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WO2005075432A1 - Derives de 1-(2h)-isoquinolone et utilisation de ceux-ci comme agents anticancereux - Google Patents

Derives de 1-(2h)-isoquinolone et utilisation de ceux-ci comme agents anticancereux Download PDF

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Publication number
WO2005075432A1
WO2005075432A1 PCT/JP2005/001787 JP2005001787W WO2005075432A1 WO 2005075432 A1 WO2005075432 A1 WO 2005075432A1 JP 2005001787 W JP2005001787 W JP 2005001787W WO 2005075432 A1 WO2005075432 A1 WO 2005075432A1
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Prior art keywords
group
dimethylamino
aryl
alkyl
isoquinoline
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PCT/JP2005/001787
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English (en)
Japanese (ja)
Inventor
Kazuo Hattori
Satoshi Niizuma
Hiroyuki Eda
Kenji Tatsuno
Miyuki Yoshida
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Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2005075432A1 publication Critical patent/WO2005075432A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • 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 novel 1- (2H) -isoquinolone derivatives and pharmaceuticals containing them as an active ingredient, particularly an antineoplastic agent useful as a therapeutic agent for diseases such as solid cancer.
  • Patent Document 1 International Publication No. 98Z51307 pamphlet
  • Patent Document 2 U.S. Pat.No. 4,942,163
  • Patent Document 3 International Publication No. 99Z11624
  • Non-Patent Document 1 J. Chem. Soc. (C), pp. 2205-2208 (1968)
  • Non-Patent Document 2 J. Org. Chem., 47, pp. 3787-3788 (1982)
  • Non-Patent Document 3 Arch. Pharm. Res., Vol. 20, pp. 264-268 (1997)
  • Non-Patent Document 4 Bioorg. Med. Chem. Lett., Pp. 8, 4146 (1998)
  • Non-Patent Document 5 Arch. Pharm. Res., Vol. 24, pp. 276-280 (2001)
  • Non-Patent Document 6 Bioorg. Med. Chem., Vol. 10, pp. 2953-2961 (2002) Disclosure of the Invention
  • An object of the present invention is to provide compounds having high antitumor activity, useful for therapeutic and prophylactic drugs effective for proliferative diseases such as cancer, and pharmaceutical compositions containing these compounds. I do.
  • the present inventors have diligently developed a 3-aryl-1- (2H) -isoquinolone derivative, and as a result, a derivative having a unique structure has an excellent antitumor effect, Seen to be useful as a therapeutic agent (especially a therapeutic agent) for proliferative diseases! However, the present invention has been completed.
  • R 1 and R 2 are independently selected from a hydrogen atom and a C alkyl group
  • X is a phenyl group or a heteroaryl group; wherein the phenyl group and the heteroaryl group may be substituted with one or more substituents selected from Group A;
  • Group A is a C alkyl group (the alkyl group is a halogen atom, an aryl group, a heteroaryl group).
  • Lumpur groups is 1 or more substitution by substituents selected from OR 11 and NR 12 R 13 /, even I /,), C Aruke - Le group (said C Aruke - Le group Is a halogen atom, C
  • the C alkynyl group includes a halogen atom, a C alkyl group, an aryl C alkyl group,
  • 2-7 1-8 1-6 may be substituted with one or more substituents selected from aryl groups, heteroaryl groups and SiR 15 R 16 R 17 ), halogen atoms, hydroxyl groups, aryl groups, hetero groups Aryl group, cyano group, amino group (the amino group may be a C alkyl group optionally substituted with OR 11 or NR 12 R 13 , an aryl group, an aryl C alkyl group and a heteroaryl group)
  • a nitrogen atom may be substituted by one or two substituents selected), -S (O) R 14 (where n represents an integer of 0 to 2), a C alkoxy group (The alkoxy group is n 1-6
  • Ariru group, Heteroariru group, OR u which may be substituted one NR 12 R 13 and halogen nuclear, by one or more groups et selected), Ariruokishi group, Heteroa Riruokishi group, selected Group B force Consisting of a 4- to 7-membered heterocyclic group and an alkylenedioxy group which may be substituted by one or more groups;
  • R U , R 12 , R 13 and R "independently represent a hydrogen atom, a C alkyl group (the alkyl group is
  • Halogen atom hydroxyl group, c alkoxy group, amino group, C alkylamino group, di-C
  • aryl and heteroaryl groups may be substituted with one or more selected substituents), aryl and heteroaryl groups may also be selected.
  • R 12 and R 13 together with the nitrogen to which they are attached, may form a 417-membered heterocycle containing at least one nitrogen atom;
  • R 15 , R 16 and R 17 are independently selected from a C alkyl group and an aryl group;
  • Group B includes a halogen atom, an aryl group, a heteroaryl group, an aryloxy group, a heteroaryloxy group, an amino group (the amino group is a C alkyl group, a hydroxy C alkyl group,
  • a nitrogen atom may be substituted by one or two substituents selected), a hydroxyl group, a C alkoxy group (the alkoxy group may be a halogen atom, a hydroxyl group, a C
  • a C alkyl group (the alkyl group may be substituted with
  • Halogen atom hydroxyl group, C alkoxy group, amino group, aryl group, heteroaryl group, C
  • Alkylamino group and di C alkylamino group power selected one or more
  • a compound of the above formula (1) which is an alkylamino group, or a prodrug thereof, or
  • the group NR 2 is a di C alkylamino group
  • a compound of the above formula (1) or a prodrug thereof, or a pharmaceutically acceptable thereof Salt is also provided.
  • a compound of the above formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof which is a NR 2 group dimethylamino group.
  • the above formula (1) wherein the X force and the Group A force are also substituted by one or more selected substituents, or are a phenyl group ) Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is also provided.
  • the group A is a C alkyl group, a C alkylthio group, a di C alkylamino group, an optionally substituted one or more halogen atoms.
  • the compound of formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the alkoxy group may be substituted with one or more halogen atoms) and a hydroxyl group are also provided. Is done.
  • group A is selected from the group consisting of a hydrogen atom, a trifluoromethyl group, a trifluoromethoxy group, a methylthio group, a methoxy group, a chloro group, a vinyl group, an ethur group, and a dimethylamino group.
  • a X alkyl group, a C alkylthio group, a diC alkylamino group, a diC alkylamino group which may be substituted with one or more halogen atoms.
  • a C alkyl group or a C alkoxy group substituted with one or more halogen atoms in at least the X-position at the X force (the alkoxy group may be one or more
  • a benzyl group at least at the 3-position, a C alkyl group, a C alkenyl group, a C alkynyl group,
  • a pharmaceutical composition comprising, as an active ingredient, the compound of the above formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent and prophylaxis for a malignant tumor comprising a compound of the above formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An agent is also provided.
  • the malignant tumor mentioned here includes, for example, solid cancer.
  • a 1 (2H) isoquinolone derivative having an excellent antitumor effect is provided. Further, the present invention provides compounds useful as therapeutic and prophylactic agents effective for proliferative diseases, for example, cancer, and pharmaceutical compositions containing these compounds.
  • aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • the “heteroaryl group” means a 5- to 10-membered aromatic heterocyclic group containing one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms.
  • Tastes for example, furyl, chenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxaziazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazur, pyridazyl, indolyl, quinolinyl , Isoquinolyl and the like.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • Preferred halogen atoms include, for example, fluorine atoms.
  • the “C alkyl group” is a straight-chain or branched-chain alkyl having 118 carbon atoms.
  • cyclic and partially cyclic alkyl groups having 3-8 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, etc.
  • C alkyl groups include, for example, linear or branched
  • a C alkyl group more preferably a linear or branched C alkyl group
  • a "C 2 -alkyl group” is a straight-chain or branched-chain C 2-7 carbon group.
  • alkenyl group includes, for example, ether (Bulle), 1-probe, 2-probeyl (aryl), propene 2-yl, 3-butyru (homoallyl) and the like.
  • the "C alkynyl group” is a straight-chain or branched-chain C 2-7 aryl group.
  • alkyl group includes, for example, ethynyl, 1-propyl, 2-propyl, 1-butyl, 2-butynyl, 3-butynyl and the like.
  • the "C alkoxy group” is a straight-chain alkyl group having 116 carbon atoms.
  • an alkyloxy group having a branched chain, and a cyclic or partially cyclic alkyl group having 3 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy , T-butoxy, n-pentoxy, 3-methylinobutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, Includes 1-methylpentoxy, 3-ethylbutoxy, and 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cyclopropylmethoxy, and the like.
  • the "aryloxy group” means an aryloxy group having an aromatic hydrocarbon group having 6 to 10 carbon atoms already defined as an aryl moiety, and examples thereof include phenoxy, 1-naphthoxy and 2-naphthoxy. included.
  • heteroaryloxy group has already been defined as a heteroaryl moiety.
  • C alkylamino group refers to a C1-C6 alkyl group as an alkyl moiety.
  • alkylamino group having a chain or branched chain and a cyclic and partially cyclic alkyl group having 3 to 6 carbon atoms, such as methylamino, ethylamino, n-propylami, i-propylami, n-butylami, s-butylami, etc.
  • di C alkylamino refers to a compound having 11 carbon atoms as two alkyl moieties.
  • dialkylamino means a dialkylamino group having a straight-chain or branched-chain, and a cyclic and partially cyclic alkyl group having 3 to 6 carbon atoms, wherein the two alkyl moieties may be the same or different.
  • the “di C alkylamino” includes, for example,
  • the "C alkylthio group” is a straight-chain alkyl having 1 to 16 carbon atoms.
  • alkylthio group having a chain or branched chain, and a cyclic or partially cyclic alkyl group having 3 to 6 carbon atoms such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio , I-butylthio, t-butylthio N-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio Luthio, 3-ethylbutylthio, 2-ethylbutylthio and the like.
  • aryl C alkyl group has already been defined as the aryl moiety.
  • a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom refers to a heteroatom containing one or more nitrogen atoms and additionally selected from an oxygen atom and a sulfur atom. It means a saturated or unsaturated heterocyclic ring having an atomic force of 17 contained in a ring which may contain one or more atoms, and also includes an aromatic heterocyclic ring. Specifically, for example, azetidine, pyrrolidine, piperidine, piperazine, pyrrole, imidazole, imidazoline, virazole, pyrazoline, oxazoline, morpholine, thiomorpholine, hexamethyleneimine and the like are included.
  • a 4- to 7-membered heterocyclic group containing at least one nitrogen atom refers to a group containing one or more nitrogen atoms, and additionally an oxygen atom and a sulfur nuclear atom.
  • a saturated or unsaturated heterocyclic group having 417 atoms in the ring which may contain one or more atoms, including an aromatic heterocyclic group.
  • azetidinyl, pyrrolidinyl, piberidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, birazolinyl, oxazolinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrazyl, pyrimidinyl, pyridazyl, Hexamethylene imino etc. are included.
  • the substitution position of the heterocyclic group is not particularly limited as long as the substitution position is on a carbon atom or a nitrogen atom.
  • the term "4- to 7-membered heterocyclic group” refers to a nitrogen atom, an oxygen atom and a sulfur atom, which contain one or more selected heteroatoms or may be contained in a ring. It means a saturated or unsaturated hetero ring of 17 atoms, including an aromatic hetero ring.
  • azetidur pyrrolidyl, piberidil, piperazil, pillory , Imidazolyl, imidazolyl, pyrazolyl, birazolyl, oxazolyl, morpholinyl, thiomorpholinyl, pyridyl, pyrazyl, pyrimidinyl, pyridazyl, hexamethyleneylene, furyl, tetrahydrofuryl, chenyl, tetrahydroche Nil, dioxolanil, oxathiol and dioxal.
  • the substitution position of the heterocyclic group is not particularly limited as long as it is a substitutable position on a carbon atom or a nitrogen atom.
  • the “C alkylenedioxy group” has 1 carbon atom.
  • 1-6 len -0- ", and includes, for example, methylenedioxy, ethylenedioxy, methylmethylenedioxy, dimethylmethylenedioxy and the like.
  • the substituents when an arbitrary group is substituted with one or more substituents, the substituents may be the same or different, and the number of the substituents may be from 1 to the chemical structure Up to the maximum number that can be replaced.
  • the number of substituents is, for example, 117, typically 115, preferably 113.
  • the present invention includes a salt of the compound represented by the formula (1) and a pharmaceutically acceptable salt of a prodrug of the compound.
  • These salts comprise the compound or a prodrug of the compound, It is produced by contacting with an acid or a base that can be used in the production of pharmaceuticals.
  • Such salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate, acetate, citrate, malate, salicylate
  • Alkali metal salts such as sodium salt, potassium salt, etc .
  • alkaline earth metal salts such as magnesium salt, calcium salt, etc .
  • ammonium salts such as trialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.
  • the "prodrug” of the present invention refers to a compound represented by the formula (1), which is enzymatically or non-enzymatically converted to a compound of the formula (1) or a pharmaceutically acceptable salt thereof under physiological conditions. Means a derivative of the compound.
  • a prodrug may be inactive when administered to a patient, but is present in vivo in a form converted to the active compound of formula (1).
  • the compound represented by the formula (1) of the present invention includes the following formula:
  • Me indicates a methyl group
  • Et indicates an ethyl group
  • t Bu indicates a butyl group
  • * indicates a binding portion
  • the production method described below when the defined group undergoes a desired transformation under the conditions of the working method, for example, means for protecting or deprotecting a functional group, etc.
  • the production can be carried out by using.
  • the selection and desorption operations of the protecting group can be performed, for example, by the methods described in ⁇ Greene and Wuts, 'Protective Groups m Organic 3 ⁇ 4ythesis (Brother 2nd edition, John Wiley & 3 ⁇ 4ons 1991)' ' May be used as appropriate.
  • the order of the reaction steps such as introduction of a substituent can be changed as necessary.
  • Various methods are conceivable as a method for producing the compound of the present invention represented by the general formula (1).
  • the compound can be synthesized using ordinary organic synthesis means. can do.
  • the compound represented by the formula (1) of the present invention can be produced, for example, according to the following method.
  • the method for producing the compound of the present invention is not limited thereto.
  • Each of the compounds of the present invention is a novel compound which has not been described in any literature, but can be produced by a well-known chemical method.
  • As the starting material used in the production a commercially available product may be used, or may be produced by an ordinary method as required.
  • x R 2 has the same meaning as described in the above formula (1).
  • the abbreviations used in the following reaction schemes have the usual meanings that can be understood by those skilled in the art.
  • L represents a halogen atom
  • G represents hydrogen or a methyl group.
  • 2-Methyl-5-trobenzamide can be easily obtained from a commercially available reagent, 2-methyl-5-torobenzoic acid I, by using a general amidation method. After isolating and purifying the obtained 2-methyl-5-nitrobenzamide, the 2-methylbenzamide derivative III is obtained by a known method (reductive amination; Japanese Patent Application Laid-Open No. 2000-095740). A method known from the obtained 2-methylbenzamide derivative (US Pat. No. 4,942,163; Won-Jea Cho et al., Arch. Pharm. Res., 20, 264-268 (1997); Bioorg. Med. Chem. Lett. 8, 41-46 (1998); Arch. Pharm. Res., 24, 276-280 (2001); Bioorg.
  • the compound represented by the formula (la) is prepared by adding a 2-methylbenzamide derivative (III) in a suitable solvent (eg, THF and Et0) and a suitable base (eg, LDA t BuLis—BuLi and BuLi).
  • a suitable solvent eg, THF and Et0
  • a suitable base eg, LDA t BuLis—BuLi and BuLi.
  • a commercially available reagent or an aromatic or aromatic prepared by a known method. It can be obtained by reacting with a heteroaromatic-tolyl derivative.
  • the 4-promo 2-methylbenzamide derivative V can also be easily obtained by using a common amidation method as in Reaction step 1 for the 4-promo 2-methylbenzoic acid IV power, which is a commercial reagent. After isolating and purifying the obtained 4-promo 2-methylbenzamide derivative V, a known method (aromatic amidation: Org. Lett., 2, 1101-1104 (2000); Tetrahedron Lett., 42, 7155-7157 (2001) )) To give the 2-methyl-4-acetylamidobenzamide derivative VI. After hydrolyzing the obtained 2-methyl-4-acetylamidobenzamide derivative VI, the 2-methylbenzamide derivative VIII can be obtained by a known method (reductive amination).
  • the compound represented by the formula (lb) can be obtained by a known method similar to that in reaction step 1 (US Pat. No. 4,942,163; Won-Jea Cho, et al, Arch. Pharm. Res., 20, 264-268). Chem. Lett. 8, 41-46 (1998); Arch.Pharm. Res., 24, 276-280 (2001); Bioorg.Med.Chem. 10, 2953-2961 (2002) )) Can be produced from the 2-methylbenzamide derivative VI II.
  • the isolation and purification of the target compound shown in the above-mentioned reaction process which is an example of the method for producing the compound of the formula (1) according to the present invention, includes extraction, concentration, distillation, and crystallization. It can be performed by applying ordinary chemical operations such as filtration, recrystallization and various types of chromatography.
  • the compound of the present invention and pharmaceutically acceptable salts thereof include all stereoisomers of the compound represented by formula (1) (eg, enantiomers, diastereomers (cis and trans geometric isomers). ;)), Racemic forms of said isomers, and other mixtures.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof can exist in several tautomeric forms, for example, enol and imine forms, keto and enamine forms, and mixtures thereof.
  • Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer is usually predominant. Although one tautomer may be described, the present invention includes all tautomers of the compounds of the present invention.
  • the compound of the present invention when obtained as a free form, it can be converted into a salt or a hydrate or solvate thereof which may be formed by the compound according to a conventional method.
  • the compound according to the present invention when obtained as a salt, hydrate or solvate of the compound, it can be converted into a free form of the compound according to a conventional method.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has excellent antitumor activity, is excellent in stability in the body and solubility in water, and is a prophylactic or therapeutic agent for a proliferative disease. (Especially a therapeutic agent).
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be used for breast cancer, colon cancer, ovarian cancer, lung cancer, spleen cancer, liver cancer, uterine cancer, brain cancer, prostate cancer, acute leukemia, and gastric cancer. It is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for such proliferative diseases such as cancer.
  • These methods may be used to determine whether a pharmaceutically effective amount of a pharmaceutical composition comprising a disclosed compound of the invention or a pharmaceutically acceptable salt thereof can be administered to a subject in need of such treatment or to a therapeutically effective amount.
  • the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for a proliferative disease such as cancer.
  • the method of administration is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, vaginal, intraperitoneal, intravesical, topical (drip, Powders, ointments, gels or tablets) and inhalation (buccal or nasal spray).
  • the dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and containers filled into individual doses. Parenteral solutions. Dosage forms may also be adapted for various modes of administration, including controlled release formulations, such as subcutaneous implantation.
  • the above-mentioned preparations are produced by known methods using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, diluents and the like.
  • excipient examples include starch such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
  • Examples of the coating agent include ethyl cellulose and hydroxypropyl cellulose.
  • Hydroxypropyl methylcellulose shellac, talc, carnaupa wax, paraffin and the like.
  • binder examples include polybutylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients.
  • disintegrant examples include the same compounds as the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polybutylpyrrolidone. .
  • Examples of the stabilizer include: paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenolethyl alcohol; benzalkonium chloride; and phenols such as phenol and tarezol. Anols; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agent examples include, for example, commonly used sweeteners, sour agents, flavors and the like.
  • a solvent for producing a liquid preparation ethanol, phenol, black cresol, purified water, distilled water and the like can be used.
  • surfactant or emulsifier examples include polysorbate 80 and polyoxystearate. Sil 40, Lauro Macrogol and the like.
  • the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the symptom, age, body weight, relative Target conditions, the presence of other medications, administration methods, etc.
  • the generally effective amount is the amount of the active ingredient (the compound of the present invention represented by the formula (I)) in the case of an oral preparation, which is equivalent to 1 kg of body weight per day per day. It is preferably 0.01-100 mg, more preferably 0.1-300 mg / kg body weight, and the daily usage is preferably in the range of 1-15000 mg for a normal weight adult patient.
  • the amount is preferably 0.01 to 1000 mg / kg of body weight per day, more preferably 1 to 5000 mg / kg of body weight. It is desirable to administer this depending on the symptoms.
  • the organic synthesis reaction was performed without further purification of a commercially available reagent. Room temperature is in the range of about 20-25 ° C. All water inhibition reactions were performed under a nitrogen atmosphere. Concentration under reduced pressure or distilling off of the solvent is performed using a rotary evaporator unless otherwise specified.
  • the functional group was protected with a protecting group, if necessary, and after the protected body of the target molecule was prepared, the protecting group was removed.
  • the selection and desorption operations of the protecting group were carried out, for example, by the method described in "ureene and Wuts," Protective Group in Organic Synthesis, Brother Edition 2, John Wiley & Sons 1991 ".
  • the reaction solution was weighed with 100 mL of water, extracted with methylene chloride (500 mLxl, 300 mLxl), and the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Dimethyl-5-nitrobenzamide (25.6 g, 96%) was obtained as a colorless solid.
  • Examples 2 to 39 were synthesized by a method similar to that in Step C of Example 1 using commercially available or known -tolyl as a raw material.
  • [ ⁇ 3 ⁇ 4] [solo] be "[one be fi ⁇ HS (/ ⁇ / — ⁇ — ⁇ ⁇ ⁇ im ⁇ [ ⁇ ]
  • the compound was synthesized in the same manner as in Example 42 using —1 on as a raw material.
  • the extract was dried over anhydrous sodium sulfate.
  • Example 46 Synthesis was carried out by a method similar to that in step A.
  • Example 46 A compound was synthesized according to a method similar to that of Step B.
  • Example 46 A compound was synthesized by a reaction similar to that of Step A.
  • the organic layer was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate.
  • Example 51 was synthesized by a method similar to that in step B.
  • Example 51 Synthesis was carried out by a method similar to that in step B.
  • the compound was synthesized in the same manner as in Example 51, Step C, using —1 on.
  • Example 52 To 5 mL of a methanol solution of 65 mg (0.275 mmol) of 7 amino-3 feru-2H isoquinoline 1H obtained in Step B, 22 mg of a 37% formalin aqueous solution was added, and 30 mg of 10% palladium carbon was further added. The mixture was stirred under a hydrogen atmosphere for 4 hours. An additional 88 mg of 37% formalin aqueous solution was further added, and the mixture was stirred overnight.
  • Cell proliferation inhibitory activity was measured for representative examples of the compounds of the present invention.
  • the cancer cell growth inhibitory activity was measured using Cell Counting Kit-8 manufactured by Dojindo Laboratories Inc. 2000 human colon cancer cell lines, HCT116, obtained from American Type Culture Collection (Virginia, USA) per 96-well culture plate After adding the compound at a predetermined concentration, the cells were cultured for 4 days at 37 ° C. in a 5% CO environment. 4 days of culture

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Abstract

Composés qui ont une activité anti-tumeur élevée et qui sont utiles comme médicaments thérapeutiques et préventifs efficaces vis-à-vis de maladies prolifératives telles que le cancer ; et compositions médicinales contenant les composés. Plus précisément, composés représentés par la formule générale (1) ou promédicaments de ceux-ci ou sels acceptables du point de vue pharmaceutique des deux ; et médicaments ou compositions médicinales contenant les composés : (1) dans laquelle le groupe -NR1R2 est lié au noyau isoquinolone au niveau de la position 6- ou 7- ; X est un phényle ou hétéroaryle éventuellement substitué ; et R1 et R2 sont chacun indépendamment un hydrogène ou un alkyle en C1-8.
PCT/JP2005/001787 2004-02-06 2005-02-07 Derives de 1-(2h)-isoquinolone et utilisation de ceux-ci comme agents anticancereux WO2005075432A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004031213 2004-02-06
JP2004-031213 2004-02-06

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WO2006090743A1 (fr) * 2005-02-22 2006-08-31 Chugai Seiyaku Kabushiki Kaisha Dérivé de 1-(2h)-isoquinolone
EP1724262A4 (fr) * 2004-02-06 2009-10-21 Chugai Pharmaceutical Co Ltd Derive de 1-(2h)-isoquinolone
JP2010510217A (ja) * 2006-11-17 2010-04-02 レグザン ファーマシューティカルズ，インク． 抗腫瘍薬としての５，６，又は７−置換−３−（ヘテロ）アリールイソキノリンアミン誘導体
WO2010061908A1 (fr) 2008-11-28 2010-06-03 中外製薬株式会社 Dérivé de 1-(2h)-isoquinolone
WO2014023390A3 (fr) * 2012-08-08 2014-04-10 Merck Patent Gmbh Dérivés de (aza-)isoquinolinone
WO2014080290A2 (fr) * 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Amines cycliques servant d'inhibiteurs de bromodomaines
US9193689B2 (en) 2012-03-07 2015-11-24 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9611223B2 (en) 2013-09-11 2017-04-04 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors

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EP1724262A4 (fr) * 2004-02-06 2009-10-21 Chugai Pharmaceutical Co Ltd Derive de 1-(2h)-isoquinolone
US7820693B2 (en) 2005-02-22 2010-10-26 Chugai Seiyaku Kabushiki Kaisha 1-(2H)-isoquinolone derivative
WO2006090743A1 (fr) * 2005-02-22 2006-08-31 Chugai Seiyaku Kabushiki Kaisha Dérivé de 1-(2h)-isoquinolone
AU2006216289B2 (en) * 2005-02-22 2011-08-25 Chugai Seiyaku Kabushiki Kaisha 1-(2H)-isoquinolone derivative
US8314123B2 (en) 2006-11-17 2012-11-20 Rexahn Pharmaceuticals, Inc. 5, 6, or 7-substituted -3-(hetero) arylisoquinolinamine derivatives and therapeutic use thereof
US8034829B2 (en) 2006-11-17 2011-10-11 Rexahn Pharmaceuticals, Inc. 5, 6, or 7-substituted-3-(hetero)arylisoquinolinamine derivatives and therapeutic use thereof
EP2423196A1 (fr) 2006-11-17 2012-02-29 Rexahn Pharmaceuticals, Inc. Dérivés de 3-phénylisoquinolinamine à substitution 5, 6 ou 7 et leur utilisation thérapeutique
JP2013151546A (ja) * 2006-11-17 2013-08-08 Rexahn Pharmaceuticals Inc 抗腫瘍薬としての５，６，又は７−置換−３−（ヘテロ）アリールイソキノリンアミン誘導体
JP2010510217A (ja) * 2006-11-17 2010-04-02 レグザン ファーマシューティカルズ，インク． 抗腫瘍薬としての５，６，又は７−置換−３−（ヘテロ）アリールイソキノリンアミン誘導体
WO2010061908A1 (fr) 2008-11-28 2010-06-03 中外製薬株式会社 Dérivé de 1-(2h)-isoquinolone
US8420668B2 (en) 2008-11-28 2013-04-16 Chugai Seiyaku Kabushiki Kaisha 1-(2H)-isoquinolone derivative
US9193689B2 (en) 2012-03-07 2015-11-24 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
WO2014023390A3 (fr) * 2012-08-08 2014-04-10 Merck Patent Gmbh Dérivés de (aza-)isoquinolinone
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9073878B2 (en) * 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
WO2014080290A3 (fr) * 2012-11-21 2014-10-23 Rvx Therapeutics Inc. Amines cycliques servant d'inhibiteurs de bromodomaines
WO2014080290A2 (fr) * 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Amines cycliques servant d'inhibiteurs de bromodomaines
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9598367B2 (en) 2012-12-21 2017-03-21 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US9861637B2 (en) 2012-12-21 2018-01-09 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11446306B2 (en) 2013-06-21 2022-09-20 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10010556B2 (en) 2013-06-21 2018-07-03 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10772892B2 (en) 2013-06-21 2020-09-15 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US9611223B2 (en) 2013-09-11 2017-04-04 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains

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