EP0555347A1 - INDOLIZINO 1,2-b]QUINOLINONES SUBSTITUEES - Google Patents

INDOLIZINO 1,2-b]QUINOLINONES SUBSTITUEES

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Publication number
EP0555347A1
EP0555347A1 EP91920258A EP91920258A EP0555347A1 EP 0555347 A1 EP0555347 A1 EP 0555347A1 EP 91920258 A EP91920258 A EP 91920258A EP 91920258 A EP91920258 A EP 91920258A EP 0555347 A1 EP0555347 A1 EP 0555347A1
Authority
EP
European Patent Office
Prior art keywords
compound
llff
quinolin
lower alkyl
indolizino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP91920258A
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German (de)
English (en)
Other versions
EP0555347A4 (en
Inventor
Hameed Sheik Allaudeen
David Alan Berges
Robert Philip Hertzberg
Randall Keith Johnson
William Dennis Kingsbury
Stephen Robert Petteway, Jr.
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication date
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Publication of EP0555347A1 publication Critical patent/EP0555347A1/fr
Publication of EP0555347A4 publication Critical patent/EP0555347A4/en
Ceased legal-status Critical Current

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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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • This invention relates to methods of treating viral infections, antiviral compounds, and pharmaceutical compositions thereof. More specifically, this invention relates to a method of treating viral infections, certain indolizino [1,2-Jb]-quinolinyl derivatives which have antiviral activity and pharmaceutical compositions thereof. Background
  • Camptothecin is an example of such compounds. It is a water-insoluble, cytotoxic alkaloid produced by Camptotheca acuminata trees indigenous to China and Nothapodytes foetida trees indigenous to India. Camptothecin and a few close congeners are the only class of compounds known to inhibit eukaryotic topoisomerase I . In fact, the cytotoxic and antitumor activity of camptothecin and its close congeners results from inhibition of eukaryotic topoisomerase I ( Cancer Res .
  • camptothecin possesses antiviral activity.
  • camptothecin and its close analogs that have an E-ring hydroxylactone moiety cannot be considered as useful in vivo antiviral agents because they undesirably inhibit mammalian topoisomerase I, as well as host cell DNA replication, and are cytotoxic to mammalian cells.
  • camptothecin is not an attractive candidate for drug development as an antiviral agent because of unacceptable dose-limiting toxicity, unpredictable toxicity, and poor aqueous solubility, and/or unacceptable shelf life stability.
  • One aspect of the present invention provides a method for treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier
  • R 11 is -H, -CN, or -OR
  • R 12 is -H or lower alkyl
  • R 13 is lower alkyl
  • R and R 1 are independently selected from the group consisting of -H, -C1-6 alkyl, and, when R and R 1 are substituted on nitrogen, R and R 1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;
  • X is -H, -OH, -CN, -SOR, -CH (OH) CH (OH) CH3 , -CHR 3 R 4 ,
  • R 2 is -H, -C(0)H, -C(0)Ci-5alkyl, -C(0) Ci-4alkylCOOH or -C(0)C ⁇ -4alkylNRR 1 ;
  • R 3 is -OH, halo, or -NH2;
  • R 4 is -H, lower alkyl, or -OR
  • This invention also provides compounds having the formula of Formula I as described hereinabove, except that: a) when R 7 , R 9 , R 10 , and R 11 are all -H and Y is -CH3, then X is not -H, -C(0)H, -CH2OH, -CH(0H)CH(0H)CH3, -C(0)CH2CH3, or -CH(OH)CH2CH3; b) when R 7 , R 9 , R 10 and R 11 are all -H and Y is -CH2 ⁇ C(0)H, then X is not -C(0)CH2CH3; c) when R 7 , R 9 , R 10 , R 11 , and Y are all -H, then X is not -CH2OH, -C(0)H, -CH2Br, -OH, or -H; and d) when R 7 is -OCH3, then X and Y are not -H.
  • compositions comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier or excipient.
  • present invention relates to processes for making a compound of Formula I.
  • Aliphatic is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination.
  • the phrase “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form.
  • Lower alkoxy means the group lower alkyl-O-.
  • Halo means fluoro, chloro, bromo or iodo.
  • Acyl means the radical having a terminal carbonyl carbon.
  • 5-7 membered saturated heterocyclic ring containing the nitrogen is intended to include saturated rings such as piperidine, pyrrolidine, morpholine, piperazine, and N-alkyl piperazine.
  • Salts of any sort may be made from these compounds, provided that an acidic group or a sufficiently basic nitrogen in the acid or base.
  • Particularly preferred are the pharmaceutically acceptable salts of the instant compounds. These salts are defined as those which are acceptable in their application to a pharmaceutical use, meaning that the salt will retain the biological activity of the parent compound and that the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound, in a suitable solvent, is reacted with an excess of an organic or inorganic acid in the case of acid addition salts of a base moiety; or an excess of organic or inorganic base in the case where the parent contains an acid group.
  • acids are hydrochloric acid, hydrobromic acid, suifuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid and methanesulfonic acid.
  • Cationic salts are readily prepared from alkali metals such as sodium, potassium, calcium, magnesium, zinc, copper or the like as well as ammonia.
  • Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, and the like.
  • the chemical nomenclature used throughout this patent application to name the compounds of the present invention is in accordance with the structural formula represented as Formula II.
  • the present invention includes the racemic mixture, the pure enantiomers, and any enantiomerically enriched mixture thereof.
  • the present invention provides a method of treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I as described hereinabove, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier or excipient.
  • the present method is useful for treating viral infections in animals and plants caused by a broad variety of viruses.
  • the present method is particularly useful in treating viral infections caused by herpes simplex virus, particularly herpes simplex virus type 1 (HSVl) and herpes simplex virus type 2 (HSV2) , or cytomegalovirus when the infected host is a mammal, particularly when the infected host is human.
  • herpes simplex virus particularly herpes simplex virus type 1 (HSVl) and herpes simplex virus type 2 (HSV2)
  • cytomegalovirus when the infected host is a mammal, particularly when the infected host is human.
  • a preferred method of treating viral infections according to the present invention uses compounds of Formula IMl
  • Formula IM2 corresponding to Formula I wherein R 7 , R 9 , and R 1 are each H, R 1 ⁇ is as defined hereinabove for Formula I except that R 1 ⁇ is not -H, and X and Y are as defined hereinabove in Formula I.
  • a more preferred method uses compounds of Formula IM2 where R 1 ⁇ is -OR, -CN, COR 12 , or -(CH2) n CH2V, X is -CHR 3 R 4 where R 3 is -OH and R 4 is -H or
  • R 9 and R 1 ⁇ are as defined hereinabove for Fomula I except that R 9 and R 1( ⁇ are each not -H, and X and Y are as defined hereinabove in Formula I.
  • a more preferred method uses compounds of Formula IM3 wherein R 9 is - (CH2)n H2V, R 10 is -OR, X is CHR 3 R 4 where R 3 is -OH and R 4 is -H or
  • Another preferred method of use according to the present invention uses compounds of Formula IM4
  • Formula IM4 corresponding to Formula I wherein R 9 , R 1( ⁇ and R 11 are each -H, R 7 is as defined hereinabove except that R 7 is not -H, and X and Y are as defined hereinabove in Formula I .
  • a more preferred method uses compounds of Formula IM4 where R 7 is lower alkyl, -CN, -(CH2) n H2V or -NHCH2Ar, X is CHR 3 R 4 where R 3 is -OH and R 4 is -H or
  • R 9 is as defined hereinabove for Fomula I except that R 9 is not -H, and X and Y are as defined hereinabove in Formula I .
  • a more preferred method uses compounds of Formula IM5 where R 9 is -OR, X is CHR 3 R 4 where R 3 is -OH
  • Still another preferred method of use according to the present invention uses compounds is represented by Formula IM6
  • Formula IM6 corresponding to Formula I wherein R 7 , R 9 and R ⁇ O are each H, R 11 is -CN or -OR, and X and Y are as defined hereinabove in Formula I.
  • a more preferred method uses compounds of Formula IM6 where R 11 is -OCH3, X is CHR 3 R 4 where R 3 is -OH and R 4 is -H or lower alkyl, or
  • the present invention also provides compounds having antiviral activity, and pharmaceutically acceptable salts thereof, said compound having the structure represented by Formula I hereinabove except that: a) when R 7 , R 9 , R 10 , and R 11 are all -H and Y is -CH3, then X is not -H, -C(0)H, -CH2OH,
  • Prefered compounds of the present invention include those of Formula INI
  • R 11 are -H
  • Formula IN2 corresponding to Formula I wherein R 7 , R 9 and R 11 are each -H, R 1 ⁇ is as described hereinabove for Formula I except that R 1 ⁇ is not -H, and X and Y are as defined hereinabove for Formula I . More preferred compounds of Formula IN2 include those where R 1 ⁇ is -OR,
  • Another preferred group of compounds of the present invention are the compounds of Formula IN3
  • Formula IN3 corresponding to Formula I wherein R 7 and R 11 are each -H, R 9 and R 1 ⁇ are as described hereinabove for Formula I except that R 9 and R 1 ⁇ are not -H, and X and Y are as defined hereinabove for Formula I .
  • More preferred compounds of Formula IN3 include those where R 9 is -(CH2) n CH2V, R 10 is -OR, X is CHR 3 R 4 where R 3 is -OH and - R5
  • Still another preferred group of inventive compounds are the compounds of Formula IN4
  • Formula IN4 corresponding to Formula I wherein R 9 , R 1 ⁇ and R 11 are each -H, R 7 is as described hereinabove for Formula I except that R 7 is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN4 include those compounds where R 7 is lower alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar, X is CHR 3 R 4
  • Another preferred group of compounds according to the present invention are the compounds of Formula IN5,
  • Formula IN5 corresponding to Formula I wherein R 7 , R 1 ⁇ and R 11 are each -H, R 9 is as described hereinabove for Formula I except that R 9 is not -H, and X and Y are as defined hereinabove for Formula I .
  • Formula IN6 corresponding to Formula I wherein R 7 , R 9 and R 10 are each -H, R 11 is -CN or -OR, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN6 are compounds where R 11 is -OCH3, X is CHR 3 R 4 where R 3 is -OH and R 4 is -H or lower alkyl,
  • the compounds of the present invention can be prepared by several means from known starting materials or by adding the appropriate substituent to the starting materials used in published synthetic methods for making camptothecin.
  • the preferred synthetic methods for preparing the inventive compounds are outlined in the following reaction flow charts.
  • the inventive compounds are prepared by opening the E ring of camptothecin or a camptothecin derivative which may have the desired R 7 - R 11 substituent to obtain an 8-methyl-7- (1-oxopropyl) indolizino [1,2- i>]quinolin-9 (11H)-one.
  • the E ring may be opened and then the R 7 - R 11 substituents introduced.
  • an existing R 7 - R 11 group is modified to obtain the desired compound.
  • the resulting X and Y groups may be further modified as needed to make the subject compounds.
  • Starting materials are commercially available or can be made by published methods.
  • Camptothecin, 10- hydroxycamptothecin and 9-hydroxy-camptothecin are natural products . Camptothecin and 10-hydroxycamptothecin are available from sources in the People's Republic of China.
  • a 9-hydroxy camptothecin compound which can be used as starting material for making some of the inventive compounds is described in Published Japanese Patent Application No. 59-51,289.
  • the synthesis of 9- nitrocamptothecin is described by Wall, et al. J. Med. Chem. 1986, 29, 2358.
  • a total synthesis of camptothecin is described by Wall, et al. , J. Med. Chem . 1980, 23, 554. The 1980 Wall, et al.
  • synthesis can be used as a means to introduce one or more R 7 - R 11 substituents into the compounds of Formula I. This involves modifying the Wall synthesis at the appropriate step in a manner which puts in place the desired substituent, then continuing with the described synthesis .
  • Compounds of formula 1 are converted to compounds of formula 2 by heating the compounds in a high boiling, preferably unreactive, solvent such as N,N- dimethylformamide or triglyme (triethylene glycol dimethyl ether) .
  • a high boiling, preferably unreactive, solvent such as N,N- dimethylformamide or triglyme (triethylene glycol dimethyl ether) .
  • the keto group of compounds of formula 2 can be reduced to give the corresponding hydroxy compounds 3 from which the halo compounds 4 can be derived.
  • the keto group also can be converted to an oxime (compounds 5) which can in turn be reduced to give the primary amino compounds 6.
  • the keto group also can be converted to a ketal group such as a 1, 3-dioxolane (compounds 7, which are useful intermediates for further transformations) .
  • the hydroxyl group of compounds 3 can also be acylated to produce esters (8) and carbamates (9) wherein R indicates an alkyl group while R'
  • camptothecins are also derived from camptothecins which are formed by hydrogenolytic cleavage of the lactone ring as shown in Scheme 4.
  • Some ring substituents may be labile to the conditions used in the preferred method of making compounds 2 as given in Scheme 1.
  • the sequence set out in Scheme 5 can provide access to certain of those compounds or provide intermediates for making other compounds .
  • keto group of compounds 16 is first protected as a ketal (17) , and then the pyridine ring is reduced to give compounds 18, for example with sodium cyanoborohydride in an acidic solvent such as acetic acid. Finally, oxidation of compounds 18, for example by iodobenzene diacetate, gives the 2-hydroxy ketals 19 which along with the keto compounds 20 derived from the ketals by acid hydrolysis can be used to make compounds with other substituents as illustrated in Scheme 6.
  • the compounds in Scheme 6 are prepared either by alkylation (compounds 21) or acylation (compounds 22, 23, and 24) of the 2-hydroxy ketones 20 or by replacement of the 2-hydroxy group in the ketals (19) via the triflates (25) .
  • Cyanation of the triflates following the method of Kosugi, M, et al, Chem. Lett . 1981, 69 gives compounds 26 which are hydrolyzed to compounds 27.
  • Catalytic hydrogenation of the cyano group of compounds 26 gives aminomethyl ketals 28 which upon hydrolysis gives the ketones 29.
  • a carbonyl group can be introduced onto the ring, for example by the procedure of Cacchi, S, et al, Tetrahedron Lett . 1986, 27, 3931. If an amine or alcohol is used, the corresponding amides (30) or esters (32) are obtained which are then hydrolyzed to the respective keto compounds 31 and 33. Reduction of the esters 32 with a hydride gives the primary alcohols 34 which upon hydrolysis produce the keto alcohols 35 which can be acylated to give carboxylates, carbonates and carbamates by methods similar to those used for preparing compounds 22, 23, and 24.
  • Aldehydes (compounds 36) can be made by oxidizing the alcohols 34 using a mild oxidant which gives the aldehyde in preference to the acid (for example, Mn ⁇ 2 ) . Deprotection gives the keto aldehydes 37.
  • the triflates are converted to vinyl ethers 38 following the method of Cabri, W., et al. (J. Org. Chem . 1990, 55, 3654) , and then compounds 38 are hydrolyzed to diketones 39.
  • Selective hydrolysis of the enol ether function in compounds 38 produces the 2-keto compounds that can be reduced to secondary alcohols from which the ketal groups can be removed and the alcohol function acylated to give carboxylates, carbonates and carbamates as described for compounds 20 and 35.
  • amines can be alkylated (42) , sulfonylated (44) , or acylated (46) by known means and then deprotected to compounds 43, 45, and 47, respectively.
  • Halogenation of compounds 19 is accomplished by standard means to produce 1-halo ketals 48 which are cleaved to the corresponding ketones 49.
  • Cyano ketals 50 are prepared using the iodides (48) in the cyanation reaction described for the synthesis of compounds 26. Cleavage of compounds 50 gives compounds 51, or alternatively, the hydroxy function can be removed from 50 by converting the compounds to the corresponding triflates 52 and then reducing them to compounds 53 by the method of Cacchi, S. et al. , Tetrahedron Lett . 1986, 27, 5541. Hydrolysis of ketals 53 gives ketones 54.
  • the hydroxy compounds 57 are made as described by Sugasawa, T., et al. , Chem . Pharm. Bull . 1974, 22, 111 .
  • the triflates (58) are prepared in the usual manner. Reduction to compounds 59 is carried out by the same method used for compounds 52. Cyanation of the triflates to give compounds 60 uses the method employed to prepare compounds 26. Alkoxyvinylation of the triflates to give compounds 61 is carried out as in the preparation of compounds 38; acid hydrolysis of the vinyl ethers gives the ketones 62 which upon reaction with diazomethane by the method of Kametani, T., et al.
  • 12-Hydroxymethyl compounds 75 are prepared by the method of Miyaska, T. et al. (Heterocycles 1981, 16, 1713) using ferrous sulfate, hydrogen peroxide and methanol with suifuric acid. These alcohols are acylated as described for compounds 20 and 35 to produce carboxylates, carbonates and carbamates.
  • 12- alkyl compounds 77 are prepared by the method of Miyasaka, T. et al. (US patent 4,399,282) .
  • the chloro substituent of compounds 80 can be replaced with an iodo group (85) by heating with potassium iodide in acetic acid containing some acetic anhydride.
  • iodo derivatives are easily used in various coupling reactions similar to those carried out with triflates 25 and 58. Cyanation gives compounds 86 which are deblocked to ketones 87 or are reduced to aminomethyl compounds 88 which give ketones 89 upon hydrolysis . Likewise, propynylamines 90 can be produced and then deprotected to compounds 91 or catalytically hydrogenated to compounds 92 and 94 which are hydrolyzed to keto compounds 93 and 95, respectively. Heating compounds 85 with sodium acetate in acetic acid gives the 12-hydroxy compounds 96 which can be alkylated using either base and alkyl halides or diazoalkanes to give 12- alkoxy compounds 97 which upon deprotection afford ketones 98.
  • the 12-hydroxymethyl compounds 76 can be protected and then activated for displacement reactions by conversion to a sulfonate (99), for example, a mesylate. Cyanide displacement on compounds 99 gives the ketals 100 which upon hydrolysis give 12-cyanomethyl ketones 101. The cyano ketals can also be reduced to aminoethyl compounds 102 that give ketones 103 after hydrolysis . Treatment of sulfonates 99 with alcohols in the presence of bases gives ethers 104 which can be converted to keto ethers 105. The reactions illustrated in Scheme 9 for the 12- hydroxymethyl compounds 76 could likewise be applied to hydroxymethyl compounds 34 to produce derivatives corresponding to compounds 99 through 105.
  • the compounds of the present invention exhibit antiviral activity and are generally useful in treating a wide variety virus infections in both plants and animals . These compounds are particularly useful in treating DNA replicating animal virus infections, more particularly those caused by herpes simplex virus (HSV) . More specifically, these compounds are useful in treating infections caused by the following human pathogens :
  • Herpes Simplex virus types 1 and 2 Cytomegalovirus; Varicella Zoster virus; Epstein Barr virus; and Papilloma virus (multiple types) . Infections caused by the following animal pathogens may also be treated with the present compounds:
  • Equine Herpes virus Porcine Herpes virus
  • Marek's disease virus Marek's disease virus
  • the assay used to test the compounds of the present invention for antiviral activity was taken from the literature and was modified in well-known ways to adapt it to currently available technology. A generalized description of the assay follows. Ass y procedure
  • Well plates were seeded with the appropriate cells at a concentration of 1x10 s cells per well suspended in 0.5 mL of Earle's Minimum Essential Medium (EMEM) containing 10% fetal bovine serum (FBS) and antibiotic and antimycotic solution. After cells were 80-90% confluent (24 hours), old medium was removed and washed with Hank's buffered saline solution (HBSS) . Cells were then infected for 1 hour at 37°C with 100-200 plaque forming units per well of a herpes simplex virus suspended in 250 ⁇ L HBSS. Following adsorption, the following were added:
  • EMEM Earle's Minimum Essential Medium
  • FBS fetal bovine serum
  • HBSS Hank's buffered saline solution
  • This procedure can be used to test compound efficacy against many viruses, besides herpes simplex by simply modifying the cell type used in the first step to match the virus being tested and following the procedure outlined above.
  • Other cell types which could be used in this assay include mouse mammary tumor cells, human lung fibroblasts, sheep chorioplexus cells, and green monkey kidney cells.
  • assays which are useful for determining the antiviral activity of the present compounds include the following types: cell count, clonogenic, cytopathic effect, dish-colony formation, microtiter-growth inhibition, thymidine incorporation and yield reduction. Each of these well-known assays is in the literature and selected assays are available commercially. Pharmaceutical Compositions and Method of Treatment.
  • compositions prepared from compounds of the persent invention.
  • Such compositions have utility for human and veterinary antiviral use, and for treating viral infections in plants, e.g., agricultural or ornamental seeds and plants .
  • Such compositions comprise a carrier which is acceptable for the intended end use together with at least one inventive compound.
  • the carrier may be a liquid, or spray, or may be formulated in a solid, non-degradeable or degradeable form for insertion in the rumen.
  • the compound can be mixed with a fertilizer, other microbiocides such as fungicides, or insecticides and the like.
  • the present compounds may also be formulated in powders or sprays for application to plant surfaces .
  • compositions of this invention comprise one or more compounds of the present invention in admixture with an inert pharmaceutically acceptable carrier or diluent.
  • Compositions may contain an effective amount of the inventive compound in one unit, such as in a single pill, capsule, or pre-measured intravenous dose or pre-filled syringe for injection, or, as is frequently the case, the composition may be prepared in individual dose forms where one unit, such as a pill, contains a sub-optimal dose with the user being instructed to take two or more unit doses per treatment.
  • the composition is presented as a cream, it contains a discrete amount of drug and the user applies an effective amount of the cream one or more times until the disease is in remission or has been effectively treated.
  • Concentrates for later dilution by the end user may also be prepared, for instance for IV formulations and multi-dose injectable formulations.
  • Carriers or diluents contemplated for use in these compositions are generally known in the pharmaceutical formulary arts. Reference to useful materials can be found in well known compilations such as Remin ⁇ ton' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA,
  • compositions and the pharmaceutically acceptable carrier or diluent will, of course, depend upon the intended route of administration, for example, by intravenous and intramuscular injection, parenterally, topically, orally, or by inhalation.
  • parenteral administration the pharmaceutical composition may be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • topical administration the pharmaceutical composition may be in the form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for administration to the skin, eye, ear, nose or genitalia.
  • pharmaceutical composition may be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • the pharmaceutically acceptable carrier employed may be either a solid or liquid.
  • solid carriers are lactose, kaolin, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, mannitol, stearic acid and the like.
  • liquid carriers or diluents examples include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water.
  • pharmaceutically acceptable carriers include dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the carrier or diluent may include time delay materials well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • a pharmaceutically acceptable salt of a compound of the present invention is dissolved in an aqueous solution of an organic or inorganic acid or base.
  • the inventive compound may be dissolved in a suitable co-solvent or combinations thereof.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • the actual preferred dosages of the compounds of the present invention used in the pharmaceutical and other compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated.
  • These compounds are active in the concentration ranges of two commercial antiviral drugs, Cytovene (ganciclovir) and Zovirax (acyclovir) .
  • Cytovene ganciclovir
  • Zovirax acyclovir
  • the latter is manufactured in 200 mg capsules with instructions for treating herpes simplex viruses by taking one capsule every 4 hours, but not to exceed 5 capsules per day.
  • 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.
  • the solid which formed was suspended in Et2 ⁇ , collected by filtration and dried.
  • the solid was purified by column chromatography on basic alumina (deactivated by addition of 15 wt% H2O) , eluting with CH2CI2 •
  • the solid obtained was further purified by radial chromatography on silica gel, eluting with 2% MeOH in CH2CI2 to provide the title compound as a beige solid .
  • Example 5 7- (1-Hvdroxyiminopropvl)-8-methvlindolizino- r1,2- ⁇ >1quinolin-9.llff)-one
  • This salt was dissolved in 10% H2O in MeOH (370 mL) and allowed to stand at room temperature overnight. The yellow-colored solution gradually became colorless, and the solvent was removed in vacuo . The residue was treated with additional 10% H2O in MeOH, and the solid which formed was collected by filtration. The filtrate was concentrated under reduced pressure, and the residue was treated with 10% H2O in MeOH. The solid which formed was collected by filtration.
  • 77 mg (0.30 mmol) osmium tetroxide was added to a suspension of 55 mg (0.19 mmol) of 8-methyl-7- [1 (E)-propenyl] indolizino[1, 2-b]quinolin-9 (llff) -one in 2.0 mL dry pyridine.
  • Ci8Hi6N2 ⁇ 3-l/2 H2O C, 68.13; H, 5.40; N, 8.83. Found:
  • Example 13 7-(?.-F. hvl-1.3-dioxo_an-2-vl)-2-hvdroxv-8- met.hylindolizinori.2-b1 ⁇ uinolin-9 (llff) -one
  • Hydrogen chloride gas was bubbled into a suspension of 15.0 g (49 mmol) 8-methyl-7- (1- oxopropyl) indolizino[1,2-b]quinolin-9 (llff)-one in 150 mL ethylene glycol (exothermic) and gradual dissolution of the solid.
  • the solution had become saturated with hydrogen chloride, it was warmed on a steambath for 40 minutes and then allowed to cool to room temperature. After standing overnight, the viscous solution was poured into a 1 L mixture of ice and concentrated ammonium hydroxide to produce a tan colored solid. This mixture was extracted three times with 1 L CH2CI2 .
  • Example 17 8-Methyl-7- (1-oxopropyl) indolizinoTl.2-blquinolin-9 (llff)- on-2-vl ri.4'-bipiperidine1-l'-carboxvlate.
  • Example 19 1- (Dimethvlamino)methvl-2-hvdrox ⁇ -8-meth ⁇ l-7- (1- oxopropyl) indolizino ri,2-bl ⁇ uinolin-9 (llff) -one.
  • the filtrate was purified by reversed phase chromatography (Whatman 40 ⁇ M ODS-3 support) , eluting with a solvent gradient of 0-15% MeOH in H2O to provide 2-aminomethyl-7- (2-ethyl-l,3-dioxolan-2-yl) -8-methylindolizino[1,2- b]quinolin-9 (llff) -one, hydroacetate as a pale yellow solid.
  • acetic acid (2 mL) and 2 N HCl (0.30 mL, 0.6 mmol)
  • the resulting mixture was heated at 70°C under an argon atmosphere. After heating for 3 hours, the reaction mixture was concentrated under reduced pressure.
  • Example 22 2-Acet ⁇ l-8-methyl-7- (1-oxopropyl) indolizinoQ.2- blquinolin-9 (llff)-one
  • 7- (2-ethyl-l,3-dioxolan-2-yl)-8- methyl-2-trifluoromethylsulfonyloxyindolizino[1,2- b]quinolin-9 (llff) -one 40 mg, 0.08 mmol
  • anhydrous DMF 0.4 mL
  • argon atmosphere were added successively triethylamine (31 mL, 0.22 mmol), n-butyl vinyl ether (71 mL, 0.55 mmol), 1,3-bis (diphenylphosphino)propane (1.4 mg, 3.4 mmol) and palladium acetate (0.6 mg, 2.7 mmol) .
  • the reaction mixture was dissolved in CH2CI2 containing a small amount of MeOH and purified by radial chromatography on silica gel eluting with a solvent gradient of 0-5% MeOH in CH2CI2.
  • the material which was isolated was further purified by recrystallization from MeOH in CH2CI2 to afford the title compound , mp 232-7°C.
  • Example 33 7-Cvanoindolizino r1.2-bl ⁇ uinolin-9 (llff)-one
  • the reaction mixture which became homogeneous during this time, was allowed to cool, and 7-trifluoro- methanesulfonyloxyindolizino[1,2-b]quinolin-9 (llff)-one
  • Example 37 7-Acetyl-8-methylindolizino .1,2-blquinolin-9 (llff) -one
  • a solution of 7-acetylindolizino[1,2-b]quinolin- 9 (llff)-one 64 mg, 0.23 mmol
  • 5:1 CHCl3/MeOH (18 mL) at 0°C was added dropwise a solution of diazomethane in Et2 ⁇ (10 mL) .
  • the resulting mixture was stirred at 0°C for 0.5 h and then allowed to slowly warm to room temperature and stir overnight.
  • the excess diazomethane was destroyed by the addition of acetic acid, and the mixture was concentrated under reduced pressure.
  • Example 38 7- T3- (Dimethylamino)-1-propyn-l-vll indolizino ri.2- blquinolin-9 (llff)-one
  • 7- trifluoromethanesulfonyloxy-indolizino[1,2-b]quinolin- 9 (llff)-one (191 mg, 0.5 mmol), triethylamine (0.3 mL, 2.2 mmol) and 90% N,iV-dimethylpropargylamine (82 mL, 0.7 mmol) in anhydrous DMF (1.5 mL) under an argon atmosphere was added bis (triphenylphosphine)palladium(II) chloride (10 mg, 14 mmol) .

Abstract

Procédé de traitement d'infections virales à l'aide de composés antiviraux d'indolizino[1,2-b]quinolinones substituées, de certains composés nouveaux d'indolizino[1,2-b]quinolinones substituées présentant une activité antivirale, et de compositions pharmaceutiques desdits composés.
EP91920258A 1990-10-31 1991-10-30 Substituted indolizino 1,2-b)quinolinones Ceased EP0555347A4 (en)

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US606216 1990-10-31
US78306391A 1991-10-25 1991-10-25
US783063 1991-10-25

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US5883255A (en) * 1990-10-31 1999-03-16 Smithkline Beecham Corporation Substituted indolizino 1,2-b!quinolinones
JPH07506099A (ja) * 1992-04-17 1995-07-06 スミスクライン・ビーチャム・コーポレイション 置換インドリジノ［１，２−ｂ］キノリノン
JPH08509742A (ja) * 1993-05-03 1996-10-15 スミスクライン・ビーチャム・コーポレイション 置換メチレンジオキシ［３’，４’：６，７］インドリジノ［１，２−ｂ］キノリノン
US5491237A (en) * 1994-05-03 1996-02-13 Glaxo Wellcome Inc. Intermediates in pharmaceutical camptothecin preparation
ATE275132T1 (de) * 1995-06-27 2004-09-15 Takeda Chemical Industries Ltd 4-acylamino(halogen)alkyl-chinolin derivate, deren herstellung und deren verwendung als melatonin-agonisten
ES2247606T3 (es) 1995-11-02 2006-03-01 Osi Pharmaceuticals, Inc. Metodo para preparar derivados de camptotecina.
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
JP3046258B2 (ja) * 1997-04-11 2000-05-29 株式会社ヤクルト本社 １−クロロカルボニル−４−ピペリジノピペリジンまたはその塩酸塩の製造方法
US7482366B2 (en) 2001-12-21 2009-01-27 X-Ceptor Therapeutics, Inc. Modulators of LXR
CA2469435A1 (fr) 2001-12-21 2003-07-24 X-Ceptor Therapeutics, Inc. Modulateurs de lxr
AU2003225642A1 (en) * 2002-03-01 2003-09-16 Fluorous Techonologies Inc Mappicine analogs, intermediates in the synthesis of mappicine analogs and methods of synthesis of mappicine analogs
US7064202B1 (en) * 2003-05-12 2006-06-20 University Of Kentucky Research Foundation Camptothecin intermediates and prodrugs and methods of preparation thereof
US20050267141A1 (en) 2004-05-28 2005-12-01 Phytogen Life Sciences Inc. Process to prepare camptothecin derivatives
US20050272757A1 (en) * 2004-06-04 2005-12-08 Phytogen Life Sciences Inc. Process to prepare camptothecin derivatives and novel intermediate and compounds thereof
WO2006019955A2 (fr) * 2004-07-14 2006-02-23 President And Fellows Of Harvard College Methodes et compositions antivirales
US9888690B2 (en) 2011-06-22 2018-02-13 Council Of Scientific & Industrial Research Insecticidal compounds from Nothapodites foetida and process for the extraction thereof
KR101721029B1 (ko) 2014-10-16 2017-03-29 연세대학교 산학협력단 인돌리지노[3,2-c]퀴놀린 유도체, 이의 약제학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 낭포성 섬유증 예방 또는 치료용 약학조성물
WO2017014601A1 (fr) * 2015-07-23 2017-01-26 서울대학교 산학협력단 Sonde de fluorescence à base d'indolizino [3,2-c] quinoline
KR101850607B1 (ko) 2015-07-23 2018-04-19 서울대학교산학협력단 인돌리지노[3,2-ｃ]퀴놀린계 형광 프로브

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JPH06502642A (ja) 1994-03-24
PT99412A (pt) 1992-10-30
CA2095219A1 (fr) 1992-05-01
KR930702289A (ko) 1993-09-08
AU8940491A (en) 1992-05-26
IE913790A1 (en) 1992-05-22

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