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Thermosensitive cyclotriphosphazene-platinum complex conjugate, its preparation method and anticancer agent containing the same

A cyclotriphosphazene and conjugate technology, which is applied in the field of cyclotriphosphazene-platinum composite conjugates, can solve the problems of high toxicity, limited use, low anticancer activity and the like

Inactive Publication Date: 2003-01-01
KOREA INST OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its high toxicity (LD 50 =13mg / Kg, M.J.Cleare, biochemistry (Biochimie) 60,835 (1978)), make its use restricted
Although the second-generation anticancer agent carboplatin showed much lower toxicity than cisplatin (LD 50 =180mg / Kg, M.J.Cleare, Biochemistry 60,835(1978)), but because its anticancer activity is lower than cisplatin, and its price is more expensive than cisplatin, it is not widely used

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] {NP[(OCH 2 CH 2 ) 2 OCH 3 ][L-Asp·Pt(dmpda)] 3 preparation of

[0034] Will {NP[(OCH 2 CH 2 ) 2 OCH 3 ][NHCH(CH 2 COOC 2 h 5 )COOC 2 h 5 ]} 3 (1.00g, 0.95mmol) was dissolved in methanol (50ml), and the temperature of the reaction vessel was controlled at 0-5°C with an ice-water bath. Slowly add the solution containing excess Ba(OH) under stirring 2 ·8H 2O (1.19 g, 3.78 mmol) in methanol. The ice-water bath was removed after 30 minutes, and the reaction was continued for 3 hours. The reaction mixture was concentrated under reduced pressure until only a small amount of solvent remained. Excess ether or hexane was added to the concentrated reaction mixture to cause precipitation of the hydrolyzate. The precipitate thus obtained is redissolved in a small amount of methanol and then reprecipitated by adding excess ether or hexane. After the precipitation process was repeated 2-3 times, the final precipitate was vacuum-dried to obtain 0.99 g of cyclotripho...

Embodiment 2

[0048] {NP[(OCH 2 CH 2 ) 2 OCH 3 ][L-Asp·Pt(dach)]} 3 preparation of

[0049] Use {NP[(OCH 2 CH 2 ) 2 OCH 3 ][NHCH(CH 2 COOC 2 h 5 )COOC 2 h 5 ]} 3 (0.73g, 0.69mmol), Ba(OH) 2 ·8H 2 O (0.87g, 2.76mmol), cyclotriphosphazene-barium salt (0.69g, 0.61mmol), and (dach)PtSO 4 (0.63g, 1.83mmol), obtain the final conjugated product {NP[(OCH 2 CH 2 ) 2 OCH 3 ][L-Asp·Pt(dach)]} 3 (1.05 g, 95.5% yield).

[0050] Molecular formula: C 45 h 87 N 12 o 21 P 3 Pt 3

[0051] Elemental analysis (%): C, 29.01; H, 4.79; N, 9.39; P, 5.01; Pt, 30.95

[0052] Theoretical values: C, 29.85; H, 4.84; N, 9.28; P, 5.13; Pt, 32.33

[0053] Proton NMR spectroscopy (D 2 O, ppm):

[0054] δ1.1-1.4(b, 4H,

[0055] δ1.5-1.7(b, 2H,

[0056] δ2.0-2.2(b, 2H,

[0057] δ2.3-2.5(b, 2H,

[0058] Phosphorus NMR spectroscopy (D 2 O, ppm): δ34-44

[0059] Lower critical solution temperature: 92.0°C.

Embodiment 3

[0061] {NP[(OCH 2 CH 2 ) 2 OCH 3 ][L-Asp·Pt(dmach)]} 3 preparation of

[0062] Use {NP[(OCH 2 CH 2 ) 2 OCH 3 ][NHCH(CH 2 COOC 2 h 5 )COOC 2 h 5 ]} 3 (0.82g, 0.78mmol), Ba(OH) 2 ·8H 2 O (0.87g, 2.76mmol), cyclotriphosphazene-barium salt (0.74g, 0.65mmol), and (dmach)PtSO 4 (0.72g, 1.96mmol), obtain the final conjugated product according to the same method as in Example 1, {NP[(OCH 2 CH 2 ) 2 OCH 3 ][L-Asp·Pt(dmach)]} 3 (0.97 g, 78.2% yield).

[0063] Molecular formula: C 51 h 99 N 12 o 21 P 3 Pt 3

[0064] Elemental analysis (%): C, 30.22; H, 5.15; N, 8.80; P, 4.82; Pt, 29.05

[0065] Theoretical values: C, 32.33; H, 5.27; N, 8.87; P, 4.90; Pt, 30.89

[0066] Proton NMR spectroscopy (D 2 O, ppm):

[0067] δ1.3-1.6(b, 10H, H 2 NCH 2 C(C 5 h 10 )CH 2 NH 2 ),

[0068] δ2.4-2.8(b, 6H, H 2 NCH 2 C(C 5 h 10 )CH 2 NH 2 ,-NHCH(CH 2 COO)COO),

[0069] δ3.4(s, 3H, -O(CH 2 CH 2 O) 2 CH 3 ),

[0070] δ3.6-3.8(b,6H,-OCH 2 CH 2 OCH 2 CH ...

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Abstract

The present invention provides a novel thermosensitive cyclotriphosphazene-platinum complex conjugates represented by Formula (1) wherein m is a repeating unit of poly(alkoxyethylene glycol) selected from the integers 2, 7 and 12; n represents the length of the alkyl chain selected from the integers 0, 1, 2 and 3; x represents the length of the anionic amino acid residue selected from the integers 0 (amino malonic acid derivatives), 1 (aspartic acid derivatives) and 2 (glutamic acid derivatives); A2 is a bidentate chelating diamine selected from the group consisting of 2,2-dimethyl-1,3-propanediamine (dmpda), trans(+ / -)-1,2-diaminocyclohexane (dach) and 1,1-diaminomethylcyclohexane (dmach).

Description

field of invention [0001] The present invention relates to a thermosensitive cyclotriphosphazene-platinum complex conjugate which can be administered systemically or locally and has excellent anticancer activity, a preparation method thereof, and an anticancer agent containing the conjugate as an active component. More particularly, the compound of the present invention is a biodegradable cyclotriphosphazene-platinum complex conjugate exhibiting thermosensitivity in the temperature range including body temperature. Background of the invention [0002] The inventors found that by hexachlorocyclotriphosphazene ((NPCl 2 ) 3 ) derivatives obtained by nucleophilic substitution of chlorine atoms of low or high molecular weight hydrophilic poly(alkoxyethylene glycol) and hydrophobic amino acid esters can show thermosensitivity (Korean Patent Application No. 99-48800). The present inventors succeeded in preparing platinum complexes of these trimer derivatives by introducing (diami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00A61K31/282C07F9/02C07F9/6593C07F15/00C09K3/00
CPCC07F15/0093C07F9/65815A61P35/00C07F9/02
Inventor 孙莲秀宋秀昶李祥汜
Owner KOREA INST OF SCI & TECH
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