WO2004014873A1 - Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci - Google Patents

Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci Download PDF

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WO2004014873A1
WO2004014873A1 PCT/JP2003/009789 JP0309789W WO2004014873A1 WO 2004014873 A1 WO2004014873 A1 WO 2004014873A1 JP 0309789 W JP0309789 W JP 0309789W WO 2004014873 A1 WO2004014873 A1 WO 2004014873A1
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group
substituted
substituent
alkyl group
halogen atom
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Futoshi Shiga
Yasuo Takano
Jyunichi Ishiyama
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Kyorin Pharmaceutical Co., Ltd.
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Priority to AU2003252314A priority Critical patent/AU2003252314A1/en
Priority to JP2004527321A priority patent/JPWO2004014873A1/ja
Publication of WO2004014873A1 publication Critical patent/WO2004014873A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention provides a 4-substituted quinazolin-8-carboxylic acid amide derivative, a pharmaceutically acceptable addition salt thereof, and a poly (ADP-ribose) synthase inhibitory activity containing these as an active ingredient.
  • a 4-substituted quinazolin-8-carboxylic acid amide derivative a pharmaceutically acceptable addition salt thereof, and a poly (ADP-ribose) synthase inhibitory activity containing these as an active ingredient.
  • a poly (ADP-ribose) synthase inhibitory activity containing these as an active ingredient.
  • Poly (ADP-ribose) polymerase abbreviated as “PARP.”
  • PARP Poly (ADP-ribose) polymerase
  • NAD nicotinamide adenine dinucleotide
  • poly (ADP-ribose) as a DNA-polymerase and other proteins. Is an enzyme that is sequentially transferred to Therefore, it is thought that excessive activation of PARP causes a decrease in intracellular energy producing ability due to the depletion of NAD, which is essential for the electron transport system, and leads to cell death (Szabo, Free Radic. Biol.
  • PARP is a substrate of caspase-3, one of the protease-like proteazefamily of leucine-1 / 5 converting enzyme, and is limitedly degraded. Therefore, it is also attracting attention as an apoptosis-related enzyme.
  • PARP inhibitors include antiretroviral agents including HIV (GA Cole et al., Biochem. Biophys. Res. Comraun., 180 ⁇ 504 (1991)) and sensitizers for anticancer therapy (Arundel-Suto, et al., Radiat. Res., 126, 367 (1991); S. Boulton et al., Br. J. Cancer, 72, 849 (19-95)).
  • compounds having PARP inhibitory activity are useful for diseases caused by excessive PARP activation, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory Diseases (inflammatory bowel disease, multiple sclerosis, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma It is expected to be useful as a prophylactic and / or therapeutic agent for such as.
  • JP-A-62-48669 discloses a compound having the general formula (3)
  • R 2 is independently hydrogen atom or a lower alkyl group, halogen, CF 3, CN ⁇ S0 2 CH 3, N0 2, OH ⁇ NH 2, 0R ⁇ NHR 3
  • R 3 is a hydroxyl group, an amino group, etc.
  • Y represents C (NH) NH 2 , NHC (NH) NH 2 or NR 4 R 5
  • R 4 and R 5 represent a hydrogen atom or a hydroxyl group, an amino group, etc.
  • n represents 2 to 6 (The description of the substituent is partly excerpted), but JP-A-10-291988 discloses a compound represented by the general formula (4) as a compound useful for treating bone diseases caused by abnormal bone metabolism: ) '
  • R 1 represents an optionally substituted heterocyclic group or aryl group
  • R 2 represents a hydrogen atom or a lower alkyl group
  • R 3 represents a hydrogen atom, a halogen atom, etc.
  • R 4 Represents a substituted amino group, a substituted hydrazino group, a substituted or unsubstituted heterocyclic group, etc.
  • R 5 , R 6 and R 7 represent a hydrogen atom, a halogen atom or a lower alkyl group
  • A represents (Representing -C0NH-, -NHC0-, etc.) are known.
  • all of these compounds have a secondary carboxylic acid amide at the 8-position of the quinoline and a different structure from the compound of the present invention, which is characterized by a primary carboxylic acid amide. There is no description.
  • W096 / 91474 also discloses a compound having the endoselin converting enzyme inhibitory activity of the general formula (5)
  • A represents N, CH or S (0) n, n represents 0, 1 or 2
  • R represents a lower alkyl group, an aryl group, an aryl lower alkyl group, etc.
  • R 1 is hydro.
  • R 2 represents a hydrogen atom, a lower alkyl group, etc.
  • R 3 , R 4 , R 5 , R 6 independently represent a hydrogen atom, a halogen atom, a lower alkyl group, CONR 1 ⁇ 12, etc.
  • R 5 and R 6 independently represent a hydrogen atom, a lower alkyl group, an aryl group, or the like (substituents are partially excerpted).
  • No. -3144 describes a compound having a strong vasodilator action as a potassium channel opener, which has the general formula (6) '
  • R 1 and R 2 are a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a halogen atom, a cyano group, a nitro group, an acyl group.
  • R 4 is a compound represented by a saturated or unsaturated heterocyclic group, an amino group which may have a substituent, or a lower alkoxy group, an aryloxy group, etc.
  • W096 / 09294 has the general formula (7)
  • R 3 and ' are the same or different and are respectively amino, hydrogen, halogen, hydroxy, carboxy, carbamoyl, peridode, ⁇ ⁇ ⁇ alkyl carbamoyl, N, N- Di [ ⁇ ⁇ alkyl] represents a rubamoyl group, etc.
  • EP399267 also discloses a compound represented by the general formula (9) as a K + / H + -ATPase and a compound that inhibits gastric acid secretion.
  • R 1 represents a hydrogen atom
  • human Dorokishi group properly represents the ( ⁇ - (optionally substituted by alkoxy group ( ⁇ - (4 alkyl group
  • R 2 represents a hydrogen atom or -
  • R 3 represents a group of 1-3 ⁇ -( 4 alkyl groups and / or a phenyl group optionally substituted by 1-2 halogen atoms
  • R 4 represents a hydrogen atom or ⁇ ⁇
  • R 5 is human Dorokishi group, amino group, ( ⁇ - ( ⁇ Arukirua amino group, ⁇ ⁇ 0 6 alkoxycarbonyl group, ⁇ amino carbonyl group, such as di ( ⁇ alkyl) Aminokaruponiru based Represents a hydrogen atom or a ⁇ ⁇ alkyl group, etc.
  • Quinolinin which is a feature of the compound of the present invention, and has a primary carboxylic acid amide (carboxyl group) at the 8-position corresponding to the 8-position of quinazoline.
  • Examples include 2-methyl-4-((3-methyl-2-thenyl) methylamino) quinoline-8-carboxylic acid amide (di ( ⁇ 3, Has only been disclosed, but is not described as having PAHP inhibitory activity.
  • W097 / 4771 includes the general formula (26)
  • ⁇ is a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, a hydroxyxethyl group), an acyl group (for example, an acetyl group or a benzoyl group), or an aryl group which may have a substituent.
  • R and are a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, a hyboxyloxyshetyl group), and an acyl group
  • compounds represented by an acetyl group, a benzoyl group), an aryl group (for example, a phenyl group) or an aralkyl (for example, a benzyl group or a carboxybenzyl group) which may have a substituent are known.
  • the structure is different from the compound of the present invention which is characterized by quinazoline-8-carboxylic acid amide
  • W099 / 59973 has the general formula (27)
  • Y is a fused 5- or 6-membered aromatic or non-aromatic hydrocarbon ring, or a hetero atom containing an oxygen, sulfur, or nitrogen atom Which constitutes a ring
  • PN is a hydrogen atom
  • Y and other hetero atoms are unsubstituted or alkenyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, carboxy, and halogen.
  • X is the 1-position of the ring Y, and C0 2 R 5 or
  • R 7 represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, etc.
  • ⁇ 1 represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, etc.
  • R 3 , R 4 and R 5 independently represent an alkyl group, an alkenyl group, a cycloalkyl group, an amino group, a hydroxyl group, etc.), but the quinazoline- It does not include 8-carboxylic acid amide, and differs in structure from the present invention. Also, the disclosed compounds do not have sufficient PARP inhibitory activity.
  • the present invention relates to diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple brain sclerosis, arthritis) , Rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc.
  • Another object of the present invention is to provide a novel compound having PARP inhibitory activity, which is expected to be developed as a therapeutic agent. Disclosure of the invention
  • the present inventors have conducted intensive studies in search of a compound having a novel PARP inhibitory activity, and as a result, have found that the 4-substituted quinazoline-8-carboxylic acid amide derivative of the present invention and its pharmacologically acceptable Excellent PARP inhibitory activity was found for addition salts.
  • R 1 represents a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally substituted, an aralkyl group optionally substituted, or a general formula (2 )
  • ring Ar represents a phenyl group, a naphthyl group, a 5- or 6-membered complex ring and a condensed ring thereof,
  • R 6 and R ⁇ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 9 R 1 Q N Lower alkyl group substituted with a group, cyclic alkyl group which may have a substituent, substituted with a halogen atom Which may be a lower alkoxy group, human Dorokishi substituted lower ⁇ alkoxy group group, R 9 R 1D N-substituted lower alkoxy group group, a lower alkoxy group substituted by a carboxy group, substituted with a lower alkoxycarbonyl group A lower alkoxy group, an optionally substituted aralkyloxy group, a nitro group, an optionally substituted amino group, an optionally substituted phenyl group, An optionally substituted naphthyl group, a 5- or 6-membered
  • R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, or a lower alkoxy group optionally substituted with a halogen atom,
  • X is an oxygen atom or NR 11 (where R 11 is a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, or a substituent Represents an aralkyl group),
  • ⁇ R 4 are the same or different, a hydrogen atom:., Represents a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkyl group substituted with human Dorokishi group,
  • R 5 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR 1 Q , C0NR 9 10 ,
  • a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5- or 6-membered heterocyclic ring and a fused ring thereof, 1Q is the same or different and represents a hydrogen atom, a lower alkyl group optionally substituted with a halogen atom, a cyclic alkyl group optionally having a substituent, an aralkyl group optionally having a substituent, or R 9 and R 1Q represent a 5-membered or 6-membered heterocyclic ring which may have a substituent bonded together
  • X a represents an oxygen atom or NH
  • R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group,
  • R 6 and R 7 are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group,
  • Il 9 R 1 Q A lower alkyl group substituted with an N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group
  • X a represents an oxygen atom or NH
  • R 3 and R 4 are the same or different and are each substituted with a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, or a hydroxy group;
  • R 6 and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 9 R 1 Q N A lower alkyl group substituted with a group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 9 R 1Q A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group,
  • n 0 to 3]
  • the 4-substituted quinazoline-8-carboxylic acid amide derivative represented by the formula (1) and its pharmacologically acceptable addition salt have excellent PARP inhibitory activity.
  • the invention has been completed.
  • These preferred compounds include, for example, the compounds described in the following Tables 3 to 5, but the present invention is not limited to these compounds or pharmacologically acceptable addition salts thereof.
  • more preferred compounds include, for example, Exemplified No. 11.12, 14, 1517 to 34, 42 to 58, 74 to 93, 113 to 131, 150 to 170 186 to 209. it can.
  • halogen atom in “lower alkyl : alkyl group optionally substituted by halogen atom” and “lower alkoxy group optionally substituted by halogen atom” is used. Includes fluorine, chlorine, bromine, and iodine.
  • the “lower alkyl group” is a straight-chain or branched carbon atom having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, and iso-propyl.
  • Examples of the “lower alkoxy group” include straight-chain or branched ones having 1 to 4 carbon atoms such as methoxy, ethoxy, and propoxy.
  • cyclic alkyl group optionally having substituent (s) “aralkyl group optionally having substituent (s)”, “phenyl group optionally having substituent (s)”, “substituted In the ⁇ naphthyl group which may be substituted '' and the ⁇ 5- or 6-membered heterocyclic ring which may have a substituent and the condensed ring thereof '' are substituted with a halogen atom, a hydroxyl group or a halogen atom.
  • lower alkoxycarbonyl group means methoxycarbonyl or ethoxycarbonyl.
  • arylsulfonyl group for example, acetyl, methanesulfonyl, .phenylsulfonyl, etc., or a lower alkyl group optionally substituted with a halogen atom, or a substituent.
  • the term “5- or 6-membered cyclic amino group” in [1] includes pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl and the like.
  • the substituent here refers to the “substituent” described above.
  • cyclic alkyl group includes those having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, and cyclohexyl, and is referred to as “heterocycle” in “5- or 6-membered heterocycle and fused ring thereof”. ] Is a saturated or unsaturated monocyclic or polycyclic, which may have one or more substituents.
  • Heterocyclic group which can contain one or more nitrogen, oxygen and sulfur atoms, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, chenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyriyl Examples thereof include jyl, pyrimidyl, pyridazyl, and pyracyl.
  • the condensed ring is a benzene condensed ring of the above “heterocycle” (for example, indolyl, tetrahydroquinolyl, benzoxaxazolidinyl, benzoyl) Thiazolidinyl, benzofurel, benzothenyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc.) or a condensed ring composed of two rings arbitrarily selected from the above “heterocycle” Ring (eg, imidazopyridine, pyrazo Mouth pyridine, imidazopyrimidine and the like). ⁇
  • the compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable salt, if necessary.
  • Pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acid salts such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid and tosylic acid.
  • base salts such as sodium salts, calcium salts, calcium salts, and ammonium salts.
  • the compound represented by the general formula (1) and a pharmacologically acceptable salt thereof of the present invention may be an inner salt thereof, an anhydride thereof, a hydrate or a solvate thereof.
  • the compound represented by the general formula (1) having the PARP inhibitory activity of the present invention can be synthesized from a known compound by a combination of known methods.
  • the compound represented by the general formula (1-h) in which X is an oxygen atom can be easily synthesized by the following method (Production method I). Can be. ⁇ Production method I>
  • ⁇ R ⁇ R 4, R 5, R 9, R 1G, n represents the agreed definitions as those described above.
  • the conversion of the compound represented by the general formula (37) to the compound represented by the general formula (38) (Step IA) can be carried out without solvent or in a suitable solvent such as water, acetic acid, hydrochloric acid, sulfuric acid, or the like.
  • a suitable solvent such as water, acetic acid, hydrochloric acid, sulfuric acid, or the like.
  • a suitable oxidizing agent such as selenium dioxide.
  • the reaction can be carried out at 20 to 250 ° C for 0.1 to 10 hours using chromium oxide, chromium oxide, potassium permanganate, or the like.
  • the conversion of the compound represented by the general formula (38) to the compound represented by the general formula (39) can be carried out without a solvent or with a suitable solvent such as benzene, chloroform, In a solvent such as 2-dichloroethane, use a suitable halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc., and react for 60 to 60 hours at L30 ° C for 0.5 to 6 hours. The reaction can be carried out by reacting at 0.1 to 3 hours at 0 to 60 ° C. with ammonia in a suitable solvent such as water, methanol, tetrahydrofuran, etc. .
  • a suitable solvent such as benzene, chloroform
  • a suitable halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc.
  • step ⁇ -C The conversion of the compound represented by the general formula (39) to the compound represented by the general formula (40) (step ⁇ -C) is carried out by using a suitable solvent, for example, solvent, ethanol, In tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, or a mixture thereof, use an appropriate catalyst, for example, palladium-carbon, platinum-carbon, etc. at normal pressure or under pressure if necessary.
  • the reaction can be carried out by subjecting to a hydrogenation reaction at 80 ° C. for 1 to 72 hours.
  • Step ID The conversion of the compound represented by the general formula (40) to the compound represented by the general formula (41) (Step ID) is carried out by using a suitable solvent such as tetrahydrofuran, 1,4-dioxane, In a solvent such as ⁇ , ⁇ -dimethylformamide or a mixture thereof, in the presence of a suitable base, for example, triethylamine, pyridine, 4-dimethylaminopyridine, and the like, a compound represented by the general formula (42)
  • R 1 has the same meaning as described above, and R 12 represents a halogen atom.
  • a suitable solvent such as water, tetrahydrofuran, 1,4-dioxa 9789
  • the reaction is carried out at 50 to 100 ° C for 1 to 10 hours using a suitable base such as sodium hydroxide or potassium hydroxide in a solvent such as methane or a mixture thereof. Can be performed.
  • a suitable base such as sodium hydroxide or potassium hydroxide in a solvent such as methane or a mixture thereof.
  • step I-E The conversion of the compound represented by the general formula (41) into the compound represented by the general formula (1-h) (step I-E) is carried out by using a suitable solvent such as ⁇ , ⁇ -dimethylformamide, ⁇ In a solvent such as, ⁇ -dimethylacetamide or tetrahydrofuran, in the presence of a suitable base, for example, sodium carbonate, potassium carbonate, triethylamine, pyridine, etc., the general formula (43)
  • R 3 , H 4 , R 5 , and n have the same meanings as described above, and Y represents a lower alkylsulfonyloxy group optionally substituted with a halogen atom or a halogen atom).
  • the reaction can be carried out using a compound at 20 to 80 ° C for 1 to 24 hours.
  • the compound represented by the general formula (1-h) is a halogen atom.
  • the compound represented by the general formula (1-h) is It can be converted to a compound represented by the general formula (1-i), which is NR 9 R 1Q . That is, in a suitable solvent such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, tetrahydrofuran or the like (an appropriate iodide salt such as sodium iodide, if necessary) , And an iodide-powered room may be added), and the general formula (44)
  • reaction can be carried out at 60 to 180 ° C for 1 to 24 hours.
  • the compound in which R 5 is a lower alkoxycarbonyl group is obtained by the process IG, wherein R 5 is selected from the compounds represented by the general formula (1-h) It can be converted to a compound represented by the general formula (l_j) which is a carboxy group. That is, in a suitable solvent, for example, a solvent such as water, methanol, ethanol, or the like, an appropriate alcohol, for example, 20 to 100% by using a hydroxide, sodium hydroxide, carbonate, or the like. The reaction can be carried out at 0.5 ° C. for 0.5 to 10 hours.
  • a suitable solvent for example, a solvent such as water, methanol, ethanol, or the like
  • an appropriate alcohol for example, 20 to 100% by using a hydroxide, sodium hydroxide, carbonate, or the like.
  • the reaction can be carried out at 0.5 ° C. for 0.5 to 10 hours.
  • the compound represented by the general formula (1-k) wherein R 5 is C0NR 9 R 1G is a compound represented by the general formula (1-j) From the process IH. That is, in a solvent such as N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, tetrahydrofuran and the like, a suitable condensing agent, for example, 1- [3- (dimethyl. Lamino) p.mouth pill] -3-ethylcarbodiimide, dicyclohexylcarbodiimide, etc. (if necessary, by adding an appropriate base such as triethylamine, pyridine, 4-dimethylaminopyridine, etc.)
  • a suitable condensing agent for example, 1- [3- (dimethyl. Lamino) p.mouth pill] -3-ethylcarbodiimide, dicyclohexylcarbodiimide, etc. (if necessary, by adding an appropriate base such as trieth
  • compound X is represented by the general formula is NR 11 (Bok 1), for example Can be easily synthesized by the following method (Production method II)
  • R 2 , R 3 , R 4 ⁇ R 5 ⁇ R u and n have the same meanings as described above, and Z represents a halogen atom.
  • the conversion of the compound represented by the general formula (41) to the compound represented by the general formula (45) is carried out without a solvent or an appropriate solvent such as water, acetic acid, or a mixture thereof.
  • the reaction can be carried out by using a suitable acid such as hydrochloric acid or hydrobromic acid in the above solvent at 60 to 130 ° C. for 3 to 48 hours.
  • the conversion of the compound represented by the general formula (45) to the compound represented by the general formula (46) may be carried out without solvent or in an appropriate solvent such as benzene, chloroform, In a solvent such as 2-dichloroethane, use a suitable halogenating agent, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc., and react at 60 to 130 ° C for 0.5 to 10 hours to obtain an acid.
  • a suitable halogenating agent for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, etc.
  • Step II-C Conversion of the compound represented by the general formula (46) to the compound represented by the general formula U-1) wherein X is 11 among the compounds represented by the general formula (1)
  • Step II-C Is dissolved in a suitable solvent such as ⁇ , ⁇ -dimethylformamide, ⁇ -, ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, 1,3-dimethylimidazolone (if necessary, Natural iodide, for example, sodium iodide or iodinated power may be added), a general formula (47)
  • reaction can be performed by reacting at C for 1 to 24 hours. .
  • the compound represented by the general formula (45) can also be synthesized using the following method (Production method II).
  • R 1 is the general formula (2), and at least one of R 6 , R 7 and ⁇ 8 may be substituted with a halogen atom.
  • Compounds that are alkoxy groups can be obtained in the absence of a solvent or in a suitable solvent such as water, acetic acid, or a mixture of these using a suitable acid such as hydrochloric acid, hydrobromic acid, etc.
  • a suitable chlorinating agent for example, thionyl chloride, oxychlorine, etc. in a solvent without solvent or in a suitable solvent, for example, dichloromethane, chloroform, tetrahydrofuran, etc.
  • R 1 is the general formula (2), and at least one of R 6 and is a hydroxyl group It can be converted to a compound, and in a suitable solvent, for example, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, etc., and a suitable alkylating agent, for example, rhodoethane, ethyl bromoacetate, etc.
  • the compound represented by the general formula (1) is represented by the general formula (2), and any one of R 6 ′, R 7 or The above can be converted to a compound which is a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group substituted by a lower alkoxycarbonyl group.
  • a compound in which R 1 is the general formula (2) and at least one of ⁇ 7 and R 8 is a nitrogen atom is an appropriate compound.
  • a suitable catalyst such as palladium-carbon, '.platinum-carbon, etc.
  • R 1 is the general formula (2) Yes, it can be converted to a compound in which one or more of V or R 8 is an amino group, and furthermore, a suitable solvent, for example, chloroform, tetrahydrofuran, N, N-dimethyl
  • a suitable solvent for example, chloroform, tetrahydrofuran, N, N-dimethyl
  • a suitable acylating agent such as acetic anhydride in formamide or a mixture thereof
  • the 4-substituted quinazoline-8-carboxylic acid amide derivative represented by the general formula (1) of the present invention and the addition salt thereof show excellent PARP inhibitory activity.
  • the compound of the present invention may be used alone or mixed with a pharmacologically acceptable excipient, diluent, or the like at appropriate times, to give tablets, capsules, granules, and powders. It can be administered orally with a syrup or the like, or parenterally with an injection or transdermal absorber, suppository or the like.
  • the compound of the present invention can be used in combination with other drugs. In this case, it may be administered in combination or as a combination drug.
  • Drugs used in combination include thrombolytics, antiplatelet drugs, cerebral protective drugs, anti-edema drugs, anticoagulants, antipyretics, cerebral circulation metabolism improvers, antiepileptic drugs, antidepressants, Examples include anti-inflammatory drugs, ACE inhibitors, anti-inflammatory analgesics, and glycemic control drugs. ⁇
  • the compound of the present invention can be used in combination for surgical therapy, hypothermia therapy, hyperbaric oxygen therapy and the like.
  • PARP (Trevigen 4667-050-01) was diluted 35 times with a buffer consisting of 50 ol / L Tris-HCl (pH 7.8), lOOmmol / L KC1 and lmmol / L dithiothreitol for use in experiments.
  • a buffer consisting of 50 ol / L Tris-HCl (pH 7.8), lOOmmol / L KC1 and lmmol / L dithiothreitol for use in experiments.
  • the radioactivity on the filter was measured with a liquid scintillation counter.
  • the enzyme activity in the absence of the test compound was defined as 100 ° /, and the concentration ( IC5Q value) of the test compound that reduced this to 50% was calculated. [Table 10]
  • Table 10 shows the test results. From these results, it was confirmed that the novel 4-substituted quinazoline-8-carboxylic acid amide derivative and the salt thereof of the present invention have excellent PARP 'inhibitory activity. . Industrial applicability
  • the compound of the present invention is a novel 4-substituted quinazoline-8-potassium sulfonic acid amide derivative and a salt thereof, and has excellent PARP inhibitory activity. .
  • Compounds having PARP inhibitory activity include diseases caused by excessive PARP activation, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple occurrences) Prevention and / or treatment of cerebral sclerosis, arthritis, rheumatoid arthritis, etc., neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc.
  • diseases caused by excessive PARP activation such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple occurrences)
  • inflammatory diseases inflammatory bowel disease, multiple occurrences
  • Prevention and / or treatment of cerebral sclerosis, arthritis, rheumatoid arthritis, etc. neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease,

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Abstract

L'invention concerne un médicament présentant une activité inhibitrice de la poly(ADP-ribose) synthase, comprenant un dérivé de quinazoline-8-carboxyamide substitués en 4 et un sel d'addition pharmaceutiquement acceptable de celui-ci, en tant que principes actifs. En particulier, l'invention concerne un dérivé de quinazoline-8-carboxyamide substitué en 4 de formule (1), et un sel d'addition pharmaceutiquement acceptable de celui-ci.
PCT/JP2003/009789 2002-08-09 2003-08-01 Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci WO2004014873A1 (fr)

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WO2011058367A2 (fr) 2009-11-13 2011-05-19 Astrazeneca Ab Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase
WO2012046207A1 (fr) * 2010-10-08 2012-04-12 Paraco Technology Limited Composés azines à noyaux condensés substitués, antiparasitaires
JP2013532668A (ja) * 2010-07-29 2013-08-19 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング キナーゼｐ７０Ｓ６Ｋの阻害剤としての二環式アザ複素環式カルボキサミド
JP2013544257A (ja) * 2010-11-24 2013-12-12 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング キナゾリンカルボキサミドアゼチジン
WO2014048532A1 (fr) * 2012-09-26 2014-04-03 Merck Patent Gmbh Dérivés de quinazolinone comme inhibiteurs de parp
WO2014085528A1 (fr) * 2012-11-29 2014-06-05 Merck Patent Gmbh Dérivés carboxamide d'azaquinazoline
JP2014141522A (ja) * 2008-03-13 2014-08-07 Guangzhou Institute Of Biomedicine And Health Chinese Academy Of Sciences エストロゲン関連受容体モジュレータ化合物及びその使用
JP2016185977A (ja) * 2010-07-29 2016-10-27 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 環式アミンアザヘテロ環式カルボキサミド
CN106458843A (zh) * 2014-05-29 2017-02-22 纳幕尔杜邦公司 通过空气氧化制备3‑甲基‑2‑硝基苯甲酸的方法
WO2018197461A1 (fr) 2017-04-28 2018-11-01 Akribes Biomedical Gmbh Inhibiteur de parp en combinaison avec un glucocorticoïde et/ou l'acide ascorbique et/ou un facteur de croissance de protéine pour le traitement d'une mauvaise cicatrisation de plaie

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WO2000032579A1 (fr) * 1998-11-27 2000-06-08 Basf Aktiengesellschaft Benzimidazoles substitues et leur utilisation comme inhibiteurs de la parp
WO2003062234A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Composes de quinoxaline

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WO2000032579A1 (fr) * 1998-11-27 2000-06-08 Basf Aktiengesellschaft Benzimidazoles substitues et leur utilisation comme inhibiteurs de la parp
WO2003062234A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Composes de quinoxaline

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JP2014141522A (ja) * 2008-03-13 2014-08-07 Guangzhou Institute Of Biomedicine And Health Chinese Academy Of Sciences エストロゲン関連受容体モジュレータ化合物及びその使用
WO2011058367A2 (fr) 2009-11-13 2011-05-19 Astrazeneca Ab Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase
JP2013532668A (ja) * 2010-07-29 2013-08-19 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング キナーゼｐ７０Ｓ６Ｋの阻害剤としての二環式アザ複素環式カルボキサミド
JP2016185977A (ja) * 2010-07-29 2016-10-27 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 環式アミンアザヘテロ環式カルボキサミド
US10087166B2 (en) 2010-07-29 2018-10-02 Merck Patent Gmbh Cyclic amine azaheterocyclic carboxamides
WO2012046207A1 (fr) * 2010-10-08 2012-04-12 Paraco Technology Limited Composés azines à noyaux condensés substitués, antiparasitaires
JP2013544257A (ja) * 2010-11-24 2013-12-12 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング キナゾリンカルボキサミドアゼチジン
CN104662006A (zh) * 2012-09-26 2015-05-27 默克专利股份公司 作为parp抑制剂的喹唑酮衍生物
KR20150063474A (ko) * 2012-09-26 2015-06-09 메르크 파텐트 게엠베하 Ｐａｒｐ 억제제로서의 퀴나졸리논 유도체
JP2015535831A (ja) * 2012-09-26 2015-12-17 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Ｐａｒｐインヒビターとしてのキナゾリノン誘導体
KR102200628B1 (ko) 2012-09-26 2021-01-08 메르크 파텐트 게엠베하 Ｐａｒｐ 억제제로서의 퀴나졸리논 유도체
US9388142B2 (en) 2012-09-26 2016-07-12 Merck Patent Gmbh Quinazolinone derivatives as PARP inhibitors
WO2014048532A1 (fr) * 2012-09-26 2014-04-03 Merck Patent Gmbh Dérivés de quinazolinone comme inhibiteurs de parp
AU2013324681B2 (en) * 2012-09-26 2017-08-10 Merck Patent Gmbh Quinazolinone derivatives as PARP inhibitors
RU2650107C2 (ru) * 2012-09-26 2018-04-09 Мерк Патент Гмбх Производные хиназолинона в качестве ингибиторов parp
US9440968B2 (en) 2012-11-29 2016-09-13 Merck Patent Gmbh Substituted pyrido[3,2-d]pyrimidines for treating cancer
EA029144B1 (ru) * 2012-11-29 2018-02-28 Мерк Патент Гмбх Производные азахиназолин карбоксамида
US9981925B2 (en) 2012-11-29 2018-05-29 Merck Patent Gmbh Substituted benzo[d][1,2,3]triazines as p70S6K inhibitors
JP2016501229A (ja) * 2012-11-29 2016-01-18 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ アザキナゾリンカルボキサミド誘導体
US10233160B2 (en) 2012-11-29 2019-03-19 Merck Patent Gmbh Substituted pyrido[3,4-d]pyrimidines and pyrido[4,3-d]pyrimidines as p70S6K inhibitors
EA033655B1 (ru) * 2012-11-29 2019-11-13 Merck Patent Gmbh Производные азахиназолин карбоксамида
WO2014085528A1 (fr) * 2012-11-29 2014-06-05 Merck Patent Gmbh Dérivés carboxamide d'azaquinazoline
CN106458843A (zh) * 2014-05-29 2017-02-22 纳幕尔杜邦公司 通过空气氧化制备3‑甲基‑2‑硝基苯甲酸的方法
US10155718B2 (en) 2014-05-29 2018-12-18 Fmc Corporation Process to prepare 3-methyl-2-nitrobenzoic acid by air oxidation
WO2018197461A1 (fr) 2017-04-28 2018-11-01 Akribes Biomedical Gmbh Inhibiteur de parp en combinaison avec un glucocorticoïde et/ou l'acide ascorbique et/ou un facteur de croissance de protéine pour le traitement d'une mauvaise cicatrisation de plaie

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