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Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof

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

Inactive Publication Date: 2016-07-20
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, unsaturated fatty acids are also used to modify SN-38 by esterification, such as BoB.Lundberg et al. using oleic acid for modification (LundbergBB.Biologicallyactivecamptothecinderivativesforincorporationintoliposomebilayersandlipidemulsions[J].Anti-cancerdrugdesign,1998,13(5):453-461); China Patent CN03818985.2 discloses a preparation method using a conjugate of camptothecin derivatives and long-chain unsaturated fatty acids. The publication number is CN1675219A. Although the patent mentions modifying SN-38 with long-chain unsaturated fatty acids, In this method, an intermediate "adapter chain" is used to link SN-38 with long-chain unsaturated fatty acids. Due to the existence of the "adapter chain", the compound synthesized by it is relatively irinotecan Whether it can be more effectively converted into SN-38 is not reflected in the patent, and due to the existence of the intermediate "connecting chain", the compound it synthesizes will definitely produce long-chain unsaturated fatty acids and SN-38 in the process of human metabolism. Other substances other than these "other" substances are harmful to the human body, and there is no description in the patent, and so far there are no related compounds synthesized by this synthesis method for clinical research, so the compounds synthesized by this synthesis method The effectiveness and safety are 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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  • Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof
  • Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof
  • Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof

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 chemic...

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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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
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