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Camptothecin analogs and methods of preparation thereof

A compound and alkyl technology, applied in the field of new compounds and their preparation, can solve the problems of low solubility, limitation, and poor anti-tumor activity of camptothecin, and achieve the effect of improving blood stability and activity

Inactive Publication Date: 2002-06-05
UNIVERSITY OF PITTSBURGH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Camptothecin was limited in initial clinical trials due to its low solubility in physiologically compatible media
In addition, early attempts to form a water-soluble sodium salt of camptothecin by opening the lactone ring with sodium hydroxide resulted in poor antitumor activity of the resulting compound

Method used

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  • Camptothecin analogs and methods of preparation thereof
  • Camptothecin analogs and methods of preparation thereof
  • Camptothecin analogs and methods of preparation thereof

Examples

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preparation example Construction

[0069] Figure 7-11 The preparation of compounds of formula (2) is shown. thus Figure 7 Three representative, novel A, B ring substituted silylcamptothecin compounds (36a), (36b) and (36c) are shown.

[0070] The first step in the synthesis of these analogs is the preparation of propargyl bromide (41), as Figure 8 shown. Swem oxidation of the purchased trimethylsilylpropanol (37) can give trimethylsilylpropanal (38) with a yield of 85%. Sakar, T.K. et al., Tetrahedron 46, 1885 (1990). Aldehyde (38) was converted to dibromoalkene (39) in 55% yield following Procedure A of Corey, E.J. and Fuchs, P.L., Tetrahedron Lett., 36, 3769 (1972). Piers, E. and Gaval, A.V.J. Org. Chem., 55, 2374 (1990). 2 equivalents of n-BuLi were added in THF at -78°C, then warmed to 22°C and quenched with paraformaldehyde at reflux to give (40) in 84% yield. Finally, with anhydrous CH 2 Cl 2 Formulated triphenylphosphine and Br 2 The solution produced propargyl bromide (41) in 87% yield.

...

Embodiment 1

[0153] Preparation of (20S)-7-trimethylsilylcamptothecin

[0154] (1) (S)-4-ethyl-4-hydroxyl-6-iodo-3-oxo-7-(3-trimethylsilyl-2-propynyl)-1H-pyrano[ 3,4-c]-8-pyridone

[0155] Under argon at 0°C, in (S)-4-ethyl-4-hydroxy-6-iodo-3-oxo-1H-pyrano[3 , 4-c]-8-pyridone [iodopyridone (2), 250 mg, 0.746 mmol] was added 60% NaH in mineral oil (31.3 mg, 0.783 mmol). After 10 minutes LiBr (150 mg, 1.75 mmol) was added. After 15 minutes at room temperature, 3-trimethylsilyl-2-propynyl bromide (430 mg, 2.24 mmol) was injected and the reaction mixture was heated at 65°C for 20 hours in the dark. The final solution was poured into brine (20ml), extracted with AcOEt (6 x 15ml) and dried (Na 2 SO 4 ). After removal of the solvent, the residue was subjected to flash chromatography (CHCl 3 / AcOEt 95:5), to obtain 283 mg (85%) foam: [ α ] 20 D +36.7(c 1, CHCl 3 ); IR(pure, cm -1 )3384, 2940, 2166, 1730, 1634, 1518, 1406, 1130, 841, 752; 1 H NMR (300 MHz, CDCl 3 )δ0.14 (s, 9 H), 0....

Embodiment 2

[0159] Preparation of (20S)-7-tert-butyldimethylsilylcamptothecin (DB-202)

[0160] (1) (S)-4-ethyl-4-hydroxy-6-iodo-3-oxo-7-(3-tert-butyldimethylsilyl-2-propynyl)-1H- Pyrano[3,4-c]-8-pyridone

[0161] According to the process described in Example 1-(1), with iodopyridone (2) (200mg, 0.60mmol) and 3-tert-butyldimethylsilyl-2-propynyl bromide (280mg, 1.20 mmol) for reaction, flash chromatography (CH 2 Cl 2 / AcOEt 9:1), 173 mg (59%) of white foam was obtained: [α] D 20 +58(c 0.2, CHCl 3 );IR(CHCl 3 , cm -1 )3548, 2950, ​​2927, 2859, 1745, 1648, 1526; 1 H NMR (300 MHz, CDCl 3 )δ 0.08(s, 6H), 0.92(m, 12H), 1.79(m, 2H), 3.77(br s, 1H), 5.00-5.25(m, 3H), 5.50(d, J = 16.4 Hz, 1 H) 7.19 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )δ-4.9, 7.63, 16.6, 26.0, 31.6, 44.5, 66.3, 71.8, 89.4, 98.6, 100.0, 116.5, 118.1, 148.6, 158.0, 173.2; HRMS (EI) m / z C 19 h 26 INO 4 Si(M + ) calculated value 487.0679, measured value 487.0676; LRMS (EI) m / z 487 (M + ), 430, 386, 96, 81, 57.

[01...

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Abstract

A compound of general formula (1) and pharmaceutically acceptable salts thereof and their preparation method: in the formula, R 1 and R 2 Each is the same or different, hydrogen, alkyl, alkenyl, benzyl, alkynyl, alkoxy, aryloxy, acyloxy, -OC(O)OR d , where R d Is alkyl, carbamoyloxy, halogen, hydroxyl, nitro, cyano, azido, formyl, hydrazino, acyl, amino, -SR c , where R c is hydrogen, acyl, alkyl or aryl, or R 1 and R 2 together to form the formula -O(CH 2 ) n O-group, where n represents an integer 1 or 2; R 3 is H, F, a halogen atom, nitro, amino, hydroxyl or cyano; or R 2 and R 3 can also be combined to form the formula -O(CH 2 ) n O-group, where n represents an integer 1 or 2; R 4 Is H, trialkylsilyl, F, Cl-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, or C1-3 alkoxy; R 5 Is C1-10 alkyl, enbenzyl or propargyl; R 6 , R 7 and R 8 Each is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl or -(CH 2 ) N R 9 group, where N is an integer ranging from 1 to 10, and R 9 is hydroxyl, alkoxy, amino, alkylamino, dialkylamino, halogen atom, cyano or nitro; R 11 is an alkylene or alkenylene group.

Description

[0001] related application [0002] This application is a continuation-in-part of U.S. Patent Application No. 08 / 921,102, which is a continuation-in-part of U.S. Patent Application No. 08 / 436,799, which is a continuation-in-part of U.S. Patent Application No. 08 / 085,190, which are incorporated herein in their entirety as refer to. field of invention [0003] The present invention relates to a novel compound and a preparation method thereof, in particular to a silylcamptothecin derivative or analog and a preparation method of the silylcamptothecin analog. Background of the invention [0004] (20S)-camptothecin (CPT, below) and its derivatives are the most promising compounds for chemotherapy to treat solid tumors. See e.g. Wall, M.E. et al., Journal of Ethnopharmacology, 51, 239 (1996), "Camptothecin: A New Anticancer Drug", in Potmesil, M. and Pinedo, H., eds.; CRC, Boca Raton, FL ( 1995), Bonneterre, J., Bull. Canc., 82, 623 (1995); Sinha, D.K., Drugs, 49, 11 (1995). In ...

Claims

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Application Information

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IPC IPC(8): A61K31/695A61P35/00A61P35/02C07D471/14C07D491/044C07D491/22C07F7/08C07F7/10C07F7/12
CPCC07F7/0812C07F7/0814C07D471/14C07F7/083A61P35/00A61P35/02C07F7/02
Inventor D·P·柯伦H·乔森D·博T·G·伯克
Owner UNIVERSITY OF PITTSBURGH
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