Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them

A derivative and pharmaceutical technology, applied in the direction of drug combination, preparation of organic compounds, organic chemistry, etc.

Active Publication Date: 2006-08-30
JEIL PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, toxicity to the gastrointestinal tract and limitations on the therapeutic index are still problems for decarbocolchicine

Method used

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  • Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them
  • Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them
  • Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] 6-Nitrooxymethyl-N-[(7S)-1,2,3-trimethoxy-10-methylthio-9-oxo-5,6,7,9-tetrahydro-benzo[ a] geng Preparation of en-7-yl]-nicotinamide

[0176] 6-Hydroxymethyl-N-[(7S)-1,2,3-trimethoxy-10-methylthio-9-oxo-5,6,7,9-tetrahydro-benzene and [a] Preparation of hepten-7-yl]-nicotinamide

[0177]

[0178] 6-Hydroxymethyl-nicotinic acid was synthesized according to the method described in (Bioorg. Med. Chem. Lett, 1996, 6, 3025-3028).

[0179] EDCI (308 mg, 1.60 mmol) was added to 7-amino-1,2,3-trimethoxy-10-methylthio-6,7-dihydro-5H-benzo[a]-heptanyl at 0 °C Capten-9-one (300 mg, 0.80 mmol), 6-hydroxymethylnicotinic acid (135 mg, 0.88 mmol) and DMAP (60 mg, 0.48 mmol) were dissolved in a solution of 10 ml of acetonitrile. The reaction mixture was stirred at room temperature for 2 hours. Water was added to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered a...

Embodiment 2～4

[0186] Compounds of Example 2-Example 4 were synthesized in a similar manner to that described in Example 1, and intermediates were prepared by the methods described below.

[0187] Preparation of 5-hydroxymethyl-furan-2-carboxylic acid

[0188] 5-Hydroxymethyl-furan-2-carboxylic acid was synthesized following the method described in (Helv. Chim. Acta, 1926, 9, 1068).

[0189] Preparation of 3-hydroxymethylbenzoic acid

[0190]

[0191] Diethyl isophthalate (9.100 g, 40.95 mmol) was dissolved in tetrahydrofuran (20 mL). Then, lithium borohydride (11.26 ml, 22.52 mmol, 2M solution in tetrahydrofuran) was slowly added dropwise thereto, and the reaction mixture was refluxed for 3 hours. Water was added to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl...

Embodiment 2

[0194] Example 2: 5-Nitrooxymethyl-furan-2-carboxylic acid-[(7S)-1,2,3-trimethoxy-10-methylthio-9-oxo -5,6,7,9-Tetrahydro-benzo[a]heptalten-7-yl]-amide

[0195]

[0196] 1 H NMR (400MHz, CDCl 3 ): δ2.37-2.51(m, 3H), 2.46(s, 3H), 2.61-2.92(m, 1H), 3.74(s, 3H), 3.93(s, 3H), 3.98(s, 3H), 4.82-4.85(m, 1H), 4.85(d, J=13.2Hz, 1H), 4.90(d, J=13.2Hz, 1H), 6.39(s, 1H), 6.58(s, 1H), 6.64(s , 1H), 7.16(d, J=10.6Hz, 1H), 7.42(d, J=10.2Hz, 1H), 7.72(s, 1H), 8.99(s, 1H)

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PUM

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Abstract

The present invention relates to tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. More precisely, the present invention relates to tricyclic derivatives as colchicine derivatives, pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them. Tricyclic derivatives of the present invention show very powerful cytotoxici ty to cancer cell lines but were much less toxic than colchicine or taxol, confirmed through animal toxicity test. Tricyclic derivatives of the inventi on also decrease the volume and weight of a tumor and have a strong angiogenesi s inhibiting activity in HUVEC cells. Thus, tricyclic derivatives of the prese nt invention can effectively be used as an anticancer agent, anti-proliferation agent and an angiogenesis inhibitor.

Description

technical field [0001] The present invention relates to tricyclic derivatives as shown in the following <Formula 1>, or pharmaceutically acceptable salts thereof, their preparation and pharmaceutical compositions containing them. [0002] <Formula 1> [0003] [0004] (where R 1 , R 2 , R 3 , R 4 and X are as defined in the specification. ) Background technique [0005] Colchicine, a pseudo-alkaloid compound, has an anti-inflammatory effect, which makes it a therapeutic agent for rheumatoid arthritis [Internal Medicine, 86, No. 2, 342-345, 2000]. Colchicine and thiocolchicine derivatives have muscle relaxing and anti-inflammatory functions (USP 5 973204, EP 0870761 A1). Thiocolchicoside has been used to treat skeletal muscle contracture and inflammation. Moreover, in animal experiments, colchicine inhibited the infiltration of monocytes and T cells in transplanted organs, and at the same time inhibited the production of TNF-α, IL-1 and IL-6, and inflam...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/30C07C323/41C07C381/00C07D213/81C07D213/82C07D307/68C07D333/38
CPCC07D307/68C07D213/81C07C2101/08C07C323/41C07D333/38C07C2103/34C07C381/00C07D213/82C07C2601/08C07C2603/34A61P35/00A61P43/00C07C321/22A61K31/095
Inventor 金明华千广宇崔裁源赵宝瑛朴祥佑金光希吴炳奎崔钟熙
Owner JEIL PHARM CO LTD
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