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Novel 4'-demethyl-4'-0-substituted-1-deoxypodophyllotoxin derivative and geometric isomer thereof, process for preparation thereof and anti-cancer composition comprising same

A technology of deoxypodophyllin and demethylation, which is used in drug combinations, medical preparations containing active ingredients, antitumor drugs, etc.

Inactive Publication Date: 2004-02-11
金松培
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] After the above report, no further studies on the anticancer activity of deoxypodophyllotoxin derivatives

Method used

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Experimental program
Comparison scheme
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Embodiment approach

[0015] In the compound of formula (1), wherein R represents a group containing a double bond such as alkenyl, alkadiene, alkatriene, alkatetraene, each double bond may exist in cis or trans form. Accordingly, geometric isomers of the compound of formula (1) are included within the scope of the present invention.

[0016] In the definition of substituent A, "amino acid residue" means excluding -COOH groups and -NH 2 The amino acid portion of the group. Preference is given to residues of alanine, leucine, valine, glycine, serine, methionine, phenylalanine, threonine and tyrosine.

[0017] Representative examples of compounds of formula (1) according to the present invention are as follows:

[0018] 4'-Demethyl-4'-O-alanyl-1-deoxypodophyllotoxin;

[0019] 4'-Demethyl-4'-O-leucyl-1-deoxypodophyllotoxin;

[0020] 4'-Demethyl-4'-O-valyl-1-deoxypodophyllotoxin;

[0021] 4'-Demethyl-4'-O-glycyl-1-deoxypodophyllotoxin;

[0022] 4'-Demethyl-4'-O-seryl-1-deoxypodophyllotoxin;

[0...

Embodiment 1

[0159] Yield: 94% Example 1 Synthesis of 4'-demethyl-4'-O-alanyl-1-deoxypodophyllotoxin (1a-1)

[0160] Into a 50 ml round bottom flask was added 4'-demethyl-1-deoxypodophyllotoxin (DDPT, 384 mg, 1 mmol), dicyclohexylcarbodiimide (DCC, 1.03 g, 5 mmol) and 4-dimethylamino Pyridine (4-DMAP, 306mg, 2.5mmol), which was then dissolved in anhydrous dichloromethane (20ml). At 4°C under a nitrogen atmosphere, N-tert-butoxycarbonyl-alanine (189 mg, 1 mmol) was added thereto, and the resulting mixture was stirred for 1 hour. Distilled water (100 ml) was added to the reaction mixture. The resulting mixture was extracted 3 times with dichloromethane (100 ml). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was directly dissolved in anhydrous dichloromethane (20 ml) containing 50% trifluoroacetic acid without any purification process, and stirred at room temperature for 2 hours. The reaction soluti...

Embodiment 2

[0162] 1 H-NMR (ppm): d 7.67 (br, 2H, -NH 2 ), 6.65(s, 1H), 6.42(s, 1H), 6.36(s, 2H), 5.94(d, J=1.3Hz, 1H), 5.92(d, J=1.3Hz, 1H), 4.54(d , J=3.81Hz, 1H), 4.36(t, J=16.3Hz, 1H), 3.85(t, J=16.3Hz, 1H), 3.69~3.58(m, 7H), 3.02~2.70(m, 4H) , 1.59 (d, J=5.79Hz, 3H) Example 2 Synthesis of 4'-Demethyl-4'-O-leucyl-1-deoxypodophyllotoxin (1a-2)

[0163] Except using N-tert-butoxycarbonylleucine (231 mg, 1 mmol), the same procedure as in Example 1 was carried out to provide 403 mg of the title compound.

[0164] Yield: 81.2%

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Abstract

The present invention provides a novel 4'-demethyl-4'-O-substituted-1-deoxypodophyllotoxin derivative, a geometric isomer thereof, a process for the preparation thereof, and an anticancer composition comprising the same.

Description

technical field [0001] The present invention relates to a novel 4'-demethyl-4'-O-substituted-1-deoxypodophyllotoxin derivative, its geometric isomers, a process for its preparation, and a method comprising it The anticancer composition, described derivative is represented by following formula (1): in [0002] R means -A-NH 2 ;-NH-R 1 ; Unsubstituted or replaced by 1-5 C 1-4 Alkoxy-substituted phenyl-C 2-4 Alkenyl; unsubstituted or replaced by amino or diC 1-4 Alkylamino substituted benzyl; straight or branched C 1-21 Alkyl, C 15-21 Alkenyl, C 15-21 Alkadienyl, C 15-21 Alkatrienyl, C 15-21 Alkatraenyl, or C 15-21 Hexaenyl, Retinyl, C 5-15 Carboxyalkyl, where [0003] A represents an amino acid residue, -(CH 2 ) n1 -; or -(CH 2 ) n2 -C 6 h 5 , [0004] n1 represents an integer of 2-8, [0005] n2 represents an integer from 1-4, and [0006] R 1 Represents unsubstituted or substituted straight-chain or branched C 1-4 Alkyl, the substituent is selected fro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/365A61P35/00C07D493/04
CPCC07D493/04A61P35/00
Inventor 安丙浚金勇刘永济
Owner 金松培
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