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New derivatives of benzo[a]pyrano[3,2-h]acridin-7-one, a process for their preparation and pharmaceutical compounds containing them

A technology of compounds and medicinal acids, applied in the field of novel benzo[a]pyrano[3, which can solve the problems of low potency, limited bioavailability, low solubility, etc.

Inactive Publication Date: 2006-12-13
LES LAB SERVIER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite having a very broad spectrum of activity, caperine has low potency and moderate activity
Furthermore, the low solubility of this compound limits its bioavailability and its use in pharmaceutical compositions administered by the intravenous route

Method used

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  • New derivatives of benzo[a]pyrano[3,2-h]acridin-7-one, a process for their preparation and pharmaceutical compounds containing them
  • New derivatives of benzo[a]pyrano[3,2-h]acridin-7-one, a process for their preparation and pharmaceutical compounds containing them
  • New derivatives of benzo[a]pyrano[3,2-h]acridin-7-one, a process for their preparation and pharmaceutical compounds containing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0356] Example 1: 6-Hydroxy-3,3-dimethyl-3,14-dihydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one

[0357] 732 mg of the compound of Preparation 2 was dissolved in 20 ml of anhydrous dimethylformamide, and then 732 mg of anhydrous potassium carbonate was added. The mixture thus obtained was stirred under argon at 65° C. for 15 minutes, then 876.5 mg of anhydrous potassium iodide and 2.47 g of 3-chloro-3-methyl-1-butyne were added. At the end of 5 hours, the reaction mixture was heated at 130° C. for 2 hours to rearrange the propargyl ether. Then, the reaction mixture was diluted with 50ml of water and extracted with dichloromethane (3 x 40ml). The combined organic phases were washed with water and then with 1M potassium hydroxide solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. By silica gel chromatography (cyclohexane followed by a gradient of 1-5% acetone / cyclohexane), 326 mg of the desired product could be isolated.

[0...

Embodiment 2

[0359] Example 2: 6-Hydroxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one

[0360] 1.324 g of sodium carbonate were added to 411.6 mg of the compound of Example 1 dissolved in 50 ml of dry acetone. The mixture was kept under argon atmosphere at 0° C. for 15 minutes with stirring, then after the addition of 852 mg of methyl iodide, the reaction mixture was heated to reflux for 2 hours. After cooling, excess methyl iodide was destroyed by adding 40 ml methanol and 50 ml water. Methanol was distilled off and the aqueous phase was extracted with dichloromethane (3 x 30ml). The combined organic phases were washed with 10% aqueous NaOH, then water, dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. By chromatography on silica gel (cyclohexane followed by a gradient of 0.5-5% acetone / cyclohexane), 374.2 mg of the desired product were isolated.

[0361] Mass spectrometry (DIC / NH 3 ): m / z=358(M+H) +

Embodiment 3

[0362] Example 3: 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one

[0363] A solution of 604.3 mg of the compound of Example 2 in 40 ml of anhydrous acetone was gradually added to a suspension of 61 mg of sodium hydride in 10 ml of acetone maintained at 0°C under an argon atmosphere. The mixture thus obtained was kept at 0° C. for 30 minutes, and then 1.2 g of methyl iodide were added. The reaction mixture was heated to reflux for 6 hours. After cooling, excess methyl iodide was destroyed by adding 40 ml methanol and 50 ml water. Methanol was distilled off and the aqueous phase was extracted with dichloromethane (3 x 30ml). The combined organic phases were washed with 10% aqueous NaOH, then water, dried over anhydrous sodium sulfate, then filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (cyclohexane followed by a gradient of 1-10% acetone / cyclohexane) yielded 469.5 mg of the desired product.

[0364] Mass...

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Abstract

A compound selected from those of formula (I): wherein: X and Y represent a group selected from hydrogen, halogen, hydroxy, alkoxy, nitro, cyano, alkyl, trihaloalkyl and NRaRb, wherein Ra and Rb are as defined in the description R1 represents hydrogen or alkyl R2 represents a group selected from hydrogen, alkyl, -OR'a, -NR'aR'b, -Ta-a'a, -N'a-Ta-NR'aR'b, -N'a-C(O)-TaH, -O-C(O) TaH, Ta-NR'aR'b, -NR'a-Ta-OR'a, -NR'a-Ta-CO2R'a and -N'a-C(O)-Ta-NR'aR'b, wherein R'a, R'a, R'b and Ta are as defined in the description R3 and R4 represent hydrogen or alkyl A represents a group of formula -CH(R5)CH(R6), -CH=C(R7)-, -C(R7)=CH-, -C(O)CH(R8) or -CH(R8)-C(O), wherein R5, R6, R7 and R8 are as defined in the description its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

Description

technical field [0001] The present invention relates to novel benzo[a]pyrano[3,2-h]acridin-7-one compounds, processes for their preparation and pharmaceutical compositions containing them. Background technique [0002] The compounds of the present invention are derivatives of caperine, an alkaloid which has been shown to have anticancer properties in experimental models (J.Pharm.Sci., 1966, 55 (8), 758-768). However, despite having a very broad spectrum of activity, caperine has low potency and moderate activity. Furthermore, the compound has low solubility, which limits its bioavailability and its use in pharmaceutical compositions administered by the intravenous route. [0003] Various modifications have been made to this molecule, such as those described in J. Med. Chem., 1996, 39, 4762-4766 or EP 1042326, which lead to marked improvements in the potency, anticancer efficacy and solubility of the product. However, the demands of anticancer therapy require the continuou...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/052C07D491/147C07D491/153A61K31/4741A61P35/00C07D491/048C07D491/04C07D491/14
CPCC07D491/14C07D491/04A61P35/00A61P35/04C07D491/052
Inventor M·科克F·蒂勒奎S·米歇尔J·希克曼A·皮埃尔S·莱昂斯B·普法伊费尔P·雷纳德
Owner LES LAB SERVIER