WO2002051849A1 - Inhibiteurs cdk4 - Google Patents

Inhibiteurs cdk4 Download PDF

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Publication number
WO2002051849A1
WO2002051849A1 PCT/JP2001/011354 JP0111354W WO02051849A1 WO 2002051849 A1 WO2002051849 A1 WO 2002051849A1 JP 0111354 W JP0111354 W JP 0111354W WO 02051849 A1 WO02051849 A1 WO 02051849A1
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group
compound
title compound
same operation
compound obtained
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PCT/JP2001/011354
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English (en)
Japanese (ja)
Inventor
Kouichi Uoto
Takao Horiuchi
Kouichi Akabane
Yasuyuki Takeda
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Daiichi Pharmaceutical Co., Ltd.
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Priority to JP2002552943A priority Critical patent/JPWO2002051849A1/ja
Publication of WO2002051849A1 publication Critical patent/WO2002051849A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel conjugate or a salt thereof, or a hydrate or solvate thereof, having an antitumor effect by a cell cycle regulating action.
  • the present invention also relates to an antitumor agent containing the above substance as an active ingredient, and a method for preventing, treating or treating a tumor using the antitumor agent.
  • chemotherapeutic agents are used as antitumor agents.
  • conventional chemotherapeutic agents act on gene replication and cell division mechanisms in the S phase and M phase, which are the proliferative phases of the cell cycle, and thus kill cells in the proliferative phase non-specifically. This also affects the growth of normal cells typified by bone marrow hematopoietic cells.
  • These are mainly responsible for the side effects of chemotherapeutic agents.
  • serious side effects include reduced immunity due to a decrease in blood cells, infection associated therewith, and diarrhea due to a decrease in gastrointestinal mucosal cells.
  • side effects such as liver dysfunction, nausea, and hair loss and numbness of limbs are known.
  • Cdk cyclin-dependent kinase
  • tumor suppressor genes regulate the cell cycle mainly in the G1 phase, which is a stage before the initiation of cell division.
  • the present inventor believes that this is the case. Therefore, compounds that accumulate cell populations in the G1 phase of the cell cycle can inhibit the growth of cancer cells whose growth control mechanisms are disrupted by impaired function of tumor suppressor genes. The present inventors believe that this may result in a highly specific antitumor effect.
  • the transition from the G1 phase to the S phase of the cell cycle is regulated mainly by the action of the transcription factor E 2 F-1 and the complex of citalin and C dk (Ce 11, 79, 573-582). , 1 994).
  • the transcription factor E2F-1 is inactivated in the G1 phase by Rb protein, a product of the tumor suppressor gene Rb.
  • Rb protein a product of the tumor suppressor gene Rb.
  • a complex of cyclin D and C dk subtype Cdk 4 or C dk 6 and a complex of cyclin E and Cdk 2 are formed, and the complex of these cyclins and C dk is formed.
  • the phosphorylated Rb protein is released from E2F-1, and E2F-1 induces the transcription of various genes, and the cell cycle shifts from G1 to S phase (Cancer D etect P Rev., 24, 107-118, 2000.).
  • Cancer cells such as cancer, colorectal cancer, and skin cancer, have increased expression of cyclin D and E (Breast Cancer Res. Treat., 52, 1-15, 1998 ⁇ ) .
  • Endogenous proteins that suppress the phosphorylation ability of the complex between cyclin and C dk include the pi6, p27 and p21 proteins (Cancer and Chemotherapy., 24, 1407-1413, 1997) ).
  • the pi6 protein is the product of the tumor suppressor gene p16, which binds specifically to Cdk4 and is complexed with cyclin D and Cdk4: inhibits phosphorylation of Rb protein (proteins, nucleic acids, enzymes, 42 , Sup pl., 1 554-1561, 1997.).
  • the binding of pi6 protein to Cdk4 causes the p27 protein to dissociate from Cdk4 and bind to the complex of Cdk2 and cyclin E, and the Rb protein by the complex of Cdk2 and cyclin E. Inhibits the phosphoric acid illness (Cancer Res., 60, 3689 -3695, 2000 ⁇ ).
  • the expression of p21 protein is induced by the product of the tumor suppressor gene p53.It binds to the complex of Cdk2 and cyclin E and inhibits the phosphorylation of Rb protein by the complex of Cdk2 and cyclin E. It suppresses the transition of the cell cycle to the S phase and is also involved in gene repair (Pathoi. Biol., 48, 190-202, 2000.).
  • a compound inhibiting C dk 4 activity suppresses the phosphorylation of the Rb protein by the complex of cytaline D and C dk 4, thereby suppressing the transition of the cell from G 1 phase to S phase, and inhibiting cell population. Is likely to accumulate in the G1 phase.
  • the present inventors have proposed that the activity of the transcription factor E 2 F-1 is determined when a compound inhibiting C dk 4 activity binds to C dk 4 and phosphorylation of the R b protein by the complex of cyclin D and C dk 4 is inhibited.
  • the transition from G1 phase to S phase is suppressed, and as a result, the compound inhibiting Cdk4 activity suppresses the growth of cancer cells whose growth control mechanism has been disrupted. Therefore, it is considered that the C dk4 activity-inhibiting compound has a potential as an antitumor agent with reduced side effects.
  • C d k has subtypes.
  • C dk 4 is specifically activated as a complex with cytalin D in the G 1 phase in preparation for transition to the S phase of the cell cycle.
  • C dk 2 is activated in the final stage of the transition of the cell cycle to the S phase as a complex with cytaline E in the G1 phase, and as a complex with cytaline A in the S phase. Activated during the transition from S phase to G2 phase.
  • subtypes that form a complex with cyclin B and are involved in the transition from G2 phase to M phase such as Cdkl, are also known.
  • the present inventors have found that inhibition of the activity of each of the above subtypes of C dk without quantitatively discriminating it does not increase the G1 phase mainly in the population of cells. To accumulate in the G1 phase, it is necessary to specifically inhibit the activity of Cdk4, which is involved in cell cycle regulation, only in the G1 phase.
  • the present inventors induced cancer cells in which the proliferation mechanism was disrupted because the tumor suppressor gene became nonfunctional due to a defect or the like in the G1 phase to the G1 phase (G1-phase inducing action). It is thought that suppressing growth is effective in suppressing cancer itself (growth suppressing effect) and can reduce side effects. Therefore, as a compound that can be an antitumor agent by this new mechanism of action, a compound that specifically increases the G1 phase in a cell population is desirable, and a compound that specifically inhibits C dk4 activity is that compound. We believe it will be a powerful catcher.
  • the problem of the present invention is that it has a novel chemical structure that has not been known before and acts on the cell growth phase (S phase or M phase) like a conventional chemotherapeutic agent with serious side effects. Rather, it is a compound that specifically inhibits the activity of Cdk4, which is involved in the cell cycle, in the G1 phase, which is the early stage of cell division, and inhibits the growth of cancer cells by inducing the G1 phase.
  • An object of the present invention is to provide an antitumor compound having an effect and, consequently, reduced side effects.
  • general formula (I) means either of the following general formulas (IA) or (IB)).
  • the present invention provides a compound represented by the following general formula (I) or a salt thereof, or a hydrate or solvate thereof.
  • X represents a sulfur atom, an oxygen atom, or N—R 5 (R 5 represents a hydrogen atom or an alkyl group which may have a substituent);
  • Y represents a nitrogen atom or CH
  • Z is a nitrogen atom or C-R 6 ( 6 is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a carbamoyl group, a carboxy group, or a C ⁇ 2 R 61 (R 61 is Which represents an alkyl group);
  • R 1 and R 2 each independently represent a hydrogen atom, an alkyl group, an 'alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an acyl group, a mercapto group, an alkylthio group, an alkylsulfiel group, an alkylsulfo-
  • R 3 represents a hydrogen atom, an alkyl group, or an aryl group, and the alkyl group or the aryl group may have a substituent;
  • R 4 represents a hydrogen atom or an alkyl group which may have a substituent
  • A is the formula (II):
  • R 7 represents a hydrogen atom or an alkyl group which may have a substituent
  • R 8 represents an alkyl group, an aryl group, or a heterocyclic group, and these groups may have a substituent.
  • R 9 represents a hydrogen atom or an alkyl group which may have a substituent
  • a cyclin containing, as an active ingredient, a compound represented by the above general formula (I) and a salt thereof, and a substance selected from the group consisting of a hydrate and a solvate thereof.
  • a cell containing a substance selected from the group consisting of the compound represented by the general formula (I) and salts thereof, and hydrates and solvates thereof as an active ingredient; Periodic regulator; cell cycle G1 phase containing as an active ingredient a compound represented by the above general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof.
  • An accumulating agent is provided.
  • the present invention provides a compound represented by the above general formula (I) and a salt thereof, and a hydrate and a solvate thereof for the production of the above-mentioned medicament.
  • Use of the selected substance a method for preventing and / or treating a tumor, preferably a method for preventing and / or treating a malignant tumor, wherein the compound represented by the above general formula (I) and a salt thereof, and a salt thereof
  • a method comprising administering a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of hydrates and solvates thereof to mammals, including humans;
  • a method comprising the step of contacting a cell with an effective amount of a substance selected from the group consisting of the compound represented by the general formula (I) and a salt thereof, and a hydrate and a solvate thereof.
  • an alkyl group or an alkyl moiety in a substituent containing an alkyl moiety may be linear, branched, cyclic, or a combination thereof.
  • the number of carbon atoms is 1 to 15, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms.
  • the number of carbon atoms is 3 to 18, preferably 3 to 15 carbon atoms, and more preferably 3 to 10 carbon atoms.
  • alkyl group methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, n-propyl group —Pentyl / le, isopentyl, neopentyl, cyclopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, n-octyl, etc. Can be mentioned.
  • alkenyl group may be linear, branched, cyclic, or a combination thereof, unless otherwise specified, and has one or more carbon-carbon double bonds. When it has two or more double bonds, they may be either conjugated or non-conjugated.
  • the number of carbon atoms is 2 to 15, preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms.
  • the number of carbon atoms is from 4 to 18, preferably from 4 to 15, and more preferably from 4 to 10.
  • alkynyl group may be linear, branched, cyclic, or a combination thereof, unless otherwise specified, and has one or two carbon-carbon triple bonds. Have more. In the case of other than a ring, the number of carbon atoms is 2 to 15, preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms. Further, in the case of a ring, the number of carbon atoms is from 6 to 18, preferably from 6 to 15, and more preferably from 6 to 10. Specific examples include an ethyl group and a propynyl group.
  • Halogen atom means any of a fluorine, chlorine, bromine or iodine atom.
  • Aryl group means a monovalent group obtained by removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon.
  • the aromatic ring constituting the aryl group may be either a single ring or a condensed ring.
  • the number of carbon atoms is from 6 to 25, and among them, the number of carbon atoms is preferably from 6 to 20, and the number of carbon atoms is more preferably from 6 to 15.
  • a phenyl group, a tolyl group, a biphenyl group, a naphthyl group and the like can be mentioned.
  • Aryl ring means a ring structure of an aromatic hydrocarbon, and is preferably a benzene ring.
  • Alkyl group means a group in which one or more hydrogen atoms of an alkyl group are substituted with the above-mentioned aryl group.
  • the number of carbon atoms is 7 to 26, preferably 7 to 21 carbon atoms, and more preferably 7 to 16 carbon atoms.
  • a benzyl group, a benzhydryl group, a trityl group and the like can be mentioned.
  • acyl group means a carbonyl group to which a hydrogen atom, an alkyl group, an 'or an aryl group is bonded, and examples thereof include a formyl group, an acetyl group, a propanol group and a benzoyl group.
  • heterocyclic group means a group derived from a monocyclic or bicyclic saturated or unsaturated heterocyclic compound, and includes, as a ring structure atom, an oxygen atom, a nitrogen atom or a sulfur atom. Contains one or more heteroatoms selected.
  • heterocyclic ring constituting a monocyclic heterocyclic group having a carbon atom number of, for example, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, isoxazonole, Thiazole, isotiazole, oxaziazole, thiadiazo Pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, triazine, pyrazine, piperazine, dioxane, pyran, or morpholine.
  • heterocyclic ring constituting the bicyclic heterocyclic group include benzofuran, indolizine, benzothienephen, indone, naphthyridine, quinoxaline, quinazoline, and
  • Heteroaryl ring means a ring structure of an aromatic heterocyclic compound, and the aromatic heterocyclic compound may be monocyclic or polycyclic.
  • the heteroaryl ring contains one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • a pyridine ring is suitable.
  • X is preferably a sulfur atom
  • Y and Z are each preferably a nitrogen atom.
  • R 3 is a hydrogen atom.
  • a compound represented by the formula (IA) is preferable.
  • R 2 is preferably an alkyl group.
  • the alkyl group in addition to an unsubstituted alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group
  • an alkyl group having one or more substituents selected from the group consisting of a dialkylamino group, a dialkylglycyloxy group, an alkylsulfonyloxy group, and a sulfamoyloxy group is preferable.
  • Preferred among the above substituents are hydroxyl groups.
  • the alkyl group represented by R 2 a branched alkyl group having about 3 to 6 carbon atoms is preferable.
  • R 2 is more preferably a t-butyl group which may be substituted with one or more hydroxyl groups. .
  • A is preferably a group represented by the following formula (II).
  • a phenyl group can be suitably used as R 8 .
  • the phenyl group include an unsubstituted phenyl group and the following groups:
  • Fluoro chloro, bromo, eodo, alkyl, hydroxyalkyl, substituted silyloxyalkyl, propyloxyl, alkoxycarbonyl, tetrazolyl, amino, monoalkylamino, dialkylamino, Cyano group, carbamoyl group, nitro group, hydroxyl group, alkoxy group, mercapto group, sulfonamide group, benzyloxy group, N-alkylsulfamoyl group, N, N- '
  • R 11 represents a hydrogen atom, an alkyl group or a hydroxyalkynole group
  • m 2 represents an integer of 0 to 6; R 12 and R 13 each independently represent a hydrogen atom, an alkyl group, an alkoxycarbonylalkyl group, or a hydroxyalkyl group) Base
  • Is a group group represented by A is represented by formula (II), R 7 is a hydrogen atom or an alkyl group, a group R 8 is represented by formula (VII), from m 2 is 0 An integer of 6,
  • R 13 are each independently a hydrogen atom, an alkynole group, an ⁇ / recoxycarboninoalkyl group or a hydroxyalkyl group;
  • R 7 has the same meaning as described above, the nitrogen-containing ring fused to the benzene ring is a 5- to 7-membered ring, and R 14 is a hydrogen atom, an alkoxycarbonyl group, an alkyl group, an alkoxycarbonylalkyl Or a methoxylalkyl group).
  • a group represented by A is a group represented by the formula (II), R 7 is as defined above, and R 8 is a 5- or 6-membered heterocyclic group (the heterocyclic group has a substituent; And when the ring-constituting atom is 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, it is preferably a 5-membered heterocyclic group (the The heterocyclic group may have a substituent, and contains 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom);
  • a group represented by A is a group represented by the formula (II), R 7 is as defined above, and R 8 is a thiazolyl group, an oxazolyl group, a chenyl group, an imidazolyl group, a pyridinyl group, an isoxoxazolyl group , Isothiazolyl, or furyl (the above group is one selected from the group consisting of a fluoro group, a chloro group, a bromo group, an odo group, an alkyl group, an aminoalkyl group, a monoanolealkyl aminoalkyl group, and a dialkylaminoalkyl group Or may have two or more substituents); and
  • R 7 has the same meaning as described above, and R 8 is a pyridyl group. Fluoro, chloro, bromo, eodo, hydroxyl, alkoxy, benzyloxy, nitro, amino, alkyl, hydroxyalkyl, formula (IX):
  • m 3 represents an integer of 0 to 6; R 15 and R 16 each independently represent a hydrogen atom, an alkyl group, a dialkylaminoalkyl group or a cycloalkyl group) Group,
  • m 4 is an integer of 0 to 6; G is an oxygen atom, a sulfur atom, SO, S 0 2, means a CH 2 or N- R 1 7, R 1 7 is hydrogen atom or an alkyl group £), and
  • m 5 represents an integer of 0 to 6
  • m 5 represents an integer of 0 to 6
  • R 7 has the same meaning as described above; the nitrogen-containing ring fused to the thiazolyl ring is a 5- to 7-membered ring;
  • R 18 is a hydrogen atom, an alkyl group, an alkoxyl alkyl group, a carboxyl group An alkynole group or an alkoxyl group), or
  • R 7 has the same meaning as described above, and R 19 and R 2 each independently represent a hydrogen atom, an alkyl group, an alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, or a nitrogen-containing heterocyclic group.
  • a cyclic group, and the above-mentioned alkyl group may be substituted with an amino group, a monoalkylamino group or a dialkylamino group).
  • the group represented by A in the compound represented by the general formula (I) is a group represented by the formula (IV)
  • a benzene ring or a pyridine ring is preferable.
  • the group represented by A is a group represented by the following formula (XIV) or (XV).
  • R 4 is preferably a hydrogen atom
  • the group represented by A is preferably the above formula (XIII).
  • R 19 or R 2 It is more preferable that one of the degrees is a hydrogen atom and the other is an alkyl group substituted with an amino group, a monoalkylamino group, or a dialkylamino group.
  • the number of carbon atoms of the alkyl group substituted by the amino group, the monoalkylamino group, or the dialkylamino group is 1 to 4, more preferably 2 to 3 The number is particularly preferably 2.
  • X is preferably a sulfur atom
  • R 1 is a hydrogen atom
  • R 2 is preferably an alkyl group.
  • the alkyl group represented by R 2 Has preferably about 3 to 6 carbon atoms, more preferably 4 carbon atoms, and the alkyl group is preferably an alkyl group having a branched chain.
  • X is a sulfur atom
  • R 2 is an alkyl group
  • R 1 is preferably a hydrogen atom.
  • the carbon atom of the alkyl group represented by R 2 The number is preferably about 3 to 6, more preferably 4, and the alkyl group is preferably an alkyl group having a branched chain.
  • R 8 is an aryl group or a heterocyclic group (the aryl group or the heterocyclic group may have a substituent);
  • the heterocyclic group may be substituted with a 5-membered heteroaryl group, a heterocyclic group comprising a phenyl group condensed with a saturated heterocyclic ring, or a condensed heterocyclic group 5 Compounds which are membered heteroaryl groups;
  • R 1 is a hydrogen atom
  • R 2 is a branched alkyl group having about 3 to 6 carbon atoms
  • R 3 is a hydrogen atom
  • R 4 is A hydrogen atom
  • the group represented by A is the above formula (XIII)
  • R 7 is a hydrogen atom
  • R 19 or R 2 A compound in which one of is a hydrogen atom and the other is an alkyl group having 2 to 3 carbon atoms substituted with an amino group, a monoalkylamino group, or a dialkylamino group; and
  • R 1 is a branched alkyl group having about 3 to 6 carbon atoms
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is A hydrogen atom
  • a group represented by A is the above formula (XIII)
  • R 7 is a hydrogen atom
  • R 19 or one of 2 ° is a hydrogen atom
  • the other is an amino group
  • the compound of the present invention represented by the general formula (I) may have one or more asymmetric carbons depending on the type of the substituent, but may have an optical activity based on one or more asymmetric carbons.
  • Stereoisomers in pure form such as isomers or diastereoisomers, any mixture of stereoisomers, or racemates are all within the scope of the invention.
  • the arrangement of the double bond may be either Z or E, and a mixture of Z form or E form is also within the scope of the present invention. It is included in.
  • the bond represented by a wavy line indicates that the compound represented by the formula (I) is either syn or anti isomer, or both isomers.
  • the mixture containing the above-mentioned isomer in any ratio is also included in the scope of the present invention.
  • the compound of the present invention can be produced by various methods.
  • One example of the production method is shown below.
  • the reaction can be carried out, if necessary, by protecting the substituent with a protecting group, but the order of conversion of each substituent is not particularly limited.
  • the compound (5) of the present invention is obtained by reacting a hydrazine compound represented by the formula (3) with a small excess amount of an aldehyde compound or a ketone compound represented by the formula (4), and then, if necessary, removing a protecting group. Or by converting the functional group.
  • the reaction is carried out in a solvent at room temperature or under heating, but depending on the type of aldehyde and ketone, the reaction proceeds smoothly by heating under reflux, and the reaction can be further performed using a dehydrator. More advantageous.
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • the removal of the protecting group may be performed according to a conventional method.
  • an esterified compound is obtained by subjecting an alcohol compound of the compound obtained by the above-mentioned production method to acylation using a carboxylic acid or an acid chloride by a usual organic chemical method. be able to.
  • an ether compound can be obtained by, for example, a method of reacting an alcohol compound with an alkyl halide.
  • olebamate can be obtained by a method of reacting an isocyanate with an alcohol compound.
  • a halogen compound can be obtained by reacting a commonly used hagogenizing agent with the alcohol compound.
  • the compound (5) of the present invention produced by the above production method can be isolated and purified as a free form or a salt thereof. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, distillation, crystallization, filtration, recrystallization, and various types of mouth chromatography.
  • the thus obtained free conjugate or its salt can be further converted to another salt by subjecting it to a usual salt formation reaction.
  • the intermediate (3) of the compound of the present invention can be produced from the chloro compound represented by the formula (2).
  • the starting compound (2) is dissolved in an alcohol, for example, methanol, ethanol, isopropyl alcohol, butanol or an organic solvent that does not participate in the reaction, and hydrazine is cooled, at room temperature, heated or refluxed by a usual method.
  • an alcohol for example, methanol, ethanol, isopropyl alcohol, butanol or an organic solvent that does not participate in the reaction
  • hydrazine is cooled, at room temperature, heated or refluxed by a usual method.
  • Compound By acting, compound (3) can be produced.
  • the intermediate (2) of the compound of the present invention can be obtained from the aldehyde compound or ketone compound represented by the formula (1): It can be produced using the method described in literature Synth. Commun. 1996, 26, 3733).
  • R 3 is other than a hydrogen atom
  • X is a sulfur atom
  • Z and Y are both nitrogen atoms
  • they can be produced by the method reported in literature, Chein. Ber. 1966, 99, 94).
  • the compound (2) can also be produced according to the method described in Patent (SU-725433).
  • the compound (9) having a different position of the sulfur atom can be obtained from the starting compound (7) obtained from the compound represented by the formula (6) according to the method described in the literature (J. Heterocyclic Chem. 1989, 26, 1575). ) Can be manufactured from mosquitoes.
  • the compound of the present invention can be converted into a salt, preferably a physiologically acceptable salt, using an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as formic acid, acetic acid or methanesulfonic acid, if desired. it can.
  • an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid
  • an organic acid such as formic acid, acetic acid or methanesulfonic acid, if desired. it can.
  • the scope of the present invention includes any salt form of the substance.
  • the free form or salt of the compound of the present invention may exist as a solvate such as a hydrate. It goes without saying that these substances are also included in the scope of the present invention.
  • the medicament of the present invention is useful as an antitumor agent.
  • the active ingredient of the medicament of the present invention includes the compound represented by the above general formula (I), a physiologically acceptable salt thereof, and a compound thereof.
  • a substance selected from the group consisting of these hydrates and their solvates can be used.
  • the medicament of the present invention the above-mentioned substance which is an active ingredient may be administered as it is, but usually, a pharmaceutical composition is prepared by using one or more pharmaceutically acceptable additives for preparation. It is desirable to administer.
  • the administration route of the medicament of the present invention is not particularly limited. For example, parenteral administration by various injections such as intravenous injection, intramuscular injection, and subcutaneous injection, or oral administration can be selected. Among these administration methods, intravenous administration and oral administration by an aqueous preparation are preferred.
  • aqueous preparations for parenteral administration are generally prepared using physiologically acceptable salts having excellent water solubility.
  • a pharmaceutical composition for oral administration it can be prepared using a free substance or a physiologically acceptable salt.
  • compositions suitable for oral administration include, for example, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like.
  • suitable pharmaceutical compositions include injections, drops, inhalants, and suppositories. These pharmaceutical compositions can be supplemented by commonly used preparation methods.
  • Injectables may generally contain a stabilizer, a preservative, a solubilizing agent, or a painless pill.
  • a solution containing the above-mentioned substance as an active ingredient and, if necessary, these pharmaceutical additives is prepared and stored in a container, and then a pharmaceutical composition for time preparation is prepared as a solid preparation by freeze-drying or the like. You may. Also, one dose may be stored in a container, or a plurality of doses may be stored in the same container.
  • Liquid preparations for oral administration include, for example, liquid preparations, suspensions, emulsions and the like.In preparing these preparations, suspensions, emulsifiers and the like can be used as additives. . '
  • the medicament of the present invention When the medicament of the present invention is used as an antitumor agent, it is preferable to administer once a day for an adult and repeat the administration at appropriate intervals.
  • the dose is in the range of 1 Omg to 3 g, preferably 5 Omg to 2 g per day for an adult, in terms of the weight of the active substance.
  • the nuclear magnetic resonance spectrum shows the result of 400MHz-'H-MR (TMS internal standard).
  • the obtained residue was dissolved in 40 ml of chloroform, and 6.85 g of activated manganese dioxide was added at room temperature, and the mixture was stirred for 1 hour, and the same amount of a manganese reagent was further added for 1 hour.
  • Step 1 of Reference Example 1 The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate as the starting material to obtain the title compound as a yellow oily substance.
  • Step 2 of Reference Example 1 The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a starting material to obtain the title compound as a yellow oily substance.
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a pale brown solid.
  • Step 2 of Reference Example 4 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 4 was carried out to obtain the title compound as a pale yellow oily substance.
  • step 1 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of Example 4 was performed to obtain the title compound as a yellow solid.
  • step 1 Using 4-chlorosulfonylbenzoic acid and methylbiperazine as raw materials, the same operation as in Reference Example 4, step 1 was performed to obtain the title compound as a colorless solid.
  • Step 2 of Example 4 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 4 was performed to obtain the title compound as a pale yellow oily substance.
  • Step 1 of Reference Example 1 The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate and diethanolamine as raw materials to obtain the title compound as a pale yellow oily substance.
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a yellow oily substance.
  • Step 2 of Reference Example 1 The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a raw material to obtain the title compound as a yellow oily substance.
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a yellow oily substance.
  • Step 1 of Reference Example 1 The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate and-(2-hydroxyethyl) pirazine as starting materials to obtain the title compound as a brown solid.
  • Step 2 of Reference Example 1 The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a raw material to obtain the title compound as a colorless solid.
  • the obtained silyl compound was dissolved in 6 ml of -dimethylformamide, and 208 mg of sodium azide and 172 mg of sodium chloride were added. The mixture was stirred at 100 ° C for 18 hours. The reaction solution was returned to room temperature, a 1N aqueous hydrochloric acid solution was added thereto, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to obtain 519 mg of the title compound as a pale yellow oily substance. MS (FAB) m / z 415 (M + H + ).
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a yellow oily substance.
  • the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the amino compound (3.8 g).
  • 2.0 g of the obtained amino compound was suspended in 4 ml of water, and 12 ml of concentrated hydrochloric acid was added. Under ice cooling, 0.85 g of sodium nitrite dissolved in 2 ml of water was added dropwise to prepare a diazodium salt.
  • a solution of diazonium salt was added dropwise to a solution of 1.39 g of cuprous chloride in 3 ml of concentrated hydrochloric acid under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline.
  • step 1 of reference example 2 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of reference example 2 was performed, and then the same operation as in step 1 of reference example 1 and further step 2 of reference example 1 was performed, whereby the title compound was converted into a yellow oil As obtained.
  • step 1 of Reference Example 2 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Reference Example 2 was performed, and the same operation as in step 1 of Reference Example 1 was performed using the compound to obtain the title compound as a pale yellow oily substance. MS (FAB) m / z 324 (M + H + ).
  • the title compound was obtained as a pale yellow oily substance by performing the same operation as in Step 2 of Reference Example 1 using the compound obtained in the above Step 2 as the original product. .
  • the obtained monobromide was dissolved in -dimethylformamide (35 ml), phthalimide potassium salt (6.33 g) was added, and the mixture was stirred at room temperature for 20 hours.
  • the reaction solution was diluted with ethyl acetate and getyl ether, washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was reprecipitated with -hexane and ethyl acetate to give 3.64 g of a monoalcohol as a colorless solid.
  • the same procedure as in Reference Example 14 was performed using the obtained alcohol compound as a raw material, to give 2.87 g of the title compound as a colorless solid.
  • the obtained monobromide was dissolved in 70 ml of -dimethylformamide, 7.06 g of sodium azide was added, and the mixture was stirred at 120 ° C for 20 hours.
  • the reaction solution was returned to room temperature, filtered through celite, and concentrated under reduced pressure.
  • the obtained residue was diluted with ethyl acetate and getyl ether, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a colorless oily substance.
  • the obtained residue was extracted with ethyl acetate, and washed sequentially with a saturated aqueous solution of ammonium chloride and a saturated saline solution.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • step 3 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Reference Example 2 was performed, and then the same operation as in step 1 of Reference Example 1 was performed to obtain the title compound as a brown oily substance.
  • Awakening (CDC1 3 ) ⁇ : 1.41 (t, 3H, / 7.1 Hz), 2.37 (s, 6H), 3.82 (s, 2H), 4.42 (q, 2H, J2 7.1 Hz), 8.15 (s, 1H).
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a pale brown solid.
  • Step 2 of Reference Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the compound as a colorless oily substance.
  • Reference Example 33 3 The same operation as in step 1 was performed using aminoethyl oxoacetate and 2_bromo-1-cyclopropylethanone as the starting materials to obtain the title compound as a yellow oily substance.
  • step 2 of the reference example 1 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of the reference example 1 was performed to obtain the title compound as a colorless oily substance.
  • Step 1 of Reference Example 34 The same operation as in Step 1 of Reference Example 34 was carried out using formamide and ethyl 2-chloroacetoacetate as raw materials to obtain the title compound as a yellow oily substance.
  • Step 1 '
  • Ts-N Step 1 Ts-N ⁇ ⁇ S Step 2 > Ts ⁇ S
  • the extract was made alkaline with a 10N aqueous sodium hydroxide solution under ice-cooling, a solution of 0.55 g of di-dibutylbutyl dicarbonate in 20 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 23 hours.
  • the reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate.
  • step 2 of the reference example 1 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of the reference example 1 was performed to obtain the title compound as a colorless oily substance.
  • reaction solution was filtered through celite, 200 ml of ethyl acetate and an aqueous solution of saturated sodium chloride were added to the filtrate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and dried under reduced pressure.
  • the solvent was distilled off.
  • Reference Example 34 The same procedure as in Step 1 of Reference Example 34 was performed using 2- ⁇ [ ⁇ -butyl (diphenyl) silyl] oxy ⁇ acetamide as a raw material to obtain the title compound as a pale yellow oil.
  • Step 1 of Reference Example 44 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 1 of Reference Example 44 was carried out to obtain the title compound as a brown oily substance.
  • the title compound was obtained as a colorless solid by performing the same operation as in Reference Example 18 using the compound obtained in the above Step 1 as a starting material.
  • the title compound was obtained as a colorless solid substance by performing the same operations as in Step 1 of Reference Example 27 using 2-chloro_3-hydroxypyridine and styrene as raw materials.
  • step 2 of Reference Example 27 Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of Reference Example 27 was performed to obtain 17 mg of the title compound as a yellow solid.
  • Reference Example 5 7 The same operation as in Step 3 of Reference Example 43 was carried out using the compound obtained in Step 2 as a raw material and cyclopropylamine in place of methylamine to obtain the title compound as a colorless oily substance.
  • Reference Example 5 7 The same operation as in Step 3 of Reference Example 43 was carried out using the compound obtained in Step 2 as a raw material and using cyclobutylamine instead of methylamine to obtain the title compound as a colorless oily substance.
  • Step 2 of Reference Example 52 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 52 was carried out to obtain the title compound as a pale yellow oily substance.
  • step 2 Using the compound obtained in the above step 2 as a raw material, the same operation as in step 3 of Reference Example 52 was carried out to obtain the title compound as an orange oily substance.
  • Example 1 Using the compound obtained in Step 4 of Example 1 and 5-methylisatin as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 Using the compound obtained in Step 4 and 4-methoxybenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 1 Using the compound obtained in Step 4 and trimethylacetaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example. [Example 5]
  • Example 1 Using the compound obtained in Step 4 and cyclopropanecanoleboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 1 The same procedure as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and thiazole-2-phenoloxyaldehyde as raw materials to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 Using the compound obtained in Step 4 of Example 1 and thiazole-5-phenoloxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 Using the compound obtained in Step 4 and 1-methyl-imidazole-2-hexyloxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 Using the compound obtained in Step 4 of Example 1 and 2-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 1 Using the compound obtained in Step 4 of Example 1 and 5-methyl-2-thiophenecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 1 shows the structural formula and physical properties of the compound of this example.
  • Example 1 shows the structural formula and physical properties of the compound of this example.
  • step 1 of Example 1 The same operation as in step 1 of Example 1 was carried out using 3-methylbutyraldehyde as a raw material to obtain the title compound as a yellow oily substance.
  • Step 2 of Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a yellow-green solid.
  • step 3 of Example 1 The same operation as in step 3 of Example 1 was performed using the compound obtained in the above step 2 as a starting material, to give the title compound as a brown oil.
  • Step 3 Using the compound obtained in the above Step 3 as a starting material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a pale yellow solid.
  • Example 16 The title compound was obtained as a pale yellow solid by performing the same operation as in Step 1 of Example 1 using the compound obtained in the above Step 4 as a starting material.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example. .
  • Example 15 Using the compound obtained in Step 4 and 2-furaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and thiazole-5-carboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 1 5 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and thiazole-2-hexylcarboxyaldehyde as the starting materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 The same operation as in Example 1, Step 5 was performed using the compound obtained in Step 4 and 1- (2-thenyl) -1-ethanone as the starting materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and benzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and 2-cyclopentene benzaldehyde as raw materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and 3-chlorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and 4-neck mouth benzaldehyde as raw materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and 2-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and 2-fluorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and 3-fluorobenzaldehyde as raw materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 Using the compound obtained in Step 4 and 3-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example. [Example 28]
  • Example 15 Using the compound obtained in Step 4 and 4-pyridinepyridine as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 15 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 1 as starting materials to obtain the title compound as a yellow solid.
  • Table 2 shows the structural formula and physicochemical properties of the compound of this example.
  • step 1 of Example 1 The same operation as in step 1 of Example 1 was performed using 3,3-dimethylbutyraldehyde as a raw material to obtain the title compound as a yellow solid.
  • Step 2 of Example 1 Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a pale yellow solid.
  • step 3 of Example 1 The same operation as in step 3 of Example 1 was performed using the compound obtained in the above step 2 as a starting material, to give the title compound as a brown oil.
  • Step 3 Using the compound obtained in the above Step 3 as a starting material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a pale yellow solid.
  • step 5 of Example 1 The same operation as in step 5 of Example 1 was performed using the compound obtained in the above step 4 as a raw material to obtain the title compound as a colorless solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and 3-pyridinecarboxyaldehyde as the starting materials to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 4-pyridinecarboxaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 3 Using the compound obtained in Step 4 and 5-methyl-2-pyridine-functional carboxylic acid (Zr 1994, 43, 1175) as raw materials, the same operation as in Step 1 of Example 1 was performed to convert the title compound to a yellow solid. As obtained.
  • the structural formula and physicochemical properties of the compound of this example are not shown in o.
  • Example 30 The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 4 and 3-tetrafluoro-2-pyridine terboxylaldehyde (Tetrahedron 1998, 54, 6311) as raw materials, and the title compound was converted to a yellow solid. As obtained. Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 1 of Step 1 as starting materials to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and 3-nitro-2-pyridinecarboxaldehyde (Tetrahedron 1998, 54, 6311) as raw materials, the same operation as in Step 5 of Example 1 was performed, The title compound was obtained as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example. [Example 3 9]
  • Example 30 Using the compound obtained in Step 4 and 3-(-butoxycarbonyl) amino-2-pyridinecarboxaldehyde (etrahedron 1998, 54, 6311) as starting materials, the same operation as in Example 1 Step 5 was carried out. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 6, 7-dihydro-8 (5-quinolinone (J. Org. Chem. 1984, 49, 2208) as raw materials, the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 4 Using the compound obtained in Step 4 and Reference Example 5 4 as the starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 The same operation as in Step 5 of Example 1 using the compound obtained in Step 4 and 6-[(/ V; -dimethylamino) methyl] -2-pyridinecarboxaldehyde (Japanese Patent Application No. 4-1021159) as raw materials was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 6-methyl-2-pyridinecarboxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 5-fluoro-2-pyridinecarboxaldehyde a Med. Chem. 1970, 13, 1124) as the starting materials, the same operation as in Step 1 of Example 1 was performed, and the title compound was yellow. Obtained as a solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 4-chloro-2-pyridinecarboxyaldehyde (Analytical Chemistry 1994, 43, 1175) as raw materials, the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The compound obtained in Step 4 and 6-[(1,3-dioxo-1,3-dihydro-2 ⁇ -isoindole-2-inole) methyl] -2-pyridinecarboxaldehyde (Japanese Patent Application No. -1021159) as a starting material, and the same operation as in step 5 of example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 4- ⁇ [2- (N, N-dimethylamino) ethyl] ( ⁇ '-methyl) amino ⁇ -2-pyridinecarboxaldehyde- [6--butyl) thieno [2,3-d ⁇ pyrimidine-4-inole Hydrazone
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 55 as raw materials, the same operation as in Step 5 of Example 1 was carried out to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 56 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Compound 1 obtained in Step 4 and Reference Example 5 7
  • the compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed.
  • the title compound was obtained as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 6-piperidinomethyl-2-pyridine lipoxyaldehyde (Japanese Patent Application No. 4-1021159) as raw materials, the same operation as in Step 1 of Example 1 was performed. The compound was obtained as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 6-morpholinomethyl-2-pyridinecarboxyaldehyde (Japanese Patent Application No. 4-1021159) as starting materials, the same operation as in Step 5 of Example 1 was performed to give the title compound as yellow. Obtained as a solid.
  • Table 3 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 29 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 3 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Compound obtained in Step 4 and Reference Example 30 The compound obtained in Step 2 was used as a starting material. The same operation as in step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and benzaldehyde as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 2--2-trobenzaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 of Reference Example 1 and the compound obtained in Step 2 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 2,6-difluorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and isatin as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 3 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physical properties of the compound of this example. '
  • Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 2 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 4 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 6 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 5 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 7 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and -phthalaldehyde acid as raw materials, the same operation as in Step 1 of Example 5 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 3-( ⁇ 2- [6--Butyl) cheno [2,3-] pyrimidin-4-yl] hydrazono ⁇ methyl) benzo
  • Example 30 Using the compound obtained in Step 4 and phthalaldehyde acid as raw materials The same operation as in step 1 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and methyl phthalaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 14 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 10 Step 2 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 12 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 15 and step 2 as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using 60 mg of the compound obtained in Step 4 and 124 mg of the compound obtained in Step 2 of Reference Example 15 as raw materials, the same operation as in Step 5 of Example 1 was performed, and the condensate obtained was treated with ethanol. Was dissolved in 8 ml of acetic acid, and 0.4 ml of acetic acid was added, and the mixture was heated at 40 ° C for 1.5 hours and at 70 ° C for 3.5 hours. The temperature was returned to room temperature, the solvent was distilled off under reduced pressure, and the residue was solidified with ethyl acetate-hexane to obtain 95 mg of the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example. [Example 7 7]
  • Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in step 2 of Reference Example 9 as starting materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 8 as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 4-methylthiobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Same as step 5 in Example 1 except that the compound obtained in Step 4 and 7-formyl-3,4-dihydro-1 ⁇ -isoquinoline-2-carboxylate-butyl (Japanese Patent Application No. 2000-16984) were used as raw materials. By the same operation, the title compound was obtained as a yellow solid.
  • the structural formula of the compound of the present example and Table 4 shows the physical properties. [Example 8 1]
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Reference Example 1 1 Step 2 as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 18 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 16 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and 3-hydroxy-4-methoxybenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and the compound obtained in Reference Example 19 Step 2 as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 17 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compound of this example.
  • Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 2 1 as a raw material to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 22 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Example compound Table 4 shows the structural formula and physicochemical properties of 1: Example 8 9]
  • Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Reference Example 20 Step 2 as raw materials to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and Reference Example 2 5 as the starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physicochemical properties of the compounds of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 26 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Table 4 shows the structural formula and physical properties of the compound of this example.
  • Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 23 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.
  • Example compound Table 4 shows the structural formula and physicochemical properties of

Abstract

Cette invention concerne des composés représentés par les formules générale (IA) ou (IB), des sels de ces composés, qui présentent une activité inhibitrice de la kinase 4 cycline-dépendante. Dans ces formules, X est S, O ou N-R5 (R5 étant hydrogène ou alkyle) ; Y est N ou CH ; Z est N ou C-R6 (R6 étant alkyle, alkoxy ou halogéno ou alkyle); R3 est oxygène, alkyle ou aryle ; R4 est hydrogène ou alkyle ; et A est un groupe représenté par la formule générale (II) ou analogue (dans laquelle R7 est hydrogène ou alkyle, aryle ou un groupe hétérocyclique).
PCT/JP2001/011354 2000-12-26 2001-12-25 Inhibiteurs cdk4 WO2002051849A1 (fr)

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