Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems

Definitions

• This invention relates to a method for making certain 8-methyl- 7-( l -oxopropyI)indolizino[ l ,2-b]quinolin-9(l lH)-ones from 4-ethyl- 4-hydroxy- lH-pyrano[3',4':6,7]indolizino[ l ,2-b]quinolin- 3 , 14(4H, 12H)-diones.
• Camptothecin ⁇ 4- ethyI-4-hydroxy- l -pyrano[3',4':6,7]indolizino[l ,2-6]quinolin- 3 , 14(4H, 12H)-dione ⁇ is an example of one such compound. It is a water-insoluble, cytotoxic alkaloid produced by Camptotheca accuminata plants indigenous to China and Nothapodytes foetida plants indigenous to India.
• Camptothecin and a few close congeners thereof are the only class of compounds known to inhibit eukaryotic topoisomerase I. Camptothecin (and its known congeners) have no effect on topoisomerase II and none of the known topoisomerase II inhibitors has any significant effect on topoisomerase I.
• Certain modifications to the camptothecin molecule have produced compounds which have antiviral activity, but are not cytotoxic or have little cytotoxicity. One of these modifications is that of opening the E ring in camptothecin in a way which gives a 8- methyI-7-( l -oxopropyI)indolizino[l ,2-£]quinolin-9( l lH)-one. These compounds and analogs have useful antiviral activity. Such compounds are disclosed in co-pending applications filed on even date herewith .
• This invention provides a method for making certain 8-methyl- 7 -( l -oxopropyl)indoIizino[ l ,2-b]quinolin-9( l l H)-ones. These ketones can be used for preparing other antiviral agents where the indolizino or quinolino portions of these compounds are substituted.
• This invention relates to a method for making a 8-methyl-7-( l - oxopropyl)indol izin o[ 1 ,2-b ] quinolin-9( l l /)-one of formula I, which method comprises heating to about 100 C° or higher a 4-ethyl- 4-hydroxy-lH-pyrano[3',4':6,7]indolizino[l ,2-6]quinolin- 3, 14(4H,12H)-dione of the formula II
• This reaction is useful for making compounds of formula I which is unsubsitituted, or substituted with one or more substituents, represented by the R designation in formula I.
• R substituent if it is other than hydrogen, is not affected during the heating process used to make formula I.
• This efficient process can be carried by heating the compound either neat or in an appropriate solvent.
• Useful temperatures are those at which the reaction proceeds at a reasonable rate and which do not pyrolytically degrade another site on the ring of formula II, or degrades an R substituent. Too low a temperature, while it may cause loss of CO2, will proceed so slowly as to be of no practical use. It is preferred that a temperature in excess of 100°C be used for efficient operation of this reaction. The only limitation on temperature is that operation of this reaction. The only limitation on temperature is that it not be so high as to cause unwanted degradation of the molecule. The most preferred temperature range is between about 150-200°C . Solvents may be used in practicing this invention.
• solvents there is no limitation on what solvents may be used other than it must have a boiling point at or higher than the temperature at which the reaction is to be carried out.
• the solvent itself must be inert with respect to the reaction. In other words, the solvent must not interfer with the reaction in the sense of reacting with the molecule or in som means having an untoward or deleterious affect on the reaction or reactant.
• Two preferred solvents are N,N-dimethylformamide and triethylene glycol dimethyl ether (triglyme).
• Example 1 8-methyI-7-d -oxopropyOindolizinolT .2-fr1quinolin-9Cl lH)-one
• a sample of 4.6 g of 4-ethyl-4-hydroxy-lH-pyrano[3 ⁇ 4':6,7]- indolizino[l ,2-fc]quinolin-3,14(4H,12H)-dione [(20 S) camptothecin] was stirred with 46 ml of N,N-dimethylformamide.
• the suspension was heated at reflux, and the disappearance of starting material was monitored by ⁇ PLC (C18 reverse phase column, 20-25% acetonitrilerwater mobile phase, perchlorate buffer at p ⁇ approximately 3.0).
• the reaction was monitored by UV detection at a wavelength of 228 nm.
• the only responses detected under these conditions were a peak for N,N-dimethylformamide near the solvent front, a peak for the starting material and a peak for the desired product with a retention time of approximately 3.2 relative to the starting material.
• the reaction was heated until consumption of the starting material was complete (approximately 8 days). After cooling to ambient temperature the solid product was collected by filtration, and washed with methanol. After drying under vacuum to a constant weight 3.48 g (87%) of product, m.p. 233-234°C was obtained.
• Example 2 l O-hvdroxy-8 -methyl -7 - ⁇ -oxopropyOi ndolizinor i ,2-b ⁇ - q ⁇ j inolin -9( l H)-on &
• the reaction was monitored by HPLC using the conditions of the preceding example. A relative retention time of approximately 3.05 was obtained for the product versus the starting material.
• the reaction suspension gradually formed a golden yellow solution over about 2.5 hours. After 6.5 hours the starting material was completely consumed.
• the reaction was cooled to ambient temperature with stirring over 17 hours.
• the suspension was diluted with 100 ml of diethyl ether, and after stirring for an additional 2 hours, the solid product was collected by filtration and dried to a constant weight.
• the recovered product m.p.>315°C, weighed 3.35 g (95%).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Inorganic Compounds Of Heavy Metals (AREA)
• Indole Compounds (AREA)

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Publications (1)

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Cited By (1)

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• 1990
  • 1990-09-28 US US07/589,848 patent/US5155225A/en not_active Expired - Fee Related
• 1991
  • 1991-09-23 JP JP3516076A patent/JP2534000B2/ja not_active Expired - Lifetime
  • 1991-09-23 EP EP91917720A patent/EP0550621B1/en not_active Expired - Lifetime
  • 1991-09-23 KR KR1019930700923A patent/KR100192754B1/ko not_active Expired - Fee Related
  • 1991-09-23 AT AT91917720T patent/ATE173261T1/de not_active IP Right Cessation
  • 1991-09-23 ES ES91917720T patent/ES2123517T3/es not_active Expired - Lifetime
  • 1991-09-23 WO PCT/US1991/006869 patent/WO1992006095A1/en not_active Ceased
  • 1991-09-23 DK DK91917720T patent/DK0550621T3/da active
  • 1991-09-23 AU AU86398/91A patent/AU653173B2/en not_active Ceased
  • 1991-09-23 DE DE69130481T patent/DE69130481T2/de not_active Expired - Fee Related
  • 1991-09-23 CA CA002090966A patent/CA2090966A1/en not_active Abandoned
• 1999
  • 1999-02-10 GR GR990400443T patent/GR3029356T3/el unknown

Non-Patent Citations (2)

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