JP2001522370A - Derivatives of pyrido [2,3,4-k, l] acridine ring system: cytotoxic compounds - Google Patents

Abstract

(57) [Summary] Formula (I): Wherein X is selected from the group consisting of O and NR ³ , wherein R ³ represents lower alkyl; Y is selected from the group consisting of CH and N; R ¹ and R ² are independently, NH _2, NHR ⁴ and NR ⁵ ₂ (provided that, R ⁴ and R ⁵ each represents a lower alkyl group) or R ¹ and R ^2, taken together, (a), ( a ring selected from b) and (c), wherein R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkoxy; Is selected from the group consisting of O].

Description

DETAILED DESCRIPTION OF THE INVENTION           Derivatives of the pyrido [2,3,4-k, l] acridine ring system:           Cytotoxic compounds Background of the Invention   The present invention has cytotoxic properties and therefore can be used in the treatment of malignancies Series of novel polycyclic aromatic compounds having a pyrido [2,3,4-k, l] acridine skeleton Related to aromatic alkaloid compounds. The present invention also uses these novel compounds Methods and compositions are provided, as well as methods for making these compounds.   Polycyclic aromatic alcalo based on pyrido [2,3,4-k, l] acridine skeleton Id compounds often exhibit a variety of interesting biological properties, including antitumor activity Are ascidian metabolites in the growing group¹. This group of compounds Depending on the position of fusion between the basic structure present in the natural product and the additional ring, Includes structural types. For example, cystoditin^Two(Cystditines) is the above basic skeleton And, on the other hand, amphimedin^Three(Amphimedine), meridine^FourAnd And Cyst Damin^Five(Cystodamine) has an additional pyridine ring attached to the h bond. I do. Ascididemin⁶(Ascididemin), its derivatives⁷, Quanoniamine⁸(Kuan oniamines) and shellmiramine A⁹(Shermilamine A) describes this additional ring Shown on its i-plane, and elatin^Ten(Eilatine) is shown on both sides. My target The compound is considered to be both the regio isomer of meridine and amphimedine However, these compounds have not been isolated from natural sources to date. Was.  Most of these prior art compounds are very potent against a range of tumor cell lines. Shows interesting cytotoxic properties. These mechanisms of action are clearly established. None, but three general views are published biological data¹¹Revealed from There are: a) these are intercalating agents; b) these are Disrupts DNA and RNA synthesis with little effect on protein synthesis C) they inhibit topoisomerase II. These mechanisms are It is usually accepted for their antitumor activity.   Biological studies on pyridoacridine compounds are available from these natural sources The possibilities are so limited that they are exceptionally limited and therefore these mechanisms Studying mechanisms and establishing credible structure-activity relationships require the development of effective synthetic pathways. Departure is required. Description of the invention   We describe here pyrido [2,3,4-k, l] acto, which has excellent antitumor activity. A series of novel polycyclic aromatic alkaloid compounds having a lysine skeleton have been found.   Accordingly, the present invention provides, in a first aspect, a compound represented by the following general formula (I) And pharmaceutically acceptable salts thereof are provided:   Where:   X is O and NR^ThreeSelected from the group consisting of^ThreeIs a lower alkyl group Represents)   Y is selected from the group consisting of CH and N;   R¹And R^TwoIs NH_Two, NHR^FourAnd NR^Five _TwoIndependently selected from the group consisting of R (where R^FourAnd R^FiveEach represents a lower alkyl group), Iha R¹And R^TwoAre together selected from the following (a), (b) and (c) Represents a ring:(Where R⁶, R⁷And R⁸Represents a hydrogen atom, a lower alkyl group, a hydroxy group, And independently selected from the group consisting of lower alkoxy groups); and   Z is selected from the group consisting of O and NH.   In the definition of groups present in formula (I), lower alkyl groups and lower alkoxy The lower alkyl portion of the group is a straight-chain or branched alkyl having 1 to 6 carbon atoms. A alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, Butyl, sec-butyl, tert-butyl, pentyl, neopentyl and Xyl group.   R¹And R^TwoAre taken together to represent a ring of the formula (a) In the object, R⁶And R⁷Preferably has a hydrogen atom, 1-4 carbon atoms Alkyl groups, hydroxy groups and alkoxy groups having 1 to 4 carbon atoms. Independently selected from the group⁶And R⁷Is a hydrogen atom, Independently selected from the group consisting of tyl and ethyl, and most preferably , R⁶Represents a methyl group, and R⁷Represents a hydrogen atom. Furthermore, R¹You And R^TwoTogether form a ring of formula (a), wherein Z is of the formula NH Preferably it represents a group.   R¹And R^TwoTogether represent a ring represented by formula (b) or (c) In the compounds of the present invention, R⁶, R⁷And R⁸Is preferably a hydrogen atom, a carbon atom Alkyl groups having 1 to 4 carbon atoms, hydroxy groups and 1 to 4 carbon atoms Independently selected from the group consisting of alkoxy groups, more preferably R⁶, R⁷You And R⁸Is selected from the group consisting of hydrogen, methyl, ethyl and hydroxy Independently selected, and most preferably, R⁶Represents a hydroxy group, And R⁷And R⁸Each represents a hydrogen atom.   In a preferred embodiment, the present invention is represented by general structural formula (II) or (III): For newly synthesized compounds:   In each formula, R⁶, R⁷And R⁸Is as defined above.   Among the compounds represented by the general formula (II), R⁶Represents a methyl group, and R⁷ Is particularly preferred (Compound No. IB-96213) .   Among the compounds represented by the general formula (III), R⁷And R⁸Are both hydrogen Compounds representing atoms are particularly preferred (compound number: IB-98205).   The invention also relates to malignant tumors which are sensitive to compounds having the general formula (I) Providing a method of treating a mammal affected by the method, comprising a therapeutically effective amount of a general formula A compound having (I) or a pharmaceutically acceptable salt thereof, Administration to the body.   The present invention also relates to pharmaceutical compositions, particularly those useful for the treatment of malignant tumors. A process for preparing a composition of formula (I), which comprises, as an active ingredient, a compound of general formula (I) Containing compounds.   In another embodiment, the present invention provides compounds of general formula (I), in particular Provided are methods for producing Compound Nos. IB-96213 and IB-98205.   Our strategy for synthesizing target compounds includes o-nitride 4-aryl-1-di- The heterodeposition between methylamino-1,4-azadiene and the appropriate heterocyclic quinone Hetero Diels-Alder reaction followed by quinone carbonyl 1 (Scheme 1).                               Scheme 1   Of the several 4-aryl-1-azadiene compounds evaluated, o-nitro and And o- (trifluoroacetamide) derivatives gave the best results . The first derivative (compound 1a) among these derivatives is prepared by a known method.¹²Using, Manufactured from commercially available o-nitrocinnamaldehyde. Second azadiene derivative ( Compound 1b) was derived from two synthetic methods (Scheme 2). Of these methods The first is the corresponding o-amino derivative produced by reduction of compound 1a 2 including trifluoroacetylation¹². In the second synthesis method, o-amino N-trifluoroacetylation of aldehyde (3), Wadsworth-Emmons coupling with 5 used¹³.                                 Scheme 2  Compound 1b and quinone compound 6 for producing a compound represented by the formula (II) The reaction with¹⁴Diels-Alder adduct in refluxing chloroform A mixture of 7 and the second product 8 was obtained. Compound 7 was converted to Pd- By refluxing in the presence of C, the compound 9 is aromatized to give compound 9 Is first converted to the desired pentacyclic derivative 10 [general structure (II)] by hydrolytic cyclization. (Scheme 3).                                 Scheme 3  Using 6-bromo-4-chloroquinolinequinone compound 11 as dienophile A reversal of the regioselectivity of the Heterodiels-Alder reaction was then achieved. That is, when azadiene 1a is treated with compound 11 under ultrasonic irradiation, The product 12 was obtained. Compound 12 is hydrogenated in the presence of Pd-C and then tritiated. Finished with fluoroacetic acid, pyridoacridine compound 13 [General structure (III)] (Scheme 4).                                 Scheme 4  As an example, 12-methyl-9H-benzo [b] pyrido [4,3,2-d, e] (1,7) phenanthroline-8,10-dione, IB-96213 (general structure 10, where R⁶= CH_Three, R⁷= H) and 9-hydroxybenzo [b] Pyrido [4,3,2-d, e] (1,10) phenanthroline-8-one, IB −98205 (general structure 13, where R⁷= R⁸= H) A detailed method will be described as an example.   The compounds of the present invention are cytotoxic, IB-96213 and IB-9820 Compounds such as 5 show antitumor activity, especially human lung carcinoma, human colon carcinoma and human Shows antitumor activity against cell lines derived from human solid tumors, such as tomelanoma. These compounds are also useful against other tumor cell lines, such as leukemia and lymphoma. Is also active. Compounds of formula (I) such as IB-96213 and I B-98205 has in vitro anti-tumor selectivity for solid tumors.   Examples of pharmaceutical compositions include all that are suitably formulated for oral, topical or parenteral use. Solid dosage forms (tablets, pills, capsules, granules, etc.) or liquid dosage forms (solutions, suspensions, etc.) Suspensions or emulsions), which may contain pure compounds. Or in combination with any carrier or another kind of pharmaceutically active compound Can be. For parenteral administration, these compositions may need to be sterilized. You.   The precise dosage of a pharmaceutical composition containing a compound of Formula (I) will It will vary according to the composition, mode of application, and particularly the location, subject and tumor being treated. Year Age, weight, gender, diet, timing of administration, excretion rate, target condition, combination of drugs, Other factors such as response selectivity and disease severity are taken into account. Dosing is best It can be done continuously or periodically within a tolerated dose. Example   The present invention is further described by the following examples. These examples correspond to the species according to the invention. 1 illustrates the preparation of certain compounds. The reactants used were commercial products (Aldrich Fluka) and used without further purification. Solvent (SDS, Scharlau ) Was purified and dried by standard methods. The reaction was performed using a fluorescent indicator, Sc Monitoring by thin layer chromatography using harlau and Macherey-Nagel plates did. Separation by flash liquid chromatography was performed using silica gel SDS60A. It performed using CC (230-400 mesh).   Melting points are uncorrected and are measured using a Buchi immersion apparatus or Hoffler hot stage microscope. And measured with open capillaries. Combustion element analysis was performed by Perkin Elmer 2400CHN Using the analyzer, Servicio de Microanalisis Elemental, Universidad Complut Obtained by ense. Spectrophotometric data was obtained using the following equipment; IR: Perkin Elm 577 and Perki Elmer Paragon 1000 FT-IR; NMR: Varian VXR-300 (¹For H, 300MHz and¹³75MHz for C) and Bru ker AC-250 (¹For H, 250 MHz and¹³63 C for C).Example 1 12-methyl-9H-benzo [b] pyrido [4,3,2-d, e] (1,7) Phenanthroline-8,10-dione (IB-96213; Compounds where R ⁶ ＣＨCH ₃ and R ⁷ ＨH) Step 1- (a) :4 (o-trifluoroacetamidophenyl) -1-dimethyl Amino-1-azadiene (Formula 1b) Method A   Trifluoroacetic anhydride (1.39 g, 6.63 mmol) was added to dry ethyl ether. -(O-Aminophenyl) -1-dimethylamino-1-aza in toluene (10 mL) Dien (2)¹²(837 mg, 4.42 mmol) was added dropwise to the stirred solution. I got it. The solution was stirred at room temperature for 15 minutes and evaporated under reduced pressure at room temperature. Purification of the residue by chromatography on silica gel, eluting with dichloromethane The title compound 1b was obtained. Yield, 1.023 g (88%).   Data for 1b:   M_p. 110 ° C   C₁₃H₁₄F_ThreeN_ThreeAnalysis as:   Calculated: C, 54.73; H, 4.91; N, 14.73.   Found: C, 54.10; H, 4.19; N, 14.11. Method B   a) o- (trifluoroacetamido) benzaldehyde (4)   O-Nitrobenzaldehyde (3 g, 19.30 g) in 35% aqueous hydrochloric acid (35 mL). (86 mmol) of a suspension of tin (II) chloride (21 g, 93.1 mmol) in small portions Added in minutes. The suspension was stirred at room temperature for 72 hours, Neutralized with an aqueous solution of lithium and extracted with chloroform (4 × 50 mL). Chloroform The combined layers were dried over sodium sulfate and evaporated to o-aminobenzaldehyde. 1.87 g (78%) of C3 were obtained. Part of this residue (1.26 g, 10.4 g) Mmol) was dissolved in dry ethyl ether (5 mL). Cool the solution to 0 ° C Trifluoroacetic anhydride (2 mL, 14.15 mmol) with magnetic stirring It was treated dropwise. The solution was stirred at room temperature for 2 hours. Evaporate the solvent and leave the residue Is eluted on silica gel with a 7: 3 mixture of petroleum ether-dichloromethane Chromatography. Yield of compound 4, 1.65 g (77%).   Data for 4:   M_p. 71-72 ° C   C₉H₆F_ThreeNO_TwoAnalysis as:   Calculated: C, 49.78; H, 2.79; N, 6.45.   Found: C, 49.70; H, 2.59; N, 6.11.   b) Wadsworth-Emmonsre reaction between compounds 4 and 5       action)   Hydrazone 5 in dry tetrahydrofuran placed in a -78 ° C bath¹³(Route A solution of butyllithium in hexane (see scheme (see Scheme 2)) (0.1 mL, 1.1 mmol). For 40 minutes at the same temperature Stir, then aldehyde 4 (217 mg, in dry tetrahydrofuran (1 mL) (1 mmol). The reaction mixture was stirred at 0 ° C. for 4 hours, Aqueous ammonium chloride (10 mL) was added to quench the reaction, and chloroform (4 × 15 mL). The extracts are combined, dried over sodium sulfate, evaporated and the residual Chromatography on silica gel eluting with 1: 1 ethyl ether-petroleum ether Raffy. Yield 103 mg (36%) of the title compound 1b.   Step (1b) 5- (o-trifluoroacetamido) -4-methyl-5,8 -Dihydro-1,8-diazaanthracene-2,9,10-trione (R ⁶ ＣＨCH ₃ and compounds of formula 7 where R ⁷ = H)   Quinone 6 (Scheme 3: R in chloroform (50 mL)⁶= CH_Three, R⁷= H)^14aYou And the azadiene 1b (32 mg, 0.17 ml ) In a bath at 60 ° C. while flowing a stream of argon through the solution. Refluxed for hours. The reaction mixture was evaporated to dryness and the residue was Chromatograph on silica gel eluting with a gradient from ethyl acetate to raw ethyl acetate The resulting 5,8-dihydro derivative 7 (R⁶= CH_Three, R⁷= H ), 25 mg (34%), aromatic compound 9 (see Scheme 3; R⁶= CH_Three, R⁷= H), 20 mg (28%), and compound 8 (see Scheme 3) R⁶= CH_Three, R⁷= H)^14a11 mg (28%) were obtained.   Data for 7:   M_p  192 ° C (AcOEt)   C_{twenty one}H₁₄F_ThreeN_ThreeO_FourAnalysis as:   Calculated: C, 58.77; H, 3.36; N, 9.78.   Found: C, 58.49; H, 3.62; N, 9.57.   Data for 9:   M_p  285 ° C   C_{twenty one}H₁₂F_ThreeN_ThreeO_FourAnalysis as:   Calculated: C, 59.04; H, 2.80; 9.83.   Found: C, 59.22; H, 2.94; 9.59. Step 1 (C) Oxidation of 7-9   Compound 7 (R⁶= CH_Three, R⁷= H) suspension In liquid [200 mg, 0.46 mmol in methanol (50 mL)] solid on charcoal 10% palladium (100 mg, 9 mmol) was added. Stir this suspension vigorously The mixture was refluxed for 48 hours, and filtered through celite. Evaporate the solvent , Title compound 9 (R⁶= CH_Three, R⁷= H) in a yield of 136 mg (69%).   Step 1 (d) 12-methyl-9H-benzo [b] pyrido [4,3,2-d e] (1,7) phenanthroline-8,10-dione (IB-96213; Formula 1) 0, compounds of R ⁶ ＣＨCH ₃ and R ⁷ ＨH)   Compound 9 (R) made by step 1 (d) above in methanol (15 mL)⁶ = CH_Three, R⁷= H), 2N hydrochloric acid solution (2 mL) was added. Reflux this solution for 4 hours Then, the mixture was neutralized with an 8% aqueous sodium bicarbonate solution and extracted with chloroform. Organic layer Evaporate to give the title compound 10 (R⁶= CH_Three, R⁷= H) of 57 mg (78%).   Data for 10:   M_p> 300 ° C (CHCl_Three)   C₁₉H₁₁N_ThreeO_TwoAnalysis as:   Calculated: C, 72.86; H, 3.51; N, 13.41.   Found: C, 72.87; H, 2.82; N, 13.57. Example 2 9-hydroxybenzo [b] pyrido [4,3,2-d, e] (1,10) Nantrolin-8-one (IB-98205, Formula 12 in which R ⁷ = R ⁸ = H Compound) Step 2 (a) 4-chloro-8- (o-nitrophenyl) -1,5-diazaa Untraquinone (compound of formula 12 with R ⁷ = R ⁸ = H)   Quinone 11 in chloroform (1 mL) (Scheme 4; R⁷= R⁸= H)^Fifteen( 185 mg, 0.68 mmol) and o-nitrocinnamaldehyde dimethyl Dorazon 1a¹²(438 mg, 2 mmol) in a solution at 50 ° C. for 125 h Was irradiated. Evaporate the solvent and elute the residue on silica gel with ethyl acetate The title compound 11 was obtained by chromatography. Yield 52 mg (20%) Was.   Data for 12:   M_p. 146 ° C   C₁₈H₈ClN_ThreeO_FourAnalysis as:   Calculated: C, 59.13; H, 2.18; N, 11.48.   Found: C, 59.89; H, 1.99; N, 11.17. Step 2 (b) 9-hydroxybenzo [b] pyrido [4,3,2-d, e] ( 1,10) phenanthroline-8-one ^{(13, R 7 = R 8} = H)   Compound 12 (made in step 2 (a) above in methanol (25 mL) 100 mg, 0.27 mmol) and triethylamine (37 mg) 10% palladium on charcoal (22 mg) was added. 1 hour at 1 atmosphere Hydrogenated and filtered through celite. The celite layer is And a 2: 1 mixture of chloroform and 25 mL of chloroform. Evaporate these washed liquids Chromatography on silica gel, eluting with 9: 1 ethyl acetate: methanol Filtration gave 45 mg of a mixture of the two reduced intermediates. The structure of the intermediate is determined Not determined. To a 35 mg solution of this mixture in methanol (20 mL) was added charcoal ( 8 mg) and 10% palladium was added and the suspension was hydrogenated at 1 atmosphere for 1 hour. And filtered through celite. The solution is evaporated and the residue on silica gel Chromatography gave 6 mg (10%) of the title compound 13.   We have made the following specific compounds by the above synthetic route: IB-9621 3 (general structural formula 10, R⁶= CH_ThreeAnd R⁷= H) and IB-9820 5 (general structural formula 13, R⁷= R⁸= H. These are preferred herein Compound. Biological activity   The compounds of the formula (I) according to the invention show good antitumor activity . In particular, IB-96213 and IB-98205 have been identified in several mammalian cancer cells. Good antitumor activity against vesicle system. Its antitumor activity is described by Bergeron et al.¹⁶ And Schroeder et al¹⁶Culture tumor cells according to the methodology described by It was detected in vitro by feeding. Mouse lymphoma, human N Activity against different tumors such as SC lung carcinoma, human melanoma and human colon carcinoma Was also observed.   Certain tumors are more sensitive than others. For example, NSC lung carcinoma And melanoma cells are 100 times more sensitive than mouse lymphoma and 1000 times more sensitive than colon carcinoma. Example   Biological activity:   Cells are equilibrium salts of Earl, 2.0 mM L-glutamine, non-essential amino acids With no sodium bicarbonate (EMEM / neaa) and 10% wild calf Serum (Feral calf Serum) (FCS), 10^-2M sodium bicarbonate and 0.1 g / l penicillin-G + streptomycin sulfate It was maintained in the logarithmic growth phase in Suzuchi.   The tumor line used was P-388 (ATCC CCL-46, DBA / 2 mouse). Suspension culture of lymphoid neoplasm from A.-549 ( ATCC CCL-185, monolayer culture of human lung carcinoma), HT-29 (ATCC   HTB-38, a monolayer culture of human colon carcinoma), and MEL-28 (ATCC   HTB-38, a monolayer culture of human melanoma).   P-388 cells were treated with a 1 mL aliquot of MEM 5FCS containing the indicated concentration of drug. 1 × 10 per well^Four16 mm wafer Inoculated in the In another set of drug-free cultures, cells are placed in exponential growth phase (exponentia l Inoculation as control growth to ensure that it stays in the Was. All decisions were made in duplicate. 37 ° C, 10% in a humid atmosphere of 98% CO_TwoApproximate IC after incubation for 3 days at₅₀Have a drug Growth in control wells was determined by comparing growth in control wells.   A-549, HT-29 and MEL-28 were converted to M containing the indicated concentration of drug. 2 × 10 per well in 1 mL aliquots of EM 10FCS^FourIndividual cells And inoculated into a 16 mm well. Cells index in another set of drug-free cultures Inoculated as control growth to ensure that it remained in the growth phase. All decisions Went duplicate. 37 ° C, 10% CO in a 98% humid atmosphere_TwoAt 3 After incubation for one day, the wells are dressed with 0.1% crystal violet. Colored. Approximate IC₅₀Is the growth in the wells with drug compared to the growth in control wells. Was determined by comparison with   In Table I, the cytotoxicity expressed as IC at μg / mL and μM is presented Have been.

[Procedure of Amendment] Article 184-8, Paragraph 1 of the Patent Act [Submission date] July 2, 1999 (1999.7.2) [Correction contents]                                The scope of the claims   1. Formula (I): [In the formula X is O and NR^Three(However, R^ThreeRepresents a lower alkyl group).   Bare; Y is selected from the group consisting of CH and N; R¹And R^TwoTogether form (a) and (b):   (Where   R⁶, R⁷And is R⁸Is independently a hydrogen atom, a lower alkyl group,   Z is selected from the group consisting of O and NH   Represents a ring selected from the group consisting of: And pharmaceutically acceptable salts thereof, and of the formula (I): X is O, Y is N, and R¹And R^TwoIs a ring (b) (where R⁶ , R⁷And is R⁸Each of which is hydrogen). Or a pharmaceutically acceptable salt thereof.   2. The compound of claim 1, wherein X represents an oxygen atom.   3. The compound according to claim 1, wherein Y represents a nitrogen atom.   4. R¹And R^TwoRepresents a ring of formula (a) together, Any one of the preceding claims.   5. R¹And R^TwoRepresents a ring of formula (b) together, Any one of the preceding claims.   6. R⁶And is R⁷Independently represent a hydrogen atom, an atom having 1 to 4 carbon atoms. From alkyl, hydroxy, and alkoxy groups having 1 to 4 carbon atoms 5. The compound of claim 4, wherein the compound is selected from the group consisting of:   7. R⁶And is R⁷Consists independently of hydrogen, methyl and ethyl 7. The compound of claim 6, which is selected from the group.   8. R⁶Represents a methyl group and R⁷Represents a hydrogen atom. object.   9. A compound according to any one of claims 4 and 6 to 8, wherein Z represents a group of formula NH. .   10. R⁶, R⁷And is R⁸Is a hydrogen atom, an alkyl having 1 to 4 carbon atoms. A hydroxy group, an alkoxy group having 1 to 4 carbon atoms. 6. The compound of claim 5, which is selected from the group.   11. R⁶, R⁷And is R⁸Independently represent a hydrogen atom, a methyl group, an ethyl group, 11. The compound of claim 10, wherein the compound is selected from the group consisting of:   12. R⁶Represents a hydroxy group and R⁷And is R⁸Are the hydrogen sources, respectively. 12. The compound of claim 11, wherein said compound represents a child.   13. The following equation (II):(Where R⁶And R⁷Is the same as defined in claim 1) 2. The compound of claim 1, having the formula:   14. R⁶Represents a methyl group, and R⁷Represents a hydrogen atom; object.   15. The following equation (III): (Where R⁷And R⁸Is the same as defined in claim 1) 2. The compound of claim 1, having the formula:   16. R⁷And R⁸16. The compound of claim 15, wherein each represents a hydrogen atom.   17. Any of claims 1 to 16 in admixture with a pharmaceutically acceptable carrier or diluent A pharmaceutical composition comprising a compound of formula (I) as defined in any one of the preceding claims.   18. The pharmaceutical composition according to claim 17, which has antitumor activity.   19. The pharmaceutical composition according to claim 18, for treating a malignant tumor.   20. A compound of formula (I) according to any one of claims 1 to 16 for use in therapy. object.   21. Formula (I) according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of malignant tumors Use of the compound of (1).   22. An effective amount of a compound of the formula (I) according to any one of claims 1 to 16 for treating a disease. A method of treating a mammal afflicted with a malignant tumor comprising administering to an affected individual.   23. (a) Formula 1b: Of formula 6: (Where R⁶And R⁷Is the same as defined in claim 1). , Equation 7: (Where R⁶And R⁷Has the same definition as in claim 1); (B) aromatizing a compound of formula 7 in the presence of a Pd-C catalyst to give a compound of formula 9:(Where R⁶And R⁷Has the same definition as in claim 1). hand (Iii) hydrolytically cyclizing the compound of formula 9 to produce a compound of formula (II) A process for the preparation of a compound of formula (II) as defined in claim 13, comprising:   24. (a) Formula 1a: Of formula 11: (Where R⁷And R⁸Is the same as defined in claim 1). , Equation 12:(Where R⁷And R⁸Has the same meaning as defined in claim 1); hand (B) hydrogenating the compound of formula 12 in the presence of a Pd-C catalyst and then acidifying Produce compounds of formula (III) by water splitting A process for preparing a compound of formula (III) as defined in claim 15, comprising:

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 491/16 C07D 491/16 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, H, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW ( 72) Inventor Abendano Lopez, Carmen, Spain, Madrid, Carle Santi Ago Bernabén, 5 (72) Inventor Blanco Castro, Maria del Mar Spain, Madrid, Torrelodones Colonia, Carre Vicente Terz, 40 (72) Inventor Menendez Ramos , Jose Carlos Spain, Madrid, Carle San Raimundo, 7

Claims (1)

Claims 1. Formula (I): Wherein X is selected from the group consisting of O and NR ³ (where R ³ represents a lower alkyl group); Y is selected from the group consisting of CH and N; R ¹ and R ² are NH _2, NHR ⁴ and NR ⁵ ₂ (provided that, R ⁴ and R ^5, their respective a lower alkyl group) selected from the group consisting of or R ¹ and R ² together, (a) And (b): Wherein R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of a hydrogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group; and Z is a group consisting of O and NH 2 And a pharmaceutically acceptable salt thereof, and wherein X is O, Y is N, and R ¹ And R ^{2 form} a ring (b), wherein each of R ⁶ , R ⁷ and R ⁸ is hydrogen. salt. 2. The compound of claim 1, wherein X represents an oxygen atom. 3. The compound according to claim 1, wherein Y represents a nitrogen atom. 4. R ¹ and R ² together represent a ring of formula (a), any one of the compounds of claims 1 to 3. 5. R ¹ and R ² together represent a ring of formula (b), any one of the compounds of claims 1 to 3. 6. R ⁶ and R ⁷ are independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, and an alkoxy group having 1 to 4 carbon atoms. The compound of claim 4. 7. R ⁶ and the R ⁷ is independently hydrogen, selected from the group consisting of methyl and ethyl, The compound of claim 6. 8. The compound of claim 7, wherein R ⁶ represents a methyl group and R ⁷ represents a hydrogen atom. 9. A compound according to any one of claims 4 and 6 to 8, wherein Z represents a group of formula NH. 10. R ⁶ , R ⁷ and R ⁸ are selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, and an alkoxy group having 1 to 4 carbon atoms, A compound according to claim 5. 11. R ^6, R ⁷ and are R ⁸ is independently a hydrogen atom, a methyl group, selected from the group consisting of ethyl and hydroxy groups, A compound of claim 10. 12. The compound of claim 11, wherein R ⁶ represents a hydroxy group and R ⁷ and R ⁸ each represent a hydrogen atom. 13. The following equation (II): Wherein R ⁶ and R ⁷ are the same as defined in claim 1. 14. R ⁶ represents a methyl group, and R ⁷ represents a hydrogen atom, a compound of claim 13. 15. The following equation (III): Wherein R ⁷ and R ⁸ are the same as defined in claim 1. 16. R ⁷ and R ⁸ each represents a hydrogen atom, a compound of claim 15. 17. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 16 in admixture with a pharmaceutically acceptable carrier or diluent. 18. The pharmaceutical composition according to claim 17, which has antitumor activity. 19. The pharmaceutical composition according to claim 18, for treating a malignant tumor. 20. A compound of formula (I) according to any one of claims 1 to 16 for use in therapy. 21. Use of a compound of formula (I) according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of a malignant tumor. 22. A method for the treatment of a mammal affected by a malignant tumor comprising administering to an affected individual an effective amount of a compound of formula (I) according to any one of claims 1 to 16. 23. (a) Formula 1b: Of formula 6: Wherein R ⁶ and R ⁷ are the same as defined in claim 1, and reacting with a compound of formula 7: (B) wherein R ⁶ and R ⁷ are the same as defined in claim 1; (b) aromatizing the compound of formula 7 in the presence of a Pd-C catalyst to give a compound of formula 9: Wherein R ⁶ and R ⁷ are as defined in claim 1: and (iii) hydrolytically cyclizing the compound of formula 9 to form a compound of formula (II) A process for the preparation of a compound of formula (II) as defined in claim 13, comprising: 24. (a) Formula 1a: Of formula 11: Wherein R ⁷ and R ⁸ are the same as defined in claim 1 and reacting with a compound of formula 12: Wherein R ⁷ and R ⁸ are the same as defined in claim 1; and (b) hydrogenating the compound of formula 12 in the presence of a Pd-C catalyst, followed by acidic hydrolysis To produce a compound of formula (III), the method comprising preparing a compound of formula (III) as defined in claim 15.