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A 7-ethyl-10-hydroxycamptothecin compound modified by a saturated long-chain fatty acid and its long-circulating liposome

A long-circulating liposome, long-chain fatty acid technology, applied in the field of medicine, can solve the problems of no in-depth research, easy oxidation of unsaturated fatty acids, no explanation, etc., and achieves improved tumor distribution, stable properties, and is conducive to storage. Effect

Inactive Publication Date: 2018-05-25
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, unsaturated fatty acids are also used for esterification modification of SN-38, such as Bo B. Lundberg et al. using oleic acid for modification (Lundberg B B. Biologically active camptothecin derivatives for incorporation into liposome bilayers and lipid emulsions [J]. Anti-cancer drug design , 1998,13 (5): 453-461); Chinese patent CN03818985.2 discloses a kind of preparation method that adopts the conjugate body of camptothecin derivative and long chain unsaturated fatty acid, publication number is CN1675219A, although this patent It is mentioned that SN-38 is modified with long-chain unsaturated fatty acids, but in this method, an intermediate "adapter chain" is used to connect SN-38 to long-chain unsaturated fatty acids, and this connection method is due to the "adapter chain" Whether the compound it synthesizes can be more effectively converted to SN-38 compared to irinotecan is not reflected in the patent, and due to the existence of the intermediate "connecting chain", the compound it synthesizes will definitely be released in the human body. Other substances other than long-chain unsaturated fatty acids and SN-38 are produced during the metabolic process, and whether these "other" substances are harmful to the human body is not stated in the patent, and so far there is no relevant synthesis method. The compound is used for clinical research, so the effectiveness and safety of the compound synthesized by this synthesis method is questionable
At the same time, the above two patents all use unsaturated fatty acids to modify SN-38, but unsaturated fatty acids are easy to oxidize and have poor stability (Wang Wei, Zhang Weimin. Functional properties of monounsaturated fatty acids [J]. Chinese Food and Nutrition, 2005, 4:44-46), which is not conducive to preparation storage
Chinese patent application CN200410017128.5 discloses a carbonate prodrug of hydroxycamptothecin and its derivatives and its preparation method. The publication number is CN1673226A. The patent selects C 1～30 Various substituents such as alkyl, aromatic ring, aromatic heterocycle, aralkyl, substituted aromatic ring, substituted aromatic heterocycle, and substituted aralkyl modify camptothecin. The compound involved in this patent There are many types, but none of them have been studied in depth

Method used

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  • A 7-ethyl-10-hydroxycamptothecin compound modified by a saturated long-chain fatty acid and its long-circulating liposome
  • A 7-ethyl-10-hydroxycamptothecin compound modified by a saturated long-chain fatty acid and its long-circulating liposome
  • A 7-ethyl-10-hydroxycamptothecin compound modified by a saturated long-chain fatty acid and its long-circulating liposome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: Preparation of 7-ethyl-10-hydroxycamptothecin-10-palmitate

[0062]Add 1mmol of 7-ethyl-10-hydroxycamptothecin to the reaction vessel, add 0.2L of anhydrous chloroform to dissolve, then add 1.2mmol of DIPEA, stir for 5 minutes under ice bath conditions, slowly drop 1.2mmol Palmitoyl chloride, continue to react for 15 minutes under ice-bath conditions, and then react for 4 hours at room temperature. The reactant is recrystallized in acetone, and 620.12 mg of 7-ethyl-10-hydroxycamptothecin-10-palmitate is isolated , yield 98.37%.

[0063] The HNMR and MS (ESI) data of this material are as follows:

[0064] 1H NMR (CDCl3, 600MHz) δ: 8.22 (1H, d, J = 9.12Hz), 7.81 (1H, d, J = 2.46Hz), 7.64 (1H, s), 7.54 (1H, dd, J = 9.12and J =2.46Hz), 5.74(1H, d), 5.30(1H, d), 5.25(2H, s), 3.86(1H, s), 3.15(2H, q), 2.65(2H, t), 1.95-1.85 (2H, m), 1.84-1.79 (2H, m), 1.50-1.26 (27H, m), 1.03 (3H, t), 0.87 (3H, t).

[0065] MS (ESI - )m / z:629(M-H + ).

[0066] The chemica...

Embodiment 2

[0068] Embodiment 2: Preparation of 7-ethyl-10-hydroxycamptothecin-10-palmitate

[0069] Add 1 mmol of 7-ethyl-10-hydroxycamptothecin to the reaction vessel, add 1 L of anhydrous dichloromethane to dissolve, then add 2 mmol of triethylamine, stir for 30 minutes under ice bath conditions, slowly add 2 mmol of Palmitoyl chloride, continue to react for 45 minutes under ice bath conditions, and then react for 24 hours at room temperature. The reactant is recrystallized in ethyl acetate, and 7-ethyl-10-hydroxycamptothecin-10-palmitate is isolated 621.33 mg, yield 98.56%.

Embodiment 3

[0070] Example 3: Preparation of 7-ethyl-10-hydroxycamptothecin-10-palmitate

[0071] Add 1mmol of 7-ethyl-10-hydroxycamptothecin to the reaction vessel, add 0.5L of anhydrous N,N-dimethylformamide to dissolve, then add 1.5mmol of DMAP, and stir for 15 minutes under ice bath conditions , slowly add 1.5 mmol of palmitoyl chloride dropwise, continue to react for 20 minutes under ice-bath conditions, and then react for 8 hours at room temperature. The reactant is recrystallized in cyclohexane, and 7-ethyl-10-hydroxy camptotheca Base-10-palmitate 610.28 mg, yield 96.81%.

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Abstract

The invention relates to the technical field of medicine, and relates to a saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin (SN-38) compound and a long-circulating liposome thereof. Under substitution reaction conditions and the existence of an acid-binding agent, SN-38 is subjected to saturated long-chain fatty acid chloride, such that a SN-38 monounsaturated fatty acid ester compound is obtained. The compound has a following general formula (I). The long-circulating liposome prepared with the compound provided by the invention has the advantages of improving drug anti-tumor effect, enhancing drug stability, reducing drug toxic and side effects, and the like.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a saturated long-chain fatty acid modified 7-ethyl-10-hydroxycamptothecin compound and its long-circulating liposome, its preparation method, and its application in antitumor drugs . Background technique [0002] Irinotecan hydrochloride (CPT-11) is a semi-synthetic soluble camptothecin derivative. The dosage forms currently on the market mainly include injection and freeze-dried powder injection. It mainly acts on the S phase of the cell cycle. Isomerase Ⅰ, which interferes with DNA replication and cell division, is used as a first-line drug in combination with fluorouracil and leucovorin in the treatment of patients with metabolic colon or rectal cancer, and can also be used to treat patients who have failed or relapsed after fluorouracil treatment Patients with metabolic colon or rectal cancer. This product can be used alone or in combination with other drugs for the treatm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4745A61K9/127A61P35/00
Inventor 陈建明吴婵张元声余侬高保安姚建忠刘文丽陈丽娜邓莉马娟娟
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY