WO1996038446A1 - Derives heterocycliques polycycliques fusionnes - Google Patents

Derives heterocycliques polycycliques fusionnes Download PDF

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Publication number
WO1996038446A1
WO1996038446A1 PCT/JP1996/001487 JP9601487W WO9638446A1 WO 1996038446 A1 WO1996038446 A1 WO 1996038446A1 JP 9601487 W JP9601487 W JP 9601487W WO 9638446 A1 WO9638446 A1 WO 9638446A1
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Prior art keywords
ring
group
compound
added
ethyl
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PCT/JP1996/001487
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English (en)
Japanese (ja)
Inventor
Hiroyuki Sugumi
Jun Niijima
Yoshihiko Kotake
Toshimi Okada
Jun-Ichi Kamata
Kentaro Yoshimatsu
Takeshi Nagasu
Katsuji Nakamura
Toshimitsu Uenaka
Atsumi Yamaguchi
Hiroshi Yoshino
Nozomu Koyanagi
Kyosuke Kito
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Eisai Co., Ltd.
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Application filed by Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Priority to DE69634004T priority Critical patent/DE69634004T2/de
Priority to US08/952,778 priority patent/US5952335A/en
Priority to AT96920027T priority patent/ATE284401T1/de
Priority to MX9709254A priority patent/MX9709254A/es
Priority to AU58454/96A priority patent/AU703111B2/en
Priority to CA002220509A priority patent/CA2220509C/fr
Priority to NZ308657A priority patent/NZ308657A/en
Priority to EP96920027A priority patent/EP0831094B1/fr
Publication of WO1996038446A1 publication Critical patent/WO1996038446A1/fr
Priority to NO19975493A priority patent/NO310149B1/no

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    • 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
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • 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

  • the present invention relates to a novel fused polycyclic heterocyclic derivative, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.
  • Condensed polycyclic heterocyclic ring system containing cyclic imido CO-N-CO- moiety in the molecule As an antitumor substance, tricyclic amonafide [5-amino-2- [2- (dimethylamino)] 1-H—venz [de] isoquinoline-l, 3 (2 ⁇ ) dione] is the most well-known, but it has been shown to be highly It has been reported to be low [Drugs Fut .. J ⁇ _, 832 (1992)].
  • tetracyclic compounds such as azonafide [2 -— [2 '-(dimethylamino) ethyl], whose antitumor activity in preclinical studies has been increased by converting the aminononaphthalene moiety of the monafide into anthracene.
  • azonafide [2 -— [2 '-(dimethylamino) ethyl]
  • azonafide [2 -— [2 '-(dimethylamino) ethyl]
  • An object of the present invention is to provide a novel compound or a novel fused penta- and hexacyclic heterocyclic derivative having low toxicity and excellent antitumor activity. Furthermore, it is another object of the present invention to provide a method for producing the compound and a pharmaceutical composition containing the compound as an active ingredient.
  • the present inventors have conducted intensive studies in search of an excellent antitumor substance, and as a result, a novel fused penta- and hexacyclic heterocyclic compound having a uranium structure in the molecule has an excellent antitumor property.
  • the present inventors have found that they have tumor activity and have low toxicity, and have completed the present invention.
  • the present invention provides a compound represented by the general formula (I):
  • ring A means a monocyclic aromatic ring which may have a substituent, or a bicyclic fused ring in which at least one ring is an aromatic ring.
  • Ring B means pyrrole, 4 H-1,4 monooxazine, 4 H—1,4 monothiazine or 4 (1 H) —pyridone.
  • the ring C means a monocyclic or fused bicyclic aromatic ring which may have a substituent.
  • Y is a group of the formula e- ⁇ (wherein e is a lower alkylene group, ⁇ is an amidino group, a guanidino group, or a hydroxylated or lower alkylamino group) Or an amino group which may be substituted with a lower alkyl group which is not substituted).
  • both the ring A and the ring C are monocyclic aromatic rings which may have a substituent.
  • a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically effective amount of the above-mentioned condensed polycyclic heterocyclic derivative or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.
  • the present invention also relates to a method for preventing or treating a tumor by administering to a patient a pharmacologically effective amount of the above fused polycyclic heterocyclic derivative.
  • “monocyclic aromatic ring” refers to an aromatic 5 or 6 which may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom.
  • a bicyclic fused ring in which at least one ring is an aromatic ring '' may mean that each ring may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom 5
  • Rings included in ring A include, for example, benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrol, thiabour, and partially hydrogenated, and when there is a sulfur atom
  • examples thereof include the following bicyclic fused rings which may be oxidized, and these rings can be condensed with the ring B at any chemically feasible position.
  • the ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different.
  • substituents include a hydroxyl group, an oxo group, a cyano group, a halogen group, a nitro group, a lower alkyl group which may be subjected to hydroxylation or lower alkylamination, a lower alkoxy group, a lower alkoxy group, and a lower alkylation.
  • a lower alkylated, lower acylated, arylsulfonylated or lower alkylsulfonylated amino group are examples of the substituent.
  • the “monocyclic or condensed bicyclic aromatic ring” represented by the ring C is a monocyclic or bicyclic aromatic hydrocarbon or an aromatic heterocyclic ring containing one or two nitrogen atoms, There may be 1-3 substituents on the ring.
  • Examples of the ring contained in the ring C include benzene, pyridine, pyrimidine, naphthalene, quinoline, isoquinoline, indole, quinazoline and the like. Can be condensed with the B ring at the position.
  • the ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different.
  • substituents include a halogen group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a nitro group, and an amino group which may be lower-alkylated or lower-acylated.
  • the substituent which ring A and ring C may have, and the lower alkyl group in the definition of Y include a linear or branched alkyl group having 1 to 6 carbon atoms.
  • a linear or branched alkyl group having 1 to 6 carbon atoms For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl Group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1.2-dimethylbutyl group
  • preferred groups include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and among them, the most preferred groups include a methyl group and an ethyl group.
  • the lower alkylene group means a residue obtained by removing one hydrogen atom from the lower alkyl group.
  • substituent which ring A and ring C may have, and f in Y when the amino group is substituted with two lower alkyl groups, these alkyl groups are bonded to each other. Or a 6-membered ring may be formed.
  • the lower alkoxy group in the definition of the substituent which the ring A and the ring C may have is a methoxy group, an ethoxy group, an n-propoxy group, an isobromoboxyl group, an n-butoxy group, an isobutoxy group, a tert group.
  • the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
  • Examples of the lower acryl group include a formyl group having 1 to 6 carbon atoms, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, and a valeryl group.
  • the arylamino group which may be arylsulfonylated or lower alkylsulfonylated includes, for example, p-toluenesulfonylation, methylsulfonylation, It means a phenylamino group which may be ethylsulfonylated.
  • the fused polycyclic heterocyclic derivative represented by the general formula (I) may form a salt with an acid in some cases.
  • the present invention also includes a salt of compound (I).
  • salts with acids include inorganic acid salts with hydrochloric acid, hydrobromic acid, sulfuric acid, etc., and acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p — Organic acid salts with toluenesulfonic acid and the like.
  • the compounds of the present invention exhibit strong antitumor activity, but also include compounds that exhibit antitumor activity by metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo.
  • the present invention also includes a compound that undergoes metabolism such as oxidation, reduction, or hydrolysis in vivo to produce the compound of the present invention.
  • the compound (I) of the present invention can be produced by various methods. Representative methods among them are as follows.
  • the A a ring and the C a ring mean an optionally protected A ring and a C ring, respectively, and the Ba ring represents 4H-1,4-oxazine, 4H-1,4-monothiazine, 4 (1 H) — represents pyridone or pyrrole, ⁇ a represents optionally protected e, e represents the same meaning as described above) and a compound represented by the general formula (III)
  • This reaction is generally carried out by dissolving compound (II) in a nonprotonic solvent such as dimethylformamide, tetrahydrofuran, or dioxane, and then adding 2 to 3 equivalents of sodium hydride.
  • a nonprotonic solvent such as dimethylformamide, tetrahydrofuran, or dioxane
  • 2 to 3 equivalents of sodium hydride for example, phosgene, ethyl ethyl carbonate, N, N'-carbonidimidabour and the like can be mentioned.
  • the reaction is usually carried out in a temperature range from 150 to 0.
  • the target compound (I) can be obtained by performing ordinary deprotection methods such as acid treatment, alkali treatment, and catalytic reduction. Is possible.
  • the Ab ring has a lower acyl group or an oxo group, and may have another protected or unprotected substituent. At least one ring is an aromatic ring.
  • Bb ring means pyrrole, 4H-1,4-oxazine or 4H-1,4-thiazine Cb ring has a protected or unprotected substituent.
  • Y represents the same meaning as described above), and is reacted with a reducing agent for a carbonyl group.
  • a commonly used carbonyl group reduction method can be used.
  • Preferred examples thereof include catalytic reduction using a catalyst such as palladium-carbon, borane-pyridine complex, and sodium borohydride. Reduction.
  • the starting compound (II) includes known compounds and novel compounds. In the case of a new compound, it can be produced by applying a known method for synthesizing a known compound or by combining them.
  • the ring A c means a monocyclic ring which may have a substituent, is not an aromatic ring, or a bicyclic fused ring in which one or both of the rings are not aromatic rings.
  • a c means a partially or completely dehydrogenated ring.
  • the C a ring, e and fa have the same meaning as described above.
  • (X) can be produced by partially or completely dehydrogenating a non-aromatic ring in compound (IX) with a dehydrogenating agent.
  • the dehydrogenating agent include 2,3-dichloro-5,6-dicyanone-1,4-benzoquinone, chloranil, and palladium monocarbon.
  • the reaction is usually performed at room temperature or under heating. If the Ac ring is a bicyclic fused ring in which both rings are not aromatic rings, only one of the rings should be selectively dehydrated by appropriately selecting the type, amount, and reaction conditions of the reagents. Is also possible.
  • the target compound U la) can be produced by condensing the compound (X) thus obtained with the compound (VI).
  • condensation method examples include an acid chloride method, an active ester method, a mixed acid anhydride method, and 1,3-zinclohexyl carpoimide, N, N'-carbonyldimidabour, and diphenylphosphoryl azide as condensing agents. There are methods. Manufacturing method 2
  • the Ae ring means a monocyclic aromatic ring which may have a substituent, or a bicyclic fused ring in which a ring having at least one substituent GH is an aromatic ring.
  • G represents an oxygen atom or a sulfur atom
  • K and L represent a leaving group
  • R represents a lower alkyl group
  • a Ca ring e and fa have the same meanings as described above.
  • the compound represented by the formula (XIII) can be produced by reacting the compound of the formula (XI) with the compound of the formula (XII).
  • Preferred examples of the leaving group K in compound (XII) include a nitro group
  • preferred examples of L include a halogen atom.
  • the reaction can be carried out by heating in the presence or absence of a base such as triethylamine, sodium acetate, and sodium hydroxide.
  • a base such as triethylamine, sodium acetate, and sodium hydroxide.
  • the desired compound (Ub) is obtained by adding the ester of compound ( ⁇ )
  • the compound (XIV) can be produced by subjecting the compound to the compound (XIV) by hydrolysis and condensing it with the compound (VI) in the same manner as in the production method (I).
  • the compound of the present invention When the compound of the present invention is used as a medicine, it is administered orally or parenterally.
  • the dosage depends on the severity of symptoms, age, gender, body weight, sensitivity difference, administration method, administration timing, administration interval, characteristics of pharmaceutical preparation, preparation, type, type of active ingredient, etc., and is not particularly limited. However, it is usually 1 to 3000 mg, preferably about 10 to 2000 mg, more preferably 20 to 1000 rag per adult day, which is usually administered once to three times a day.
  • excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. are added to the active ingredient, and then tablets, coated tablets, Granules, pongee granules, powders, capsules, etc.
  • Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, silicon dioxide, and the like.
  • Binders include, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, and hydroxypropyl pills.
  • cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder, etc. are used.
  • These preparations and granules can be of course coated with sugar coating, gelatin coating and other appropriate coatings if necessary.
  • a pH adjuster When preparing an injection, if necessary, add a pH adjuster, buffer, suspending agent, solubilizer, stabilizing agent, isotonic agent, preservative, etc. Subcutaneous, intramuscular injection. At that time, if necessary, it may be freeze-dried by a conventional method.
  • suspending agents include methylcellulose, polysorbate 80, and hydroxy.
  • examples thereof include: cetyl cellulose, gum arabic, powdered tragacanth, sodium carboquine methylcellulose, and boroxyethylene sorbitan monolaurate.
  • solubilizing agent examples include boroxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
  • stabilizing agent examples include sodium sulfite and sodium metasulfite
  • preservative examples include methyl paraoxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, crebole, and closole cresol. Can be.
  • the present compound was dissolved in a concentration of 10_ 2 Micromax in dimethyl sulfoxide and diluted to a concentration of 10_ 4 Micromax or 10_ 5 Micromax with 10% fetal calf serum one RPMI1640 culture. Using this as the highest concentration, a 3-fold serial dilution was performed with 10% fetal calf serum-RPM640 culture solution. This was added in an amount of 0.1 ml to each well of the 388 cell culture plate described above, and cultured at 37 ° C. for 3 days in a culture vessel containing 5% carbon dioxide.
  • MTT [3- (4,5-dimethylthiazol-2-yl) -1,2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml)
  • the cells were further cultured for 2 hours. Centrifuge the microplate and remove the supernatant from each well. After removal by suction, the produced formazan was dissolved in 0.1 ml of dimethyl sulfoxide, and the absorbance at 540 nm was measured with a microblate reader to use as an indicator of the number of living cells. The inhibition rate was calculated from the following formula, and the concentration (IC 50 ) of the test compound that inhibited by 50% was determined.
  • BDF1 mice (6-7 weeks old, ⁇ ) were implanted with lxlO 6 pieces of the M5076 to the side subcutaneously.
  • the compound of the present invention was dissolved in a 5% glucose solution, and administered intraperitoneally once a day according to each schedule from the day after transplantation.
  • the control group received ⁇ glucose solution.
  • the control group was 10 animals per group, and the drug administration group was 5 animals per group.
  • the tumor growth inhibition rate of the drug administration group relative to the control group was determined by the following formula.
  • T Average tumor weight of test compound administration group
  • Table 2 shows the experimental results. Table 2: In vivo antitumor test for M 5076 Compound Dose Administration day Growth inhibition rate Judgment day (Day 21) (Example number) (mg / kg / say) (Day after transplantation) (%) Survival rate
  • a nude mouse (BAL BZC, nu / nu 6-7 weeks old, female) was subcutaneously subcutaneously implanted with approximately 1 to 3 MX-1 tumor pieces.
  • the compound of the present invention was dissolved in a 5% glucose solution about 10 days after the transplantation to reach the tumor volume of 50 fractions 3 , and intraperitoneally administered once a day according to each schedule.
  • the control group received 5 glucose solutions.
  • the experiment was performed with 10 animals per group as the control group and 5 animals per group as the drug administration group.
  • the tumor growth inhibition rate of the drug-administered group relative to the control group was determined by the following formula.
  • T Average tumor weight of test compound administration group
  • Table 3 shows the experimental results. Table 3: In vivo antitumor test against MX-1 Compound Dose Administration Growth inhibition rate Judgment date (22nd statement)
  • the compound of the present invention has an excellent antitumor effect. It is useful as an antitumor agent.
  • 2-Hydrazinobenzoic acid hydrochloride Approximately 100 in a suspension of 52 g (0.276 mol) of acetic acid in 500ral. Under stirring at C, a solution of 28 ml (0.270 mol) of cyclohexanone in 100 ml of acetic acid was dropped. After heating under reflux for 6 hours, the mixture was returned to room temperature and water 11 was added. The resulting precipitate was collected by filtration, washed with water, and dried to obtain 43 g of a powder.
  • the title compound (0.23 g) was obtained from the compound of Production Example 16 (0.24 g, 0.64 mmol) in the same manner as in Example 2 (excluding the operation of converting into a hydrochloride).
  • Production Example 20 Compound 1. To 19 g (4 mmol) of phosphorus oxychloride lOral was added and heated under reflux. After 3 hours, the reaction mixture was poured onto ice, and neutralized by adding sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography.
  • Example 5 The compound of Example 5 was separated using an optical resolution column (eluted with Daicel, Chiralcel OD, n-hexan-1-2-propanol (7: 3 to 6: 4)) and eluted first. The resulting fraction was concentrated to dryness to give the title compound.
  • the title compound was obtained by reacting the compound of Production Example 7 with 11- (2-aminoethyl) pyrrolidine in the same manner as in Production Example 8 and Example 4.
  • Melting point Coloring started at around 235 ° C, and gradually decomposed at around 260.
  • the title compound was obtained from 2-indanone and 2-hydrazinobenzoate in the same manner as in Production Examples 1, 3 and Example 2.
  • the title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 5-methoxy ⁇ -tetralone and 2-hydrazinobenzoic acid hydrochloride.
  • the title compound was obtained from 7-methoxy / S-tetralone and 2-hydrazinobenzoic acid hydrochloride in the same manner as in Production Examples 1, 2, 3 and Example 2.
  • the title compound was obtained from 5-tetralone and 5-chloro-2-hydrazinobenzoate in the same manner as in Production Examples 1, 2, 3 and Example 2.
  • the title compound was obtained from 8-methoxy S-tetralone and 2-hydrazinobenzoic acid hydrochloride in the same manner as in Production Examples 1, 2, 3 and Example 2.
  • the title compound was obtained from 6-promo / S-tetralone and 2-hydrazinobenzoic acid hydrochloride in the same manner as in Production Examples 1, 2, 3 and Example 2.
  • the title compound was obtained from —tetralone and 2-hydrazino 5-methoxybenzoic acid hydrochloride in the same manner as in Production Examples 1, 2, 3 and Example 2.
  • Example 22 After heating and refluxing the compound of Example 22 in 47% hydrobromic acid, the reaction mixture was subjected to catalytic reduction in methanol at room temperature using palladium carbon as a catalyst. The title compound was obtained by converting the product into a hydrochloride in a conventional manner.
  • Example 37 The compound of Example 37 was hydrogenated at room temperature and normal pressure in the presence of a palladium carbon catalyst to give the title compound.
  • Example 4 341 mg (0.648 mmol) of the free base of the compound of 8 and 419 mg (4.45 mmol) of phenol in 15 ml of 47% hydrobromic acid were heated under reflux for 9 hours and 30 minutes, then returned to room temperature, and saturated An aqueous solution of sodium hydrogen was added to make the solution basic. to this Ethyl acetate and tetrahydrofuran were added for extraction, and the organic layer was washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated, and the obtained residue was recrystallized from ethanol to obtain 141 rag of the free base of the title compound. This was converted into a hydrochloride by a conventional method to obtain the title compound.
  • Example 49 To a suspension of 141rag (0.379 mimol) of the compound of 9 in a dichloromethane (20 ml) suspension was added triethylamine (4 m) and acetic anhydride (2 ml) successively under stirring at room temperature, and stirring was continued for 16 hours. After concentration, 30 ml of methanol was added to the residue, and the mixture was basified by addition of an aqueous saturated sodium hydrogen carbonate solution with stirring. The precipitate was collected by filtration and washed with water (the obtained solid was ethanol Then, concentrated hydrochloric acid was added thereto while stirring at room temperature, and then methanol and dichloromethane were added, followed by stirring.

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Abstract

L'invention porte sur de nouveaux dérivés hétérocycliques polycycliques de formule générale (I) ou leurs sels pharmacocompatibles présentant une très bonne activité antitumorale, et sur leur procédé d'obtention. Dans la formule (I), le noyau A représente un noyau aromatique monocyclique facultativement substitué ou un noyau bicyclique fusionné dont l'un des cycles au moins est un cycle aromatique; le noyau B représente pyrrole, 4H-1,4-dioxane, 4H-1,4-thiazine ou 4(1H)-pyridone; le noyau C représente un anneau aromatique monocyclique ou bicyclique fusionné facultativement substitué; et Y représente -e-f (dans lequel e représente un alkylène inférieur, et f représente amidino, guanidino, ou amino facultativement substitué par hydroxy, ou un alkyle inférieur présentant éventuellement un groupe alkylaminé inférieur); à l'exclusion de la combinaison dans laquelle les noyaux A et C représentent chacun un noyau aromatique monocyclique facultativement substitué.
PCT/JP1996/001487 1995-05-31 1996-05-31 Derives heterocycliques polycycliques fusionnes WO1996038446A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DE69634004T DE69634004T2 (de) 1995-05-31 1996-05-31 Verknüpfte polycyclische heterocyclische verbindungen
US08/952,778 US5952335A (en) 1995-05-31 1996-05-31 Fused polycyclic heterocycle derivatives
AT96920027T ATE284401T1 (de) 1995-05-31 1996-05-31 Verknüpfte polycyclische heterocyclische verbindungen
MX9709254A MX9709254A (es) 1995-05-31 1996-05-31 Derivados de heterociclos policiclicos fusinados.
AU58454/96A AU703111B2 (en) 1995-05-31 1996-05-31 Fused polycyclic heterocycle derivatives
CA002220509A CA2220509C (fr) 1995-05-31 1996-05-31 Derives heterocycliques polycycliques fusionnes
NZ308657A NZ308657A (en) 1995-05-31 1996-05-31 Fused polycyclic heterocycle derivatives
EP96920027A EP0831094B1 (fr) 1995-05-31 1996-05-31 Derives heterocycliques polycycliques fusionnes
NO19975493A NO310149B1 (no) 1995-05-31 1997-11-28 Kondenserte polycykliske heterosyklusderivater, fremstilling og anvendelse av slike forbindelser, samt preparater og midler omfattende slike forbindelser

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP7/133992 1995-05-31
JP13399295 1995-05-31
JP7/309195 1995-11-28

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SG171308A1 (en) * 2008-12-11 2011-07-28 Shionogi & Co Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates
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