, 0.58mmol), thymidine (1800mg, 7.2mmol) and Triethylamine (about 0.5 mL) was dissolved in about 20 mL of anhydrous dimethylformamide (DMF), and the reaction mixture was stirred overnight. After removal of DMF under high vacuum, the 2 Cl 2 This mixture is used as eluent to purify, and the target product yield obtained reaches more than 52% (210mg), and its electronic absorption spectrum is as attached figure 1 As shown (UV-Vis, methanol concentration is 7.7 μM), λ max (MeOH), nm (ε): 663nm (5.25×10 4 ), 606nm (7.49×10 3 ), 538nm (7.51×10 3 ), 507nm (7.28×10 3 ), 412nm (10.52×10 4 ).

[0060] NMR attached figure 2 as shown, 1 HNMR (CD...

Embodiment 2

[0061] Example 2: Preparation of targeted thymidine kinase photosensitizer containing substituted phenyl

[0062] Targeted thymidine kinase photosensitizer containing substituted phenyl group ie 17 3 -Thymidine-20-(4-thymidyloxycarbonyl)phenyl-3-((1'-n-hexyloxy)ethyl)-3-desvinyl-pyropheophorbide preparation route and Concrete experiment is as follows (the present invention numbers it as compound 6):

[0063]

[0064] Step 1, the preparation of compound 4:

[0065] HPPH1 (300 mg, 0.47 mmol) and pyridinium tribromide (196 mg, 0.61 mmol) were dissolved in 10 mL of dichloromethane; 3 drops of pyridine were added to the reaction mixture. The reaction mixture was stirred for 40 minutes. After work-up, chromatograph using 5% MeOH / CH 2 Cl 2 The mixture was purified as eluting solvent. The target compound was obtained in 48% yield (160 mg). UV-visible light, λ max (CH 2 Cl 2 ), nm(ε): 672nm (4.65×10 4 ), 552nm (1.69×10 4 ), 418nm (11.1×10 4 ). 1 HNMR (CDCl 3 ; 400MHz)...

Embodiment 3

[0074] Example 3: Preparation of Targeted Thymidine Kinase Photosensitizer Containing Additional N Heterocycles

[0075] Preparation line:

[0076]

[0077] details as follows:

[0078] 3-(1-(n-butoxy)ethyl)purpurin-18-N-butyramide-17-propionic acid 7 (120mg, 0.173mmol), BOP (169mg, 0.38mmol), thymidine (1050mg , 4.32 mmol) and triethylamine (about 0.5 mL) were dissolved in approximately 15 mL of anhydrous DMF, and the reaction mixture was stirred overnight; after removal of DMF under high vacuum, the 2 Cl 2 The mixture was purified as the eluting solvent to obtain the target compound in 51% yield (80 mg). UV-visible light, λ max (MeOH), nm(ε): 699nm (4.51×10 4 ), 642 (7.31×10 3 ), 543 (1.79×10 4 ), 507 (7.29×10 3 ), 413 (12.52×10 4 ). 1 HNMR (CDCl 3 ; 400MHz): δ9.79, (s, 1H, H-5), 9.66 (s, 1H, H-10), 8.53 (s, 1H, H-15), 7.21 (s, 1H, ArH), 7.03 (m, 1H, ), 6.80(m, 3H, ), 6.22(m, 3H, ), 5.80 (q, J=6.5Hz, 1H, 3 1 -H), 5.37(m, 2H, -NCH 2 (CH 2 ) 2 CH 3 )...

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Abstract

The invention provides a targeted thymidine kinase photosensitizer, a pharmaceutical composition thereof, and applications of the targeted thymidine kinase photosensitizer in treating cancers. The targeted thymidine kinase photosensitizer is capable of increasing photosensitizer selectivity on tumor cells; tolerance is higher; and the blood concentration can be achieved in 24 hours. The targeted thymidine kinase photosensitizer possesses a larger conjugated system absorption wavelength, so that is beneficial for treatment of advanced tumors; no more energy of light output equipment is required by the wavelength zone, and it is even possible for using of LED, so that practicality and economical efficiency of PDT are improved. The targeted thymidine kinase photosensitizer can be used for diagnosis, and for treating prostatic cancer via fluorescence imaging guiding. According to the pharmaceutical composition, chemotherapeutic agents and the targeted thymidine kinase photosensitizer are combined, so that therapeutic effect of PDT is improved further, application range on tumor is enlarged, and excellent curative effects on metastatic tumors are achieved.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a photosensitizer targeting thymidine kinase, a pharmaceutical composition thereof and the application of treating cancer. Background technique [0002] Prostate cancer is the most common non-skin infectious malignancy and ranks second in the death rate among men, second only to lung cancer. In the United States, nearly 190,000 people are diagnosed with prostate cancer each year, and nearly 31,000 people die from prostate cancer. Prostate cancer is a multifocal disease that requires controlling treatment of the entire gland. Currently, treatment options mainly include observation-only (watchful waiting), surgery (radical prostatectomy), radiation (external beam or implanted radioactive source brachytherapy), radiation plus hormone therapy (new adjuvant therapy) and hormone therapy. Treatment (androgen deprivation therapy). In addition, according to the survey, some doctors also use cry...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7072A61K41/00A61P35/00A61P35/04C07H19/073C07H1/00
CPCA61K49/0036A61K47/48061C07D487/22A61K41/0071A61K31/409A61K31/7072A61K47/549A61K31/7064A61K31/7068A61K31/706A61K31/337A61K47/545A61P35/00A61P35/04A61K41/0057A61K47/546
Inventor 拉温德拉·K·潘迪陈亦晖白骅
Owner ZHEJIANG HISUN PHARMA CO LTD
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