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WO1992003136A1 - Agents antineoplastiques a base de quinobenzoxazine, de quinobenzothiazines et de pyrido-acridine - Google Patents

Agents antineoplastiques a base de quinobenzoxazine, de quinobenzothiazines et de pyrido-acridine Download PDF

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Publication number
WO1992003136A1
WO1992003136A1 PCT/US1991/006040 US9106040W WO9203136A1 WO 1992003136 A1 WO1992003136 A1 WO 1992003136A1 US 9106040 W US9106040 W US 9106040W WO 9203136 A1 WO9203136 A1 WO 9203136A1
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Prior art keywords
oxo
fluoro
carboxylic acid
quino
benzoxazine
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PCT/US1991/006040
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English (en)
Inventor
Daniel T. Chu
Jacob J. Plattner
Robert Hallas
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP91918185A priority Critical patent/EP0608215A1/fr
Publication of WO1992003136A1 publication Critical patent/WO1992003136A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to compounds which have antineoplastic activity. More particularly, this invention concerns quinobenzoxazine, quinobenzothiazine, and pyrido-acridine derivatives that are useful in the treatment of neoplastic diseases, pharmaceutical compositions containing these compounds, and to a method of treating neoplastic diseases with the quinobenzoxazine,
  • R 1 is selected from hydrogen and a carboxy-protecting group.
  • R 2 in Formula I is selected from hydrogen, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, and sulfhydroalkyl of from 1 to 6 carbon atoms.
  • R 3 in Formula I is one or more groups independently selected from the group consisting of hydrogen; halogen; nitro; alkyl of from 1 to 6 carbon atoms; carboxyl; methylenedioxy; cyano; halo-substituted alkyl of from 1 to 6 carbon atoms; hydroxy-substituted alkyl of from 1 to 6 carbon atoms; alkylsulfonyl;
  • methylenedioxy a group of the formula -YR 4 wherein Y is O or S, and R 4 is hydrogen or alkyl of from 1 to 6 carbon atoms; and an amine of the formula -NR 5 R 6 wherein R 5 and R 6 are independently selected from hydrogen or alkyl of from 1 to 6 carbon atoms.
  • W in Formula i is selected from hydrogen, alkoxy, hydroxyl, alkyl of from 1 to 6 carbon atoms, amino, alkyiamino, and halogen, and halo-substituted alkyl.
  • X in Formula I is selected from halogen, hydrogen, alkyl of from 1 to 6 carbon atoms, and halo-substituted alkyl of from 1 to 6 carbon atoms.
  • Z in Formula I is selected from (a) halogen; (b) a pyridyl or substituted pyridyl group; (c) an amino group of the formula -NR 12 R 13 wherein R 12 is hydrogen or alkyl of from 1 to 10 carbon atoms and R 13 is selected from alkyl of from 1 to 10 carbon atoms, hydroxy-substituted alkyl of from 1 to 10 carbon atoms, an amino group, an alkylamino of from 1 to 6 carbon atoms, and dialkylamino of from 1 to 6 carbon atoms; and (d) a nitrogen-containing heterocycle of the formula
  • R7 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 C H2 CH 2 -, -CH 2 CH 2 NHCH 2 -, or a group of the formula -CH 2 R 9 CH 2 - wherein R 9 is selected from S, O, or NH.
  • R 8 in Formula la is 1 or 2 groups independently selected from hydrogen, alkyl of from 1 to 6 carbon atoms, halo-substituted alkyl of from 1 to 6 carbon atoms, amino- substituted alkyl of from 1 to 6 carbon atoms, hydroxy-substituted alkyl of from 1 to 6 carbon atoms, alkylaminoalkyl of from 1 to 6 carbon atoms, hydroxy, alkanoyl of from 1 to 6 carbon atoms, a spirocycloalkyl group and an amine of the formula -NR 10 R 11 .
  • R 10 and R 11 in this instance may be independently selected from hydrogen and alkyl of from 1 to 6 carbon atoms, or, alternatively, one of R 10 and R 11 is hydrogen and the other is an alkanoyl group or a peptidyl group of from 1 to 5 ⁇ -amino acid joined to the nitrogen with an amide linkage.
  • X and Z may be taken together to form -OCH 2 O- or
  • a in Formula I is selected from O, S and CH 2 .
  • novel compounds and pharmaceutical compositions thereof having Formula I wherein R 1 , R 2 , R 3 , A, W, and X are described as above.
  • Z is selected from (a) pyridyl or substituted pyridyl, with the proviso that A is not S, and (b) a nitrogen-containing heterocycle of the formula
  • R 27 is selected from -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • X and Z when taken together may form -OCH 2 CH 2 - or -OCH 2 O-, with the proviso that R 2 may not be hydrogen.
  • R 28 in Formula 1b is selected from hydrogen, halogen, alkyl of from 1 to 6 carbon atoms, halo-substituted alkyl of from 1 to 6 carbon atoms, and spirocycloalkyl of from 5 to 10 carbon atoms.
  • R 30 and R 31 in Formula lb are each independently selected from the group consisting of hydrogen, acetyl, alkyl, an acyl group or an ⁇ -amino acid joined to the nitrogen with an amide linkage, or an acyl group of a polypeptide residue of 1 to 5 amino acids joined to the nitrogen with an amide linkage, with the provisos (a) that when A is O, R 30 and R 31 are each independently selected from a peptidyl group of from 1 to 5 amino acids joined to the nitrogen with an amide linkage, and (b) that both R 30 and R 31 may not be hydrogen at the same time.
  • the pyridyl group at Z described above can be susbtituted or unsubstituted.
  • Suitable substitutents on the pyridine ring include alkyl of from 1 to 6 carbon atoms, halogen, alkanoyl of from 1 to 6 carbon atoms, and alkanoylamido of from 1 to 6 carbon atoms.
  • the present invention relates to compounds which have antineoplastic activity and to a method of treating neoplastic diseases. More particularly, the invention relates to a method of treating neoplastic diseases comprising
  • ⁇ -amino acid refers to a single amino acid.
  • the amino acids can be naturally occurring amino acids such as valine or glycine, or they may be synthetic alpha-amino acids such as cyclohexylalanine.
  • the amino acids can be either in the L or D conf jration or a mixture or the two isomers. If not specified, amino acid substituents are optically active and have the the L configuration.
  • alkanoyl of from 1 to 6 carbon atoms refers to a substituent of formula -C(O)R 19 wherein R 19 is hydrogen or an alkyl group of 1 to 6 carbons, and includes, for example, acetyl.
  • alkoxy refers to an oxygen atom substituted with an alkyl group as defined below. Examples include methoxy, ethoxy and propoxy.
  • alkyl refers to a monovalent radical derived from an aliphatic hydrocarbon of from 1 to 6 carbon atoms by removal of one hydrogen atom.
  • Examples include methyl, ethyl and propyl.
  • alkylamino refers an amino group which may have one to three alkyl substituents, as defined above. Examples include methylamino, ethylamino, dimethylamino and the like.
  • aminoalkyl refers to an amino-substituted alkyl group as defined above. Examples include aminoethyl, aminomethyl and the like.
  • alkylaminoalkyl refers to amino groups substituted with one to three alkyl groups, as defined above, including methylamino, ethylamino and propylamino bonded to a alkyl substituent as defined above, as for example N,N-dimethylaminoethyl.
  • alkylsulfonyl refers to an alkyl group as defined above bonded to a sulfonyl groups, such as ethylsulfonyl or methylsulfonyl.
  • carboxy-protecting group refers to and includes the residue of a carboxylic acid ester group.
  • Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,319,667. In general, such carboxy-protecting groups can be relatively easily to yield the free carboxy group.
  • protecting groups include C 1 -C 8 alkyl (e.g., methyl, ethyl, tertiary, butyl), substituted alkyl (e.g., dimethylaminoethyl), benzyl and substituted derivatives thereof such as alkoxy and nitrobenzyl groups; also suitable are acyl groups such as
  • halogen refers to chloro (Cl), bromo (Br), fluoro (F), and iodo (I) groups.
  • halo-substituted alkyl refers to a alkyl group, as defined above, in which at least one hydrogen atom is replaced with a halogen atom.
  • halo-substituted alkyl of from 1 to 6 carbon atomsjnclude fluoromethyl,
  • hydroxy-substituted alkyl refers to an alkyl group having at least one hydroxyl substituent, as for example hydroxyethyl.
  • neoplastic diseases refers to disorders and disease states characterized by abnormal proliferative cell growth, such as leukemias,
  • Antineoplastic agents are chemical compounds which are effective in the treatment of any one or more neoplastic disease. Chemotherapy of neoplastic diseases is described in "Goodman and Gilman's The Pharmacological Basis of Therapeutics", seventh edition, A.G. Gilman, et al., eds., pp 1240-1306 (1985).
  • nitrogen-containing heterocycle refers to a 4- to 7- atom cyclic group containing one, two, or three heteroatoms selected from S, O or N, at least one heteroatom being nitrogen.
  • the cyclic group may be substituted or
  • nitrogen-containing heterocycles include azetidine, pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomorpholine and the like.
  • peptidyl refers to a group of one or more ⁇ -amino acids, as described above, joined by an amide bond.
  • phenyl refers to either unsubstituted benzene rings or to benzene rings having one to three non-hydrogen substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, alkyl, hydroxy-substituted alkyl, amino, (alkyl)amino, aminoalkyl and a nitrogen-containing heterocycle, as for example aziridinyl, pyrrolidinyl and the like.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, as for example by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Volume 14 of the A.C.S.
  • spirocycloalkyl refers to saturated bicyclic hydrocarbons having one carbon common to both rings, including for example spiropentane and spiroheptane.
  • pharmaceutically acceptable salts, esters and amides refers to those carboxylate salts, amino acid addition salts, esters and amides of the compounds of Formula I as well as the zwitterionic forms thereof, which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity irritation, allergic response and the like; commensurate with a reasonable benent/risk ratio; and effective for their intended use.
  • salts refers to the relatively non- toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
  • S. M. Berge, et al. See, for example, S. M. Berge, et al.
  • esters of the compounds of Formula I include C 1 to C 6 alkyl esters wherein the alkyl group is straight or branched chain. Acceptable esters also include C 5 to C 7 cycloalkyl esters. C 1 to C 4 alkyl esters are preferred. Esters of the compounds of Formula 1 may be prepared according to conventional methods.
  • compounds of Formula I include amides derived from ammonia, primary C 1 to C 6 alkyl amines and secondary C 1 to C 6 dialkyl amines wherein the alkyl groups are straight or branched chain.
  • the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, C 1 to C 3 alkyl primary amides of Formula I may be prepared according to conventional methods. It is understood that amides of the present invention include amino acid and peptide derivatives.
  • the preferred compounds of the present invention are those having the structure:
  • R 1 , R 2 , R 3 , and W are as described, A is O, Z is an amino group or an aliphatic heterocycle, and X is F.
  • Particularly preferred compounds are those having the structure as described above in which Z is aminopyrrolidinyl, 2-methyl-4-aminopyrrolidinyl, norvalylaminopyrrolidinyl or alanylaminopyrrolidinyl.
  • the chiral centers of the compounds of the present invention may have either the ⁇ , ⁇ , or racemic configuration.
  • Methods of resolution of the enantiomeric forms of these compounds are well knowr o those skilled in the art. For example, J. March provides a thorough discussion of resolution methods in "Advanced Organic Chemistry", John Wiley and Sons, Inc, New York, (1985).
  • the present invention also provides pharmaceutical compositions which comprise one or more of the compounds of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally,
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable
  • compositions may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, as for example by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract or, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyJ alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyJ alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably
  • suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from
  • Liposomes are formed by mono- or multi- lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable Iipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patieet being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • Dosage regimens must be titrated to the particular neoplasm, the condition of the patient and the response obtained, but generally dosage levels of about 0.1 to about 750 mg/kg body weight, more preferably of about 0.25 to about 500 mg/kg body weight, and most preferably about 0.5 to about 300 mg of active compound per kilogram of body weight per day are administered orally or intravenously to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.
  • the compounds of the present invention are synthesized as reported by D. Chu and R. Maleczka in the J. Heterocyclic Chem. 24: 453 (1987) or by D. Chu in U.S. Patent Nos. 4,607,032, 4,529,725 and 4,528,285 or according to reaction Schemes I to IV presented below, in which R, R 1 and R 2 are lower alkyl and R 3 is as defined above in connection with Formula I.
  • the condensation of the amino group with ammo acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimide) method, the active ester method (p- nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1 - hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis" Second Edition, M.
  • amino acid coupling reaction could be carried out before or after the amino- containing group is incorporated into the compound by displacement of the 7- fluorine atom of the appropriate intermediate.
  • branced chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chlorobenzyloxycarbonyl ((2-CI)Z)), p-nitrobenzyloxycarbonyl (Z(NO 2 )), p-methoxybenzyloxycarbony.
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlN ⁇ 2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
  • the guanidino group (NG) in arginine may be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethyl-benzenesulfonyl (Mts) and the like, and the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylbenzyl, acetomidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6-trimethyIbenzyl (Tmb) and the like, and the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP
  • the reaction may be performed by heating a compound of the Formula II with an amine of Formula III at a temperature of from 20°C to 200°, and preferably from 70°C to 150 °C, in the presence of a suitable organic polar solvent such as dimethysulfoxide, sulfolane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone or water. It is desirable to carry out the reaction in the presence of an acid acceptor such as triethylamine, potassium carbonate and the like at a molar ratio of 1.0 to 1.02 mole of the acid receptor per mole of compound of Formula II.
  • the amine III can also be used as acid acceptor in which 2 or more molar excess of this reagent may be used.
  • 2,3,4,5-tetrafluorobenzoic acid (1) is treated with thionyl chloride to produce the corresponding acid chloride which is displaced with a dialkyl malonate, preferably diethyl malonate (2) to yield the diester (3).
  • the diester (3) is then treated with p-toluenesulfonic acid to yield the 2,3,4,5-tetrafluorobenzoylacetate (4).
  • ester is then treated with a trialkyl orthoformate, preferably triethylorthoformate, (5) in acetic anhydride, followed by reaction with a substituted or unsubstituted O-hydroxyaniline (6) in methylene chloride to give the ethyl 3-(2-hydroxyanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (7).
  • a trialkyl orthoformate preferably triethylorthoformate
  • This enaminoketoester (7) is cycled in the presence of a suitable base, such as sodium bicarbonate, and an aprotic solvent such as dimethylformamide (DMF) at 100°C to give ethyl 1 ,2-difluoro-4-oxo-4H-quino[2,3,4-i,j][1 ,4]benzoxazine-5- carboxylate (8).
  • a suitable base such as sodium bicarbonate
  • an aprotic solvent such as dimethylformamide (DMF)
  • the b-ketoester (4) is treated with a trialkyl orthoformate (5) in acetic anhydride, followed by reaction with a substituted or unsubstituted 2-methoxymethylthioaniline (10) in an appropriate solvent, preferably methylene chloride or tetrahydofuran, and may be conducted at room or suitable elevated temperature, to obtain the enamino-ketoester (11).
  • the enamino-ketoester (11) is then cyclized, such as by treatment with a strong base, preferably sodium hydride, to obtain the 1 ,4-dihydro-4-oxo-quinoline-3-carboxylic acid ester (12).
  • Cyclization is conducted in the presence of an aprotic solvent, such as dimethoxyethane, dimethylformamide, tetrahydrofuran, or chlorobenzene, and is preferably conducted at temperatures of about 20°C to about 145°C, and more preferably at the reflux temperature of the solvent employed.
  • an aprotic solvent such as dimethoxyethane, dimethylformamide, tetrahydrofuran, or chlorobenzene
  • the b-ketoester (4) is treated with a trialkyl orthoformate (5) in acetic anhydride followed by reaction with a substituted or unsubstituted 2-methylaniline (14) as described in scheme II to obtain the enamino-ketoester (15).
  • the enamino-ketoester (15) is then cyclized, such as by treatment with a strong base, preferably sodium hydride, to obtain the 1 ,4-dihydro-4-oxo-quinoline-3-carboxylic acid ester (16) as described above.
  • TEDA tetramethylethyldiamine
  • 2,3,4,5,6-pentafluorobenzoyl chloride is reacted with a dialkyl malonate, preferably diethyl malonate to yield the diester (22).
  • the diester (22) is then treated with p-toluenesulfonic acid to yield the 2,3,4,5,6-pentafluorobenzoylacetate (23).
  • the beta-ketoester (24) is then treated with a trialkyl orthoformate, preferably triethylorthoformate, in acetic anhydride, followed by reaction with a substituted or unsubstituted O-hydroxyaniline or hydroxy-protected
  • the beta-ketoester (24) is treated with a trialkyl orthoformate, preferably triethylorthoformate, in acetic anhydride, followed by reaction with a substituted or unsubstituted hydroxy- protected O-hydroxyaniline(6) in methylene chloride to give an enaminoketoester (27).
  • a suitable base such as sodium bicarbonate
  • an aprotic solvent such as dimethylformamide (DMF) at 100°C to give compound (28).
  • This compound is then reacted with R 15 H where R 15 is WH, where W is as described above, or R 16 -N-H where R 16 is a nitrogen protecting group, as for example benzyl, to give the compound (29).
  • the protecting group is removed, for example by hydrogenolysis of the benzyl group to give the free amine.
  • the free amine is then reprotected with a protecting group not requiring hydrogenolysis for removal, for example, acetyl or t-butyloxycarbonyl (boc), the protecting group is removed from the phenolic hydroxyl group by selective hydrolysis, for example with pyridine hydrochloride, TFA, or boron tribromide and ether and the second ring is closed by reaction in the presence of a suitable base, such as sodium bicarbonate, and an aprotic solvent such as dimethylformamide (DMF) at 100°C to give compound (30)
  • a suitable base such as sodium bicarbonate
  • an aprotic solvent such as dimethylformamide (DMF)
  • 2,3,4,5- Tetrafluorobenzoic acid (100g, 0.515 mol) was added to 300 mL of thionyl chloride. After refluxing for 3 hours, the reaction mixture was evaporated to dryness and the resulting acid chloride was dissolved in toluene.
  • the acid chloride solution was then added in a dropwise manner to the magnesium salt solution. Addtional solvent was added and the mixture was stirred at room temperature overnight. The mixture was then poured into 600 mL of 10% sulfuric acid solution and diluted with 600 mL of chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated to yield the 169.8 g of the diester.
  • step 2 The diester from step 1 (169.8 g, 0.505 mol) was suspended in water and p-toluenesulfonic acid (730 mg) added. The suspension was stirred rapidly, refluxed for three hours, and allowed to cool to room temperature. After cooling, the solution was extracted with chloroform and washed with 5% sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness yielding a golden colored syrup. The product was azetroped several times with methylene chloride to yield 132.7 g of ethyl 2,3,4,5-tetrafluorobenzolyacetate. This was crystallized from pentane, yielding 119.43 g.
  • Example 2 Example 2
  • Ethyl-3-(2-hydroxyanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (19.92 g, 0.052 mol) was dissolved in 200 mL of dimethylformamide (DMF) and sodium bicarbonate powder (13.1 g, 0.156 mol) was added. The suspension was immersed in a pre-heated oil bath at 100°C and heated for 2 hours. The mixture was then allowed to cool slightly, diluted with chloroform, and filtered. The filtrate was evaporated to a solution of DMF and allowed to stand at room temperature overnight. After standing, the solution was co-distilled with toluene to yield a light yellow-colored solid.
  • DMF dimethylformamide
  • Step 1 Ethyl 1 ,2-difluoro-8-methyl-4-oxo-4H-quino[2,3,4-ij][1 ,4]benzoxazine-5-carboxylate
  • Ethyl-3-(2'-hydroxy, 5'-methylanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was prepared by a method similar to that described in the J. Heterocvcl. Chem.. 24:453 (1987) from ethyl 2,3,4,5-tetrafluorobenzoylacetate. m.p. 202-3°C; MS M/Z: 398 (M+H); IR (CDCI 3 ) 1630 , 1670 cm -1 ; NMR (CDCI 3 ) d: 1.15 (m, 3H), 2.35
  • Step 2 Ethyl 1-(3-acetamidopyrrolidin-1-yl)-2-fluoro-8-methyl-4-oxo-4H-quino[2,3,4-i.j][1 ,4]benzoxazine-5-carboxylate
  • Step 3 1-(3-aminopyrrolidin-1-yl)-2-fluoro-8-methyl-4-oxo-4H-quino[2,3,4- i.j][1 ,4]benzoxazine-5-carboxyl ⁇ c acid hydrochloride
  • Step 1 Ethyl 1 ,2-fluoro-9-nitro-4-oxo-4H- ⁇ uino[2,3,4-i,j][1 ,4]henzoxazine-5- carboxylate
  • Ethyl-3-(2-hydroxy-4-nitroanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was prepared by a method similar to that described in the J. Heterocycl. Chem., 24:453 (1987) from ethyl 2,3,4,5-tetrafluorobenzoylacetate. m.p. 225°C; MS M/Z: 429 (M+H): IR (KBr) r40, 1660 cm -1 ; NMR (DMSO) d: 1.05 (m, 3H), 4.07 (m, 2H), 7.57 (m, 1 H). 7.80 (m, 2H), 7.93 (m, 1 H), 8.70 (m, 1 H), 11.70 (m, 1 H). Analysis
  • Step 2 Ethyl 1-(3-acetamidopyrrolidin-1 -yl)-2-fluoro-9-nitro-4-oxo-4H-quino[2.3.4-i,j][1.4]benzoxazina-5-carboxylate
  • Step 1 Ethyl 1 ,2-difluoro-9-methyl-4-oxo-4H-quino[2.3.4-i,j][1 ,4]]benzoxazine-5-carboxylate
  • Ethyl-3-(2'-hydroxy, 4'-methylanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was prepared according by a method similar to that described in the J. Heterocycl. Chem., 24:453 (1987) from ethyl 2,3,4,5-tetrafluorobenzoylacetate. m.p.
  • Step 2 Ethyl 1-(3-acetamidopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2.3.4-i,j][1 ,4lbenzoxazine-5-carboxylate
  • Step 3 1-(3-aminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4- i,j][1 ,4]benzoxazine-5-carboxylic acid hydrochloride
  • Step 1 Ethyl 1 ,2,9-trifluoro-4-oxo-4H-quino[2.3,4-i,j][1.4]benzoxazine-5-carboxylate
  • Ethyl-3-(2'-hydroxy, 4'-fluoroanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was prepared by a method similar to that described in the J. Heterocycl, Chem., 24:453 (1987) from ethyl 2,3,4,5-tetrafluorbenzoylacetate. m.p.
  • Step 2 Ethyl 1-(3-acetamidopyrrolidin-1-yl)-2,9-difluoro-4-oxo-4H-quino[2,3,4-i.j][1.4]benzoxazine-5-carboxylate
  • Step 3 1 -(3-aminopvrrolidin-1-yl)-2,9-difluoro-4-oxo-4H-qumo[2,3,4
  • Step 1 1 -(t-N-butyloxycarbonyl-norvalylaminopyrrolidin-1-yl)-2-fluoro-4-oxo-4H-quino[2.3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 2 1-(3-norvalylaminopvrrolidin-1-yl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride
  • Step 1 1-(t-N-butyloxycarbonyl-alanylaminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 2 1-(3-alanylaminopvrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • Step 1 1-(t-N-butyloxycarbonyl-norvalylaminopyrrolidin-1-yl)-2-fluoro-9-methyl-4- oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 2 1-(3-norvalylaminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4- i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • ethyl 4-oxo-1 ,2,8,9,10- pentafluoro-4H-quino[2,3,4-i,j][1 ,4]benzoxazine-5-carboxylate can be prepared from 2-hydroxy-3,4,5-trifluoroaniline.
  • Step 3 1-difluoro-8,10 dimethyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Example15 step 4 The procedure of Example15 step 4 was followed, and 3-(N-t-butoxycarbonyiamino)pyrrolidine was replaced with (3S)-3-(N-t-butoxycarbonylamino)pyrrolidine (obtained from American Tokyo Kasei, Div. of Tokyo Kasei Kogyo, K.K.) to afford the title compound, mp 135-7°C.
  • Example 15 Step 4 The procedure of Example 15 Step 4 was followed, and 3-(N-t-butoxycarbonylamino)pyrrolidine was replaced with (3R)-3-(N-t- butoxycarbonylamino)pyrrolidine (obtained from American Tokyo Kasei, Div. of Tokyo Kasei Kogyo, K.K.) to afford the title compound, mp 135-7°C.
  • Step 1 Ethyl 1-((3S)-3-N-t-butoxycarbonylaminopyrrolidin-1-yl -2-fluoro-9-methyl- 4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylate.
  • Step 2 1-((3S)-3-aminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2.3,4-i,j][1.4]benzoxazine-5-carboxylic, acid hydrochloride
  • Step 1 Ethyl 1-((3R)-3-(N-t-butoxvcarbonylaminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2.3.4-i,j][1.4]benzoxazine-5-carboxylate.
  • Step 2 1-((3R)-3-aminopyrrolidin-1-yl)-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic,acid hydrochloride
  • Step 1 Ethyl 3-(5-t-butyl-2-hydroxyanilino)-2-(2,3,4,5-tetrafluorobenzoyl acrylate Following the procedure of Example 15 step 1 and replacing 6-amino-2,4-dimethylphenol with 2-amino-4-t-butylphenol the title compound was
  • step 2 the ethyl 3-(5-t-butyl-2-hydroxyanilino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate from step 1 was reacted and the title product was obtained.
  • Step 1 1-(t-N-butyloxycarbonyl-norvalylaminopyrrolidin-1 -yl) -2,3-difluoro-4-oxo-4H-quino[2.3.4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Example 8 Following the procedure of Example 8, substituiting 1-(3-aminopyrrolidin-1 -yl)-2,3-difluoro-4-oxo-4H-quino[2,3,4-i,j][1 ,4]benzoxazine-5-carboxylic acid hydrochloride, prepared in Example 22 above, for the 1-(3-aminopyrrolidin-1 -yl)-2- fluoro-4-oxo-4H-quino[2,3,4-i,j][1 ,4]benzoxazine-5-carboxyiic acid hydrochloride of Example 8, the boc protected title compound was compound was prepared, mp 219°C (dec). MS M/Z: 599 (M+H).
  • Step 1 1-((3R)-t-N-butyloxycarbonyl-norvalylaminopyrrolidin-1-yl))-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 1 1-((3S)-t-N-butyloxycarbonyl-norvalylaminopyrrolidin-1 -yl))-2-flunro-4-oxo- 4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 2 2-fluoro-1 -((3S)-3-norvalylaminopyrrolidin-1-yl)-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • Step 1 1-((3R)-t-N-butyloxvcarbonyl-norvalylaminopvrrolidin-1-yl))-2-fluoro-9-methyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid .
  • Step 2 2-fluoro-9-methyl-1-((3R)-3-norvalylaminopvrrolidin-1 -yl -4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • the boc protected compound from step 1 is hydrolyzed and converted to the HCl salt by the procedure of Example 8 step 2.
  • Step 1 1 ,2-difluoro-8-ethylsulfonyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5- carboxylic acid
  • Step 2 Ethyl 1-(3-(t-butyloxvcarbonylamino)pvrrolidin-1-yl)- 8-ethylsulfonyl-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylate
  • Step 3 1-(3-aminopvrrolidin-1-yl)-8-ethylsulfonyl-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • Step 1 1-(t-N-butyloxycarbonyl-norvalylaminopvrrolidin-1-yl)-2-fluoro-8-ethylsulfonyl-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid
  • Step 2 8-Ethylsulfonyl-2-fluoro-1-(3-norvalylaminopyrrolidin-1-yl)-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride.
  • Morpholine 0.281 mL (3.2 mmol) was dissolved in 10 mL of methylene cholride at room temperature in dry nitrogen. 1.6 mL (3.2 mmol) of
  • Step 1 2-difluoro-4-oxo-4H-quino[2,3,4-i,j][1.4]benzoxazine-5-(N-2,4- difluorphenyl)carboxamide
  • (2S,4S)-4-acetamido-2-methylpyrrolidine hydrochloride from the previous step is suspended in methylene chloride, triethylamine and benzyl bromide are added and the mixture heated at reflux. The product is obtained after washing and evaporation of the solvent. Step 3. (2S, 4S)-4-amino-1-benzyl-2-methylpyrrolidine hydrochloride
  • the (2S, 4S)-4-amino-1-benzyl-2-methylpyrrolidine hydrochloride is treated with triethylamine and di-t-butyl dicarbonate to protect the 4-amino group.
  • the benzyl protecting group is removed from (2S, 4S)-1-benzyl-4-t- butoxycarbonylamino-2-methylpyrrolidine by hydrogenolysis in methanol with 10% Pd/C, to give the title compound.
  • Step 7 1-((2S, 4S)-4-amino-2-methylpyrrolidin-1-yl)-8,10-dimethyl-2-fluoro-4-oxo-4H- guino[2,3,4-i,j][1 ,4]benzoxazine-5-carboxylic acid hydrochloride
  • Step 2 Ethyl 1-(3-(t-butyloxycarbonylamino)pyrrolidin-1-yl)-2-fluoro-8,9-methylenedioxy-4-oxo-4H-quino[2.3.4-i,j][1.4]benzoxazine-5-carboxylate
  • Step 3 1 -(3-aminopyrrolidin-1-yl)-2-fluoro-8,9-methylenedioxy-4-oxo-4H- quino[2.3.4-i,j][1.4]benzoxazine-5-carboxylic acid hydrochloride
  • 2-Nitrophenol is reacted with methoxyethoxymethyl chloride in the presence of a base, for example N,N-diisopropylethyl amine, to give 1- methoxyethoxymethoxy-2-nitrobenzene.
  • a base for example N,N-diisopropylethyl amine
  • This compound is hydrogenated with gaseous hydrogen in the presence of a catalyst, such as nickel, palladium,
  • the benzyl protecting group is removed by hydrogenolysis with hydrogen in the presence of a palladium catalyst, and the resulting amino group is reprotected with a acetyl protecting group by reaction with acetic anhydride in methanol at from 0°C to 50°C.
  • Ethyl 7-(3-acetamidopyrrolidin-1-yl)-5-acetamido-6-fluoro-1-(2-methoxyethoxymethoxyphenyl)-4-oxo-4H-quinoline-3-carboxylate is deprotected at the phenolic position by selective hydrolysis with trifluoroacetic acid in methylene chloride to prepare ethyl 7-(3-acetamidopyrrolidin-1-yl)-5-acetamido-6-fIuoro-1-(2- hydroxyphenyl)-4-oxo-4H-quinoline-3-carboxylate. This compound is then
  • Step 6 3-amino-1-(3-aminopvrrolidin-1-yl)-2-fluoro-4-oxo-4H-quino[2,3,4- i.j][1 ,4]benzoxazine-5-carboxylic acid hydrochloride.
  • the protecting groups are removed from ethyl 1-(3-aminopyrrolidin-1-yl)-3-t-N- butyloxycarbonylamino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1 ,4]benzoxazine-5- carboxylate by a procedure similar to that of Example 18 step 2 to prepare the title compound.
  • Metabolic activity was measured by the cells' ability to reduce the tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), to a quantifiable colored formasan derivative. Surviving cells reduce the MTT dye. The inhibitory concentrations of killing 50% of the cells (IC50S) were calculated. Testing was in accord with the following protocol:
  • Test compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted, first with Earle's Balanced Salt Solution, followed by culture medium, to twice the highest concentration of the compound to be tested. From this concentrated stock, two-fold serial dilutions were prepared in 96-well microtiter trays, each well
  • the cells were grown in the same medium used for diluting the compounds.
  • Adherent cells were harvested by trypsinization according to the following
  • Microtiter trays were incubated for three days at 36°C in a humidified atmosphere containing 5% carbon dioxide.
  • step 2 1.01 - - - - - - 0.64 0.65
  • Adriamycin 0.049 - - - - - - - - 0.031 0.016
  • P388 is a mouse leukemia cell line similar to P388-D1 , but animal-passaged;
  • P388-ADR (0.0) is an adriamycin-resistant variant of P388, the inoculum of which is grown in drug-free medium;
  • P388-ADR (0.1) is an adriamycin-resistant variant of P388, the inoculum of which is grown in medium with 0.1 mcg.ml adriamycin;
  • B16F10 is a mouse melanoma.
  • ADR is adriamycin; the data presented are averages from two tests, except for data marked with an * , which are single-test data..
  • A is 1-(3-aminopyrrolidin-1-yl)-2-fluoro-4-oxo-4H-[2,3,4-i,j][1 ,4]benzoxazine-5- carboxylic acid
  • the tumor was implanted IP into mice on day 0.
  • the compound to be tested was administered IP at days 1 , 5, and 9 and the result is recorded on day 60.
  • Compounds having %T/C values greater than 125 are considered to have significant activity.
  • M5076 ovarian sarcoma the solid tumor was implanted subcutaneously into mice on day 0. The compound to be tested was administered IP every 2 days
  • T/C Mean Mean Wt, T/C

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Abstract

L'invention se rapporte à de la quinobenzoxazine, des quinobenzothiazines et des dérivés de pyrido-acridine, représentés par la formule (I), ainsi qu'à leurs sels, esters, amides, et pro-médicaments pharmaceutiquement acceptables. Dans la formule (I), R1 représente hydrogène ou un groupe protecteur de carboxy, R2 et R3 représentent des substituants, A représente oxygène, soufre ou carbone, Z représente un halogène ou un groupe contenant de l'azote, X représente hydrogène, halogène ou alkyle, et W représente hydrogène, alkyle, amino ou halogène. Ces composés ont un pouvoir antinéoplastique puissant.
PCT/US1991/006040 1990-08-24 1991-08-23 Agents antineoplastiques a base de quinobenzoxazine, de quinobenzothiazines et de pyrido-acridine WO1992003136A1 (fr)

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EP0604181A1 (fr) * 1992-12-21 1994-06-29 Eli Lilly And Company Compositions antitumeurs et méthodes de traitement
JP2006522827A (ja) * 2003-04-07 2006-10-05 サイリーン ファーマシューティカルズ インコーポレーティッド 置換キノベンゾオキサジン類似体
US7163948B2 (en) 2003-04-07 2007-01-16 Cylene Pharmaceuticals, Inc. Heterocyclic substituted 1,4-dihydri-4ox9-1,8-naphthyridine analogs
US7354916B2 (en) 2003-04-07 2008-04-08 Cylene Pharmaceuticals Substituted quinobenzoxazine analogs
US7507727B2 (en) 2003-04-07 2009-03-24 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs and methods of using thereof
US7652134B2 (en) 2004-09-17 2010-01-26 Cylene Pharmaceuticals, Inc. Methods for converting quinolone esters into quinolone amides
US7816406B2 (en) 2004-09-17 2010-10-19 Cylene Pharmaceuticals, Inc. Quinolone analogs

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0604181A1 (fr) * 1992-12-21 1994-06-29 Eli Lilly And Company Compositions antitumeurs et méthodes de traitement
JP2006522827A (ja) * 2003-04-07 2006-10-05 サイリーン ファーマシューティカルズ インコーポレーティッド 置換キノベンゾオキサジン類似体
US7141565B1 (en) 2003-04-07 2006-11-28 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs
US7163948B2 (en) 2003-04-07 2007-01-16 Cylene Pharmaceuticals, Inc. Heterocyclic substituted 1,4-dihydri-4ox9-1,8-naphthyridine analogs
US7326702B2 (en) 2003-04-07 2008-02-05 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs
US7354916B2 (en) 2003-04-07 2008-04-08 Cylene Pharmaceuticals Substituted quinobenzoxazine analogs
US7381720B2 (en) 2003-04-07 2008-06-03 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs
US7507727B2 (en) 2003-04-07 2009-03-24 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs and methods of using thereof
US7612063B2 (en) 2003-04-07 2009-11-03 Cylene Pharmaceuticals, Inc. Substituted quinobenzoxazine analogs
US7652134B2 (en) 2004-09-17 2010-01-26 Cylene Pharmaceuticals, Inc. Methods for converting quinolone esters into quinolone amides
US7816406B2 (en) 2004-09-17 2010-10-19 Cylene Pharmaceuticals, Inc. Quinolone analogs
KR100989029B1 (ko) 2004-09-17 2010-10-25 사일린 파마슈티칼스, 인크 세포 증식 억제제로서의 퀴놀론 동족체

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EP0608215A1 (fr) 1994-08-03
IE912902A1 (en) 1992-02-26
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CA2099609A1 (fr) 1992-02-25
PT98766A (pt) 1992-07-31

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