WO2001021615A1 - Benzimidazole derivatives - Google Patents

Benzimidazole derivatives Download PDF

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Publication number
WO2001021615A1
WO2001021615A1 PCT/JP2000/006319 JP0006319W WO0121615A1 WO 2001021615 A1 WO2001021615 A1 WO 2001021615A1 JP 0006319 W JP0006319 W JP 0006319W WO 0121615 A1 WO0121615 A1 WO 0121615A1
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Prior art keywords
group
lower alkyl
substituent
carboxamide
benzimidazole
Prior art date
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PCT/JP2000/006319
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French (fr)
Japanese (ja)
Inventor
Kazuhisa Takayama
Yuji Koga
Naoyuki Masuda
Yoji Miyazaki
Takenori Kimura
Shinya Nagashima
Yoshinori Okamoto
Yohei Okada
Makoto Takeuchi
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Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU73142/00A priority Critical patent/AU7314200A/en
Publication of WO2001021615A1 publication Critical patent/WO2001021615A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to medicaments, in particular benzimidazole derivatives useful as PARP inhibitors.
  • Rheumatoid arthritis (rheumatoid arthritis: RA) is a polyarthritis that recurs and remits repeatedly, causing joint destruction, with extra-articular manifestations, and sometimes a life-threatening disease. Characteristics of RA include (1) mononuclear cell infiltration, (2) proliferation of synovial cells, and (3) consequent tissue destruction. Therefore, the purpose of drug treatment is to maintain joint function and prevent bone destruction observed by X-rays.
  • PARP Poly (ADP-ribose) polymerase
  • ADP-ribose polymerase PARP
  • Two Zn finger mochifs at the N-terminus of PARP recognize DNA strand damage, and nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) is added to various nuclear proteins including histones and DNA topoisomerases I and II in the vicinity. : NAD) is known to control the polymerization of the ADP-ribose moiety. Therefore, it is considered that excessive activation of PARP depletes intracellular NAD and ATP contents and leads to cell death (J. Clin. Invest., 77, 1312-1330 (1986)).
  • PARP inhibitors are considered to be useful as therapeutic agents for inflammatory diseases such as RA.
  • WO97 / 04771 discloses the following compounds,
  • R and R ′ each represent H, alkyl, hydroxyalkyl, acyl, optionally substituted aryl or optionally substituted aralkyl
  • WO00 / 26192 the following compounds:
  • PARP inhibitors can be expected to have excellent effects as therapeutic agents for inflammatory diseases such as RA, at present, no PARP inhibitors that are sufficiently satisfactory in terms of inhibitory activity have been found, and Development of new PARP inhibitors with inhibitory activity is eagerly awaited I have.
  • R represents a phenyl, 2-furyl, 2-thenyl, 3-thenyl, or 2-pyrrolyl group, etc.
  • the present inventors have conducted intensive studies on compounds that inhibit PARP.As a result, a benzimidazole derivative having an unsubstituted rubamoyl group at the 4-position and a heterocyclic group at the 2-position has excellent PARP inhibitory activity. They found that they were useful as preventive, therapeutic or diagnostic agents for diseases involving PARP, and completed the present invention.
  • a benzimidazole derivative represented by the following general formula (I) or ( ⁇ ), or a pharmaceutically acceptable salt thereof
  • medicaments containing one or more of these as an active ingredient particularly PARP inhibitors.
  • R 1 ⁇ , lower alkyl, s- substituted lower alkyl group
  • R 2 H, lower alkyl or CO—lower alkyl group
  • A a heterocyclic group which may have a substituent, provided that the hetero ring is a nitrogen-containing non-aromatic group
  • the heterocycle is closed from one to four groups selected from Group G 1, Group G 1: Formula (i) - X 0 - Y 2 - Z (ii) - X 0 - Y 3 - R 5 , (iii) — X 0 — Y 5 — Z 2 , (iv) — X ⁇ Y 1 - ⁇ ( ⁇ ) — X 1 - ⁇ 4 - ⁇ 3 , (vi)-— Y 5 — ⁇ 2 , (vii) — a group represented by X 2 _Y 6 _ Z 3 or (viii) — X 2 — Y 5 — z 2 ;
  • X 2 C 9-12 alkylene, CO- C 8-12 alkylene, Ji 2 - 12 Aruke two alkylene, C 2-12 aralkyl Kiniren, CO- C 2-12 alkenylene or CO- C 2-12 alkynylene,
  • R 3 H, lower alkyl or CO—lower alkyl group
  • Y 2 C0 2 or a group described in Y 1,
  • Y 3 0, S, N (R 3) CO, 0-CONH, NHC0 2, NHCONH, NHCSNH, CONHNH, NHNHCO, 0-COC0 2, 0-COCONH, NHCOC0 2, NHCOCONH, C (NH) NH, C (N-CN) NH, NHC (NH) NH, NHC (N-CN) ⁇ S0 2 -0, S0 2 NH, S0 2 NHNH or P (0) (oR 3) 0,
  • Y 4 C0 2 or a group described in Y 3,
  • Y 5 SO, S0 2, O- CO, N (R 3) C0 2, NHS0 2 or NHNHS0 2,
  • Y 6 a group described in Y 1 or Y 4
  • z 1 a heterocyclic group which may have a substituent bonded at a carbon atom which is a ring atom
  • Z 2 lower alkyl which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heterocyclic group which may have a substituent
  • Z 3 H or the group described in Z 2 .
  • alkyl means 1 to 6 carbon atoms
  • lower alkyl is preferably a lower alkyl group having 1 to 4 carbon atoms, and more preferably a methyl, ethyl and isopropyl group.
  • Al means having one or more double bonds at any position of the alkyl chain
  • alkynylene means having one or more triple bonds at any position of the alkyl chain.
  • Halogen refers to F, Cl, Br and I, preferably F, C1 and Br.
  • the "lower alkyl group substituted with halogen” is preferably a fluoromethyl, trifluoromethyl or trifluoroethyl group.
  • Cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms.
  • the “aryl group” is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms. More preferred are phenyl and naphthyl groups. Further, a 5- to 8-membered cycloalkyl ring may be condensed with the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.
  • heterocyclic group refers to a 5- to 8-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N as ring atoms. Any carbon atom that is a ring atom may be substituted with an oxo group (including an acetal such as a 1,3-dioxolane ring derived from the oxo group), and S or N is oxidized to form an oxide. May be.
  • the heterocyclic group may be cross-linked, or may form a spiro ring.
  • Non-containing non-aromatic heterocyclic group refers to a heterocyclic group having at least one N as a ring atom and optionally having one or one S atom, and does not exhibit an aromatic attribute. Indicates a heterocyclic group. Any carbon atom that is a ring atom may be substituted with an oxo group. Preferred are pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl and homopiperazinyl groups, and more preferred are pyrrolidinyl and piperidyl groups.
  • heterocyclic group bonded at a carbon atom that is a ring atom refers to a heterocyclic group whose carbon atom is bonded to a group represented by Y 1 or Y 2 which is an adjacent linker. For example, it does not include 1-piperidyl, but does include 2-, 3- or 4-piperidyl.
  • the substituent of the “heterocycle optionally having substituent (s)” in A is not particularly limited as long as it can be used as a substituent of these rings, and these substituents are 1 to 4 You may have one.
  • a substituent a group represented by the following G Q group, said G Q groups include the Group G 1.
  • Group G Group represented by the formula — X— Y— Z.
  • X is a bond, C 1-12 alkylene, C 2-12 alkenylene, C 2 _ 12 alkynylene, CO- C 1-12 alkylene, CO- C 2-12 7 Luque two alkylene or CO- C 2- 12 alkynylene
  • Y is a bond, CO, N (R 3 ), CON (R 3 ), C 0 2 , 0, S, N (R 3 ) CO, 0-CONH, NHC ⁇ 2 , NHCONH, NHCSNH, CONHNH, NHNHCO, 0-COC0 2 , 0-COCONH, NHCOC0 2, NHCOCONH, C (NH) NH, C (N-CN) NH, NHC (NH) ⁇ NHC (N-CN) NH, S0 2 -0, S0 2 NH, S0 2 NHNH, the P (0) (oR 3) 0, SO, S0 2, 0-CO, N (R 3) C0 2, NHS0 2 or NHNHS0 2, Z has a bond
  • Y is, SO, S0 2, 0- CO, N (R 3) C0 2, when the NHS0 2 or NHNHS0 2, Z represents a group other than H.
  • Z is an optionally substituted group a heterocyclic group optionally, when X is C r C 8 alkylene and Y is 0 or S, Z represents a lower ⁇ be substituted Alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group, wherein X is C 9 -C 12 alkyl In the case of kylene, C 2 -C 12 alkenylene or C 2 -C 12 alkynylene, Y is a bond, ⁇ , S or N (R 3 ), and Z is H, a lower alkyl which may have a
  • the more preferred substituents G G group in the formula one X- Y- Z, when X is a bond C r C 8 alkylene and Y, Z to which may have a substituent heterocyclic group
  • Z is lower alkyl which may have a substituent, cycloalkyl which may have a substituent, and which has a substituent
  • X is C 9 -C 12 alkylene, C 2 -C 12 alkylene or C 2 -C 12 alkynylene
  • Y is A bond, 0, S or N (R 3 )
  • Z is H, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), having substituent (s) And a heterocyclic group which may have a substituent.
  • substituent for G G group in the formula one X- Y one Z, when X is a bond C r C 8 alkylene and Y, Z to which may have a substituent heterocyclic group
  • Z is an aryl group which may have a substituent
  • X is C 9 -C 12 alkylene, C 2 -C 12 alkenylene or
  • Y is preferably a bond
  • Z is preferably a lower alkyl which may have a substituent, or an aryl group which may have a substituent.
  • a preferred range of the G Q group applies to Group G 1.
  • the substituent of the “optionally substituted lower alkyl group” is not particularly limited as long as it can be used as a substituent.
  • halogen 0H, 0—Cwo hydrocarbon group, SH, S—C 2G hydrocarbon group, CO—C 1-2G hydrocarbon group, C0 2 H, COO 1 d— 2 Q hydrocarbon group, C0NH 2 , CONH—lower alkyl, CON (lower alkyl) 2 , NHCO - lower alkyl, -NHCONH- lower alkyl, NH 2, NH- lower alkyl, N (lower-alkyl) 2, CN and groups selected from the group consisting of N0 2 group - lower alkyl, NHC0 2.
  • C 1-20 hydrocarbon group means alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene- Chloroalkyl, alkenylene-cycloalkyl, alkynylene-cycloalkyl, alkylene-aryl, alkenylene-aryl, alkynylene-aryl, etc., which may further have a substituent.
  • the substituent of the “optionally substituted cycloalkyl group” is not particularly limited as long as it can be used as a substituent of these rings, but is preferably a C ⁇ o hydrocarbon group. , 0-d ⁇ hydrocarbon group, halogen, lower alkyl substituted with halogen, and oxo group (including acetyl group such as 1,3-dioxolan ring derived from oxo group) It is a group selected, more preferably a lower alkyl group. These substituents may have 1 to 4 substituents.
  • the substituents of the "aryl group which may have a substituent” and the "heterocyclic group which may have a substituent” are groups which can be used as a substituent of these rings. If there is no particular limitation, preferably a C 1-20 hydrocarbon group, halogen, lower alkyl substituted with halogen, OH, 0-d ⁇ hydrocarbon group, SH, S—C 1-2G hydrocarbon group, CO- C 1-2 o hydrocarbon group, C0 2 H, COO- C 1-2 () hydrocarbon radical, CONH 2, CONH- lower alkyl, CON (lower alkyl) 2, NHCO- lower alkyl, NHC0 2 - lower alkyl, NHCONH - lower alkyl, NH 2, an NH- lower alkyl, N (lower-alkyl) 2, CN and N0 2 groups or Ranaru group selected from the group, more preferably, lower alkyl, halogen and 0 —A group selected from the group consisting of lower alky
  • R 1 is H, lower alkyl or halogen
  • R 2 is H or lower alkyl
  • the substituent for the heterocyclic group is preferably a nonyl group, a benzyl group, a phenylethyl group, a phenylbutyl group, a heptenyl group, a phenylethenyl group, a phenylpropyl group, a 4-methoxyphenylpropyl group, a phenyloxyl group, Chlorophenoxethyl, phenoxypropyl pill, 2-chlorophenoxypropyl, 2-cyanophenoxypropyl, 2-bromophenoxypropyl, 2-trifluoromethylphenoxypropyl, 2-methylphenoxypropyl, 2-nitrophenoxypropyl, 2-methoxycarbonylphenoxypropyl, 2,6-dichlorophenoxypropyl, 3-chlorophenoxypropyl, 3- ( 2,3-dihydrobenzo [1,4] dioxin-6-yl) oxypropyl group, 4-trifluoromethyl
  • the most preferred compounds include the following compounds: 2- (thiophen-2-yl) -1H-benzimidazole-4-carboxamide, 2- (2-methoxypyridin-5-yl) ) -1H-benzimidazole-4-carboxamide, 2- (2-ethylaminopyridin-5-yl) -1H-benzimidazol-4-carboxamide, 2- (pyridine-4-yl) -1H- Benzimidazole-4-carboxamide, 2- (1-nonylbiperidin-4-yl) -1H-benzimidazole-4-carboxamide, 2- ⁇ 1- [3- (thiophen-2-yl) propyl] piperidine -4-yl ⁇ -1 ⁇ -benzimidazole-4-carboxamide, 2- [1- (2-phenoxethyl) pyridin-4-yl] -1H-benzimidazole-4-carboxamide, 2 -[1- (3-Phen
  • the compound of the present invention may have a geometric isomer or a tautomer depending on the type of the substituent, but the present invention also includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and may have an isomer based on the asymmetric carbon atom. The present invention includes a mixture of these optical isomers and an isolated one. The present invention also includes a compound in which the compound of the present invention is labeled with a radioisotope.
  • the compounds of the present invention also include pharmacologically acceptable prodrugs.
  • a pharmacologically acceptable prodrug is defined as a solvolysate or under physiological conditions. It is a compound having a group that can be converted to light NH 2 , OH, C 2 H, and the like.
  • the group that form a prodrug Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 19 1990) groups according to the seventh Certificates Molecular Design 163-198 No.
  • the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent, and is included in the present invention as long as such a salt is a pharmaceutically acceptable salt.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleene Acid addition salts with organic acids such as acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, disulfonic acid, aspartic acid, glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc.
  • the present invention also includes various hydrates, solvates, and crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents.
  • an appropriate protecting group a group that can be easily converted to the functional group
  • Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group.
  • Examples of such a protecting group include “Protective Groups in Organic Synthesis (2nd edition)” by Greene and Wuts.
  • the protecting groups described in (1) and (2) may be appropriately selected and used according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group as necessary.
  • This production method is a method for producing the compound (I) of the present invention by reacting an ester compound (III) with ammonia to amidate it.
  • the reaction is carried out in a solvent inert to the reaction, such as water, alcohols such as methanol and ethanol, ⁇ , ⁇ -dimethylformamide (DMF), and tetrahydrofuran (THF), or in a solvent-free condition from room temperature to under heating.
  • a solvent inert such as water, alcohols such as methanol and ethanol, ⁇ , ⁇ -dimethylformamide (DMF), and tetrahydrofuran (THF)
  • performing the reaction under pressure may be advantageous for the reaction.
  • a carboxylic acid compound (Ilia) is condensed with a condensing agent (eg, dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) , ⁇ , ⁇ -carbonylbis-1H-imidazole (CDI), etc., and in some cases, further additives (eg, ⁇ -hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), etc.) )), Wherein the compound of the present invention (I) is produced by treating with ammonia.
  • a condensing agent eg, dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) ,
  • the carboxylic acid compound (Ilia) has a functional group active in a reaction such as a hydroxy group or an amino group, these functional groups are protected with a protecting group in advance, and this reaction is carried out. By removing the protecting group, the compound (I) of the present invention can be obtained.
  • the solvent examples include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethyl ether, THF, and 1,4-dioxane.
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethyl ether such as 1,4-dioxane.
  • Inert solvents such as monotells, DMF, dimethyl sulfoxide (DMSO) and pyridine can be used. These solvents can be used alone or in combination of two or more.
  • Various compounds of the present invention can be produced by using the compound of the present invention as a raw material and subjecting it to a reaction.
  • a compound having an OH group is converted into an alkyl halide such as alkyl chloride obtained by reaction with thionyl chloride or the like, or an organic sulfonate obtained by reaction with methanesulfonyl chloride or P-toluenesulfonyl chloride, and reacted with a nucleophile.
  • an alkyl halide such as alkyl chloride obtained by reaction with thionyl chloride or the like, or an organic sulfonate obtained by reaction with methanesulfonyl chloride or P-toluenesulfonyl chloride, and reacted with a nucleophile.
  • it can also be produced by subjecting it to the Mitsunobu reaction.
  • the reaction is carried out in an organic solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF and the like, or without solvent, under cooling to heating.
  • Alkylation can be performed by reacting a compound having a primary or secondary amine with a carbonyl compound such as a ketone-aldehyde.
  • a carbonyl compound such as a ketone-aldehyde.
  • a conventional method of reductive alkylation reductive amination from the viewpoint of a carbonyl compound
  • the carboxylic acid or sulfonic acid compound can be produced in the presence of a condensing agent or by using a reactive derivative thereof.
  • the reactive derivative of a carboxylic acid or sulfonic acid compound includes an acid halide, an acid anhydride and an active ester.
  • the reaction can be carried out, for example, according to the method described in “Experimental Chemistry Lecture (4th edition)”, edited by The Chemical Society of Japan, Vol.
  • the reaction of a reactive derivative of a carboxylic acid with an azide salt such as sodium azide or diphenylphosphoryl azide (DPPA) or Curtius rearrangement of an acid azide obtained by reaction with DPPA, or the primary amide Hofmann Obtained by dislocation, etc.
  • the isocyanate compound can be produced by reacting the compound with an OH group or an amine compound.
  • the reaction is carried out in an organic solvent inert to the reaction such as octogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, or the like, or without a solvent, under cooling to heating.
  • an equivalent amount or one of them can be used in excess.
  • the starting compounds (III) and (Ilia) of the compound of the present invention can be produced by a conventional method using, for example, a known reaction shown in the following synthetic scheme.
  • Other symbols have the meanings described above.
  • the diaminobenzoic acid ester compound (V) is reacted with the compound (Vic) to obtain the amide derivative (VII).
  • the reaction can be performed in the same manner by applying the conditions of the third production method (3) amidation, sulfonamidation and esterification.
  • This production method is a method for obtaining an ester compound (III) by cyclizing the amide derivative represented by the general formula (VII) in a molecule.
  • the reaction is halogenated hydrocarbons, In an organic solvent inert to the reaction of aromatic hydrocarbons, ethers, etc., or in the absence of a solvent, using an acid of a catalytic amount or a solvent amount, cooling at -78 ° C to 0 ° C, under cooling to room temperature
  • the reaction is performed at room temperature, at room temperature, or in some cases, at room temperature to under heating.
  • Examples of the acid used include acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, P-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • Oxidizing agents include copper compounds (copper acetate, copper chloride, etc.), iron compounds (iron acetate, etc.), manganese compounds (manganese dioxide, potassium permanganate, etc.), chromium compounds (oxidation, etc.).
  • Chromium Chromium
  • ruthenium compounds such as tetrapropylammonium pearl tenate
  • silver compounds such as silver oxide
  • cerium compounds such as cerium nitrate
  • Dimethyl sulfoxide benzofuroxan, nitrobenzene, quinone compounds (eg, chloranil).
  • the reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate.
  • the salt can be produced by subjecting the salt to a usual salt formation treatment.
  • Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers.
  • the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography.
  • the optical isomer can also be produced from a suitable optically active starting compound.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • it has PARP inhibitory activity, so PARP is involved in inflammatory diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.), autoimmune diseases (eg, type I diabetes) Etc.), and is useful as a prophylactic / therapeutic agent for diseases associated with ischemia reperfusion disorder (eg, stroke, myocardial infarction, organ transplantation, etc.).
  • inflammatory diseases eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.
  • autoimmune diseases eg, type I diabetes
  • ischemia reperfusion disorder eg, stroke, myocardial infarction, organ transplantation, etc.
  • Test compound desired concentration 82.5 mM Tris -HC1 (pH 8.0), 50 mM chloride force Riu arm, 10 mM magnesium chloride, 5 mM dithiothreitol I torr, 100 g / ml histone, 26 nM 3 H-
  • the reaction was performed at 25 ° (:, 3 hours) in a reaction solution containing NAD and 0.06 unit human recombinant PARP.
  • IC 5 was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%.
  • a comparative compound N '-[2- (N, N-dimethylamino) ethyl] -2- (4'-methoxyphenyl) -1H-benzoimidazole-4-potassium lipoxamide J. Med. Chem "33, 814) -819 (1990), no.21) showed no inhibitory activity at 1000 nM.
  • J774.1 cells murine monocyte / macrophage temporary cell line
  • DMEM medium 10% fetal bovine serum-containing DMEM medium and adjusted to 5Xl0 5 cells / ml, 37 ° C, 5 % C0 2 under the conditions of For 24 hours.
  • IC 5Q was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%.
  • the compound of the present invention also showed good inhibitory activity in the above in vitro test.
  • mice Male Balb / c mice (Nippon Charlsliver) of 6 to 8 weeks of age were subjected to the experiment.
  • mice were fasted and had free access to water from the evening before the test.
  • the solution was orally administered to the above Balb / c mice at a desired dose of 5 ml / kg.
  • the negative and positive control groups received 0.5% methylcellulose as a solvent at 5 ml / kg.
  • Zymozan (Sigma) was suspended in physiological saline to a concentration of 0.5 mg / ml, and the compound was orally administered and intraperitoneally at 1 ml / mouse. To the negative control group, physiological saline was intraperitoneally administered at 1 ml / mouse.
  • ED30 was calculated for each compound as the dose of test compound that inhibited the number of cells infiltrated into the peritoneal cavity by 30% by Zymozan.
  • the booster day was set as day 0, and the body weight and arthritis score of each limb were measured twice a week.
  • the arthritis score was set as follows. 0 is normal, 1 is redness and mild swelling, 2 is moderate swelling, 3 is severe swelling or joint stiffness.
  • test compound was suspended at a concentration of 5 ml of 1, 3, 10, and 30 mg in 0.5% methylcellulose as a solvent, and orally administered once daily at a dose of 5 ml / kg until the 21st day.
  • 0.5% methylcellulose as a solvent was administered at 5 ml / kg.
  • the compound of the present invention showed good activity in the above in vivo test.
  • compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be a pharmaceutical carrier commonly used in the art. It can be prepared by a commonly used method using a body, excipients and the like.
  • tablets, pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant and the like may be used.
  • solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients may be combined with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinyl pyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inactive additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl sodium salt, or a solubilizing agent, according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or a gastric or enteric coating agent.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including.
  • the composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solvents include, for example, distilled water for injection and physiological saline.
  • non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (trade name).
  • Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile injection solvent before use.
  • Transmucosal preparations such as nasal preparations are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods. For example, known pH adjusters, preservatives, thickeners and excipients are appropriately added, and the mixture is shaped into a solid, liquid or semi-solid.
  • Nasal pills are normal sp The drug is administered using a laser device, nasal drop container, tube, intranasal insert, etc.
  • the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg per body weight, which is divided into single doses or 2 to 4 doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and the dose is administered once to several times a day.
  • the daily dose is about 0.0001 to 10 mg / kg per body weight, and it is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 per body weight Is administered once to several times a day. The dose is determined as appropriate for each individual case, taking into account symptoms, age, sex, and the like.
  • 2,3-Diaminobenzoic acid methyl ester is reacted with thiophene-2-carbonyl chloride in THF in the presence of triethylamine and 4-dimethylaminopyridine, and purified by a conventional method to give 2-amino-3-[(thiophene-2 Methyl [benzoylyl) amino] benzoate was obtained as a pale gray powder.
  • Nicotinic acid is reacted with isobutyl chloroformate in a mixed solvent of triethylamine and THF, followed by reaction with 2,3-diaminobenzoic acid methyl ester, followed by purification by a conventional method to give 2-amino-3-[( Pyridine-3-ylcarbonylyl) amino] methyl benzoate Was obtained as a light brown powder.
  • 2,3-Diaminobenzoic acid methyl ester and 3-thiophenecarboxylic acid are reacted under heating in polyphosphoric acid prepared from diphosphorus pentoxide and phosphoric acid, and purified by a conventional method.
  • Thiophen-3-yl) -1H-benzimidazole-4-carboxylate was obtained as a brown powder.
  • Acetic acid, copper (II) acetate hydrate and water were added to a methanol solution of 2,3-diaminobenzoic acid methyl ester and 1H-pyrrol-2-carbaldehyde and heated. Upon boiling, the copper salt was filtered off and dried under reduced pressure. An aqueous solution of sodium disulfide nonahydrate was added to the suspension of the obtained copper salt in ethanol and concentrated hydrochloric acid, and the mixture was heated to boiling and filtered immediately. A 1M aqueous sodium hydroxide solution was added to the filtrate to adjust the pH to 6. After adding water, the solvent was concentrated under reduced pressure until the liquid volume became about half.
  • 6-Methylanthranilic acid was reacted with N-bromosuccinimide in DMF to give 5-bromo-6-methylanthranilic acid as a colorless solid.
  • 5-Bromo-6-methyl-3-nitroanthranilic acid was obtained from 5-bromo-6-methylanthranilic acid by the method described in the literature (J, Med. Chem., 33, 814-819 (1990)). . EI-MS (M +): 274.
  • the compounds of Reference Examples 25 and 26 shown in Table 1 were used in the same manner as in the method of Reference Example 9 above, using commercially available compounds or compounds known in the literature.
  • the compounds of Reference Examples 27 to 31 shown in Table 1 in the same manner as in the method of Reference Example 11
  • the compounds of Reference Examples 32 to 43 shown in Table 1 were treated in the same manner as in Reference Example 12, and the compounds of Reference Examples 44 to 65 shown in Table 3 were treated in the same manner as in Reference Example 13.
  • the compound of Reference Example 66 shown in Table 3 was treated in the same manner as in Reference Example 15, and the compound of Reference Example 67 shown in Table 3 was treated in the same manner as in Reference Example 15.
  • Example 74 was used in the same manner as in Reference Example 22 to obtain the compound of Reference Example 68 shown in Table 3 in the same manner as in the method of Reference Example 22.
  • the compounds of 3, 75-87 and the compounds of Reference Examples 88 to 89 shown in Table 2 were produced using the corresponding raw materials.
  • Table 1 shows the structures and physicochemical data of the compounds of Reference Examples.
  • the compounds of Reference Examples 9 to 11 and 25 to 43 are shown in Table 1
  • the compounds of Reference Examples 16a, 16b, 88 and 89 are shown in Table 1.
  • Reference Examples 12 to: The compounds of L5, 22 and 44 to 68 are shown in Table 3
  • the compounds of Reference Examples 17, 18, 21 and 69 to 87 are shown in Table 4. Shown respectively.
  • CDI (350 mg) was added to a suspension of 2- (2-chloropyridine-5-yl) -1H-benzoimidazolyl-4-carboxylic acid (549 mg) in THF (20 ml), and the mixture was added at room temperature. Stir for 1 hour. Ammonia-saturated THF (15 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was washed with water to give 2- (2-chloropyridine-5-yl) -1H-benzoimidazole-4-carboxamide (420 mg) as a white powder.
  • Tables 10 to 13 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-mentioned production methods, the methods described in the examples, methods obvious to those skilled in the art, or modifications thereof.

Abstract

Compounds useful in the treatment of various PARP-related diseases, which are benzimidazole derivatives having heterocyclic groups at the 2-position and carbamoyl at the 4-position as represented by general formula (I) or (II) or salts thereof, wherein R1 is H, lower alkyl, or the like; R2 is H, lower alkyl, or the like; and A is an optionally substituted heterocyclic group or the like.

Description

ミダゾール誘導体 技術分野  Midazole derivatives Technical field
本発明は、 医薬、 特に PARP阻害剤として有用なベンゾイミダゾール誘導体に関 する。  The present invention relates to medicaments, in particular benzimidazole derivatives useful as PARP inhibitors.
明  Light
3"京技術 3 "Kyo technology
田  Rice field
リウマチ様関節炎 （慢性関節リウマチ、 rheumatoid arthritis： RA) は再燃と寛解 を繰り返す多発性関節炎で、 関節破壊をきたし、 関節外症状を伴い、 ときに生命を 脅かす疾患である。 RAの特徴としては （1 ) 単核球の浸潤、 （2 ) 滑膜細胞の増 殖、 （3 ) その結果としての組織破壊が挙げられる。 そのため薬物治療の目的は、 関節機能の保持及び X線により観測される骨破壊の防止である。  Rheumatoid arthritis (rheumatoid arthritis: RA) is a polyarthritis that recurs and remits repeatedly, causing joint destruction, with extra-articular manifestations, and sometimes a life-threatening disease. Characteristics of RA include (1) mononuclear cell infiltration, (2) proliferation of synovial cells, and (3) consequent tissue destruction. Therefore, the purpose of drug treatment is to maintain joint function and prevent bone destruction observed by X-rays.
ポリ （ADP-リボース） ポリメラ一ゼ （Poly (ADP-ribose) polymerase： PARP) は 113 kDaの核内酵素である。 PARPの N末端に存在する 2箇所の Znフィンガー ·モ チーフが DNA鎖の損傷を認識し、 その近傍のヒストンや DNAトポイソメラーゼ I、 IIを含む様々な核タンパクにニコチンアミドアデニンジヌクレオチド（nicotinamide adenine dinucleotide ： NAD) の ADP-リボース部を重合していく反応を司ることが 知られている。そのため過剰な PARPの活性化は細胞内 NAD及び ATP含量を枯渴 させ細胞死へと導くと考えられている （J. Clin. Invest., 77, 1312-1330 (1986)) 。  Poly (ADP-ribose) polymerase (PARP) is a 113 kDa nuclear enzyme. Two Zn finger mochifs at the N-terminus of PARP recognize DNA strand damage, and nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) is added to various nuclear proteins including histones and DNA topoisomerases I and II in the vicinity. : NAD) is known to control the polymerization of the ADP-ribose moiety. Therefore, it is considered that excessive activation of PARP depletes intracellular NAD and ATP contents and leads to cell death (J. Clin. Invest., 77, 1312-1330 (1986)).
様々な炎症性疾患において NOや活性酸素、 あるいはこれらの反応生成物である ペルォキシ二トリ トは組織障害を引き起こす強力なメディエー夕一であることは 広く知られている。 この組織障害は、 NO、 活性酸素、 ペルォキシ二トリトによつ て生じた DNA鎖の損傷を PARPが認識 ·活性化し、 エネルギー枯渴を招いた結果 であると考えられている (Proc. Natl. Acad. Sci. USA 93 1753-1758 (1996)) 。 また PARPの活性化を阻害することにより炎症時の細胞浸潤が強く抑制されることも明 らかとなつている （J. Exp. Med., 186, 1041-1049 (1997)、 Immunology, 93, 96-101 (1998)) 。 RA 患者において、 関節液細胞では活性酸素産生能が亢進していること （Z. Rheumatol., 46, 227-232 (1987)) 、 関節液および血清中の Ν02·イオン量が著明に増加 していること (Ann. Rheum. Dis., 51, 1219-1222 (1992)) 、 末梢単核球において DNA 鎖の損傷が増加していること （Ann. Rheum. Dis., 51, 8-12 (1992)) 、 NAD含量が減 少していること (Int. J. Clin. Pharm. Res., 14, 57-63 (1994)) 等の事実から、 PARPの 活性化が示唆されており、その結果として細胞浸潤や組織破壊が引き起こされてい ると考えられている。 It is widely known that NO, active oxygen, or their reaction product, peroxynitrite, is a powerful mediator that causes tissue damage in various inflammatory diseases. This tissue damage is thought to be the result of PARP recognizing and activating DNA strand damage caused by NO, active oxygen, and peroxynitrite, resulting in energy depletion (Proc. Natl. Acad. Sci. USA 93 1753-1758 (1996)). It has also been clarified that inhibition of PARP activation strongly suppresses cell invasion during inflammation (J. Exp. Med., 186, 1041-1049 (1997), Immunology, 93, 96). -101 (1998)). In RA patients, the active oxygen-producing ability is enhanced in the synovial fluid cells (Z. Rheumatol., 46, 227-232 (1987)), increased .nu.0 2 · ion amount of synovial fluid and serum is markedly (Ann. Rheum. Dis., 51, 1219-1222 (1992)), and increased DNA strand damage in peripheral mononuclear cells (Ann. Rheum. Dis., 51, 8-12). (1992)) and the fact that the NAD content was reduced (Int. J. Clin. Pharm. Res., 14, 57-63 (1994)), etc., suggest that PARP is activated. It is thought that cell invasion and tissue destruction are caused as a result.
従って、 PARP阻害剤は RAをはじめとする炎症性疾患の治療薬として有用であ ると考えられる。  Therefore, PARP inhibitors are considered to be useful as therapeutic agents for inflammatory diseases such as RA.
PARP阻害活性を示すベンゾイミダゾール誘導体としては、 WO97/04771 号公報 に下記化合物、  As benzimidazole derivatives showing PARP inhibitory activity, WO97 / 04771 discloses the following compounds,
Figure imgf000004_0001
Figure imgf000004_0001
(式中、 R及び R'は、 H、 アルキル、 ヒドロキシアルキル、 ァシル、 置換されてい ても良いァリール又は置換されていても良いァラルキル基をそれぞれ示す。 ） 及び、 WO00/26192号公報に下記化合物、  (Wherein, R and R ′ each represent H, alkyl, hydroxyalkyl, acyl, optionally substituted aryl or optionally substituted aralkyl), and WO00 / 26192, the following compounds: ,
Figure imgf000004_0002
Figure imgf000004_0002
(式中の記号は当該公報参照。 ）  (Refer to the official gazette for symbols in the formula.)
が報告されている。 これらべンゾイミダゾール誘導体はベンゾィミダゾ一ルの 2位 の環基はフエニル基に限定されている。 そして、 これらの PARP阻害活性はなお不 充分であった。  Have been reported. In these benzoimidazole derivatives, the ring group at the 2-position of benzoimidazole is limited to a phenyl group. And these PARP inhibitory activities were still insufficient.
従って、 PARP阻害剤は RAをはじめとする炎症性疾患の治療薬として優れた効 果を期待できるものの、現状では阻害活性の点で十分満足できる PARP阻害剤は見 出されておらず、優れた阻害活性を有する新規な PARP阻害剤の開発が切望されて いる。 Therefore, although PARP inhibitors can be expected to have excellent effects as therapeutic agents for inflammatory diseases such as RA, at present, no PARP inhibitors that are sufficiently satisfactory in terms of inhibitory activity have been found, and Development of new PARP inhibitors with inhibitory activity is eagerly awaited I have.
なお、 4位に力ルバモイル基及び 2位にヘテロ環を含む環基を有する下記べンゾ イミダゾール誘導体が報告されている （J. Med. Chem.， 33， 814-819 (1990)) 、 当該 化合物の用途については抗腫瘍活性のみが報告され、 PARPへの作用については開 示も示唆もされていない。  The following benzoimidazole derivatives having a carbamoyl group at the 4-position and a ring group containing a heterocyclic ring at the 2-position have been reported (J. Med. Chem., 33, 814-819 (1990)). Only antitumor activity was reported for the use of the compound, and no effect on PARP was disclosed or suggested.
Figure imgf000005_0001
Figure imgf000005_0001
(式中、 Rは、 フエニル、 2-フリル、 2-チェニル、 3-チェニル、 又は 2-ピロリル基 等を示す。 ） 発明の開示  (Wherein, R represents a phenyl, 2-furyl, 2-thenyl, 3-thenyl, or 2-pyrrolyl group, etc.).
本発明者等は、 PARPを阻害する化合物につき鋭意検討した結果、 4位に無置換 の力ルバモイル基及び 2位にヘテロ環基を有するベンゾイミダゾ一ル誘導体が良 好な PARP阻害活性を有し、 PARPの関与する疾患の予防、 治療若しくは診断薬と して有用であることを見出し、 本発明を完成した。  The present inventors have conducted intensive studies on compounds that inhibit PARP.As a result, a benzimidazole derivative having an unsubstituted rubamoyl group at the 4-position and a heterocyclic group at the 2-position has excellent PARP inhibitory activity. They found that they were useful as preventive, therapeutic or diagnostic agents for diseases involving PARP, and completed the present invention.
即ち、 本発明によれば、 下記一般式 （ I ) 又は （Π) で示されるベンゾイミダゾ ール誘導体 （以下、 「本発明化合物」 と称する。 ） 又はその製薬学的に許容され得 る塩、並びにこれらの 1種又は 2種以上を有効成分として含有する医薬、特に PARP 阻害剤が提供される。  That is, according to the present invention, a benzimidazole derivative (hereinafter, referred to as “the compound of the present invention”) represented by the following general formula (I) or (Π), or a pharmaceutically acceptable salt thereof, Also provided are medicaments containing one or more of these as an active ingredient, particularly PARP inhibitors.
Figure imgf000005_0002
Figure imgf000005_0002
(式中の記号は以下の意味を有する。  (The symbols in the formula have the following meanings.
R1： Η、 低級アルキル、 s置換された低級アルキル基、R 1 : Η, lower alkyl, s- substituted lower alkyl group,
R2： H、 低級アルキル又は CO—低級アルキル基、 R 2 : H, lower alkyl or CO—lower alkyl group,
A：置換基を有していてもよいへテロ環基、 但し、 該ヘテロ環が含窒素非芳香属へ テロ環の場合、 該ヘテロ環は G1群から選択される基を 1〜4個有する、 G1群：式 (i)— X0— Y2— Z (ii)— X0— Y3— R5、 （iii)— X0— Y5— Z2、 (iv)— X^Y1 - Ζ (ν)— X1 - Υ4 - Ζ3、 (vi) - — Y5— Ζ2、 (vii)— X2_Y6_ Z3又は (viii)— X2— Y5— z2で表される基、 A: a heterocyclic group which may have a substituent, provided that the hetero ring is a nitrogen-containing non-aromatic group For heterocycles, the heterocycle is closed from one to four groups selected from Group G 1, Group G 1: Formula (i) - X 0 - Y 2 - Z (ii) - X 0 - Y 3 - R 5 , (iii) — X 0 — Y 5 — Z 2 , (iv) — X ^ Y 1 -Ζ (ν) — X 1 -Υ 4 -Ζ 3 , (vi)-— Y 5 — Ζ 2 , (vii) — a group represented by X 2 _Y 6 _ Z 3 or (viii) — X 2 — Y 5 — z 2 ;
X0：結合、 X 0 : join,
X1： d.8アルキレン又は co— c1-7アルキレン、 X 1 : d. 8 alkylene or co—c 1-7 alkylene,
X2 : C9-12アルキレン、 CO— C8-12アルキレン、 じ2-12ァルケ二レン、 C2-12アル キニレン、 CO— C2-12アルケニレン又は CO— C2-12アルキニレン、 X 2: C 9-12 alkylene, CO- C 8-12 alkylene, Ji 2 - 12 Aruke two alkylene, C 2-12 aralkyl Kiniren, CO- C 2-12 alkenylene or CO- C 2-12 alkynylene,
Y1： CO、 N(R3)、 CON(R3)又は結合、 Y 1 : CO, N (R 3 ), CON (R 3 ) or a bond,
R3： H、 低級アルキル又は CO—低級アルキル基、 R 3 : H, lower alkyl or CO—lower alkyl group,
Y2： C02又は Y1に記載の基、 Y 2: C0 2 or a group described in Y 1,
Y3： 0、 S、 N(R3)CO、 0-CONH、 NHC02、 NHCONH、 NHCSNH、 CONHNH、 NHNHCO、 0-COC02、 0-COCONH、 NHCOC02、 NHCOCONH、 C(NH)NH、 C(N-CN)NH、 NHC(NH)NH、 NHC(N-CN)亂 S02-0、 S02NH、 S02NHNH 又は P(0)(OR3)0、 Y 3: 0, S, N (R 3) CO, 0-CONH, NHC0 2, NHCONH, NHCSNH, CONHNH, NHNHCO, 0-COC0 2, 0-COCONH, NHCOC0 2, NHCOCONH, C (NH) NH, C (N-CN) NH, NHC (NH) NH, NHC (N-CN)亂 S0 2 -0, S0 2 NH, S0 2 NHNH or P (0) (oR 3) 0,
Y4： C02又は Y3に記載の基、 Y 4: C0 2 or a group described in Y 3,
Y5 : SO、 S02、 O- CO、 N(R3)C02、 NHS02又は NHNHS02、 Y 5: SO, S0 2, O- CO, N (R 3) C0 2, NHS0 2 or NHNHS0 2,
Y6： Y1又は Y4に記載の基、 Y 6 : a group described in Y 1 or Y 4
z1：環原子である炭素原子で結合する置換基を有していてもよいへテロ環基、 Z2：置換基を有していてもよい低級アルキル、 置換基を有していてもよいシ クロアルキル、 置換基を有していてもよいァリール又は置換基を有してい てもよいへテロ環基、 z 1 : a heterocyclic group which may have a substituent bonded at a carbon atom which is a ring atom, Z 2 : lower alkyl which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heterocyclic group which may have a substituent,
Z3： H又は Z2に記載の基。 Z 3 : H or the group described in Z 2 .
以下同様。 ） The same applies hereinafter. )
以下、 本発明について詳細に説明する。  Hereinafter, the present invention will be described in detail.
本明細書中、 「アルキル」 、 「アルキレン」 、 「ァルケ二レン」 及び 「アルキニ レン」 とは、 直鎖状又は分枝状の炭化水素鎖を意味する。 「低級」 とは、 炭素数 1 〜 6個を意味し、 「低級アルキル」 として、 好ましくは炭素数 1〜4の低級アルキ ル基であり、 より好ましくは、 メチル、 ェチル及びイソプロピル基である。 「アル ケニレン」 は、 アルキル鎖の任意の位置に 1個以上の二重結合を有することを意味 し、 「アルキニレン」 は、 アルキル鎖の任意の位置に 1個以上の三重結合を有する ことを意味する。 In the present specification, “alkyl”, “alkylene”, “alkenylene”, and “alkynylene” mean a straight or branched hydrocarbon chain. “Lower” means 1 to 6 carbon atoms, and “lower alkyl” is preferably a lower alkyl group having 1 to 4 carbon atoms, and more preferably a methyl, ethyl and isopropyl group. "Al "Kenylene" means having one or more double bonds at any position of the alkyl chain, and "alkynylene" means having one or more triple bonds at any position of the alkyl chain.
「ハロゲン」 は、 F、 Cl、 Br及び Iを示し、 好ましくは、 F、 C1及び Brである。 「ハロゲンで置換された低級アルキル基」 としては、 好ましくはフルォロメチル、 トリフルォロメチル及びトリフルォロェチル基である。  “Halogen” refers to F, Cl, Br and I, preferably F, C1 and Br. The "lower alkyl group substituted with halogen" is preferably a fluoromethyl, trifluoromethyl or trifluoroethyl group.
「シクロアルキル基」 は、 好ましくは炭素数 3乃至 8個のシクロアルキル基であ  “Cycloalkyl group” is preferably a cycloalkyl group having 3 to 8 carbon atoms.
「ァリール基」 は、 好ましくは炭素数 6乃至 1 4個の単環乃至 3環式ァリール基 である。 更に好ましくは、 フエニル及びナフチル基である。 また、 フエニル基に 5 乃至 8員のシクロアルキル環が縮環し、 例えば、 インダニル又はテトラヒドロナフ チル基を形成していても良い。 The “aryl group” is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms. More preferred are phenyl and naphthyl groups. Further, a 5- to 8-membered cycloalkyl ring may be condensed with the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.
「ヘテロ環基」 とは、 環原子として 0、 S及び Nから選択されるへテロ原子を 1乃 至 4個含有する 5乃至 8員の単環乃至三環式へテロ環基を示す。環原子である任意の 炭素原子がォキソ基で置換されていてもよく （ォキソ基より誘導される 1,3-ジォキ ソラン環等のァセタール体を含む） 、 S又は Nが酸化されォキシドを形成しても良い。 該ヘテロ環基は、 架橋されていてもよく、 また、 スピロ環を形成しても良い。 好まし くは、 ピリジル、 ピリダジニル、 ピリミジニル、 ピラジニル、 フリル、 チェニル、 ピロリル、 ォキサゾリル、 チアゾリル、 イミダゾリル、 テ卜ラゾリル、 ベンゾフラ ニル、 ベンゾチェ二ル、 ベンゾォキサゾリル、 ベンゾイミダゾリル、 ベンゾチァゾ リル、 キノリニル、 キナゾリニル、 キノキサリニル、 シンノリニル、 ピロリジニル、 ピペリジル、 モルホリニル、 ピペラジニル、 ビラゾリジニル、 イミダゾリジニル、 ホモピペラジニル、 テトラヒドロフラニル、 テトラヒドロビラニル、 クロマニル、 ジォキソラニル、 8-ァザビシクロ [3.2.1]オクタン- 3イリレ、 9-ァザビシクロ [3.3.1]ノナ ン -3-ィル、 3-ァザビシクロ [3.2.1]オクタン- 6-ィル、 7-ァザビシクロ [2.2.1]ヘプタン- 2-ィル、 2-ァザトリシクロ [3.3.1.13'7]デカン- 4-ィル、 1-ァザビシクロ [2.2.2]オクタン -2ィル、 1-ァザビシクロ [2.2.2]オクタン- 3-ィル、 1-ァザビシクロ [2.2.2]オクタン- 4- ィル、 3-ァザスピロ [5.5]ゥンデカン- 9-ィル、 2-ァザスピロ [4.5]デカン- 8-ィル、 2-ァ ザスピ口 ί4.4Ίノナン- 7-ィル及び 8-ァザスピ口 [4.5]デカン -2-ィル基等が挙げられる。 更に好ましくは、 ピリジル、 ピラジニル、 フリル、 チェニル、 チアゾリル、 ピロリ ジニル、 ピぺリジル及び 8-ァザビシクロ [3.2.1]ォク夕ン -3-ィル基等である。 The term "heterocyclic group" refers to a 5- to 8-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N as ring atoms. Any carbon atom that is a ring atom may be substituted with an oxo group (including an acetal such as a 1,3-dioxolane ring derived from the oxo group), and S or N is oxidized to form an oxide. May be. The heterocyclic group may be cross-linked, or may form a spiro ring. Preferably, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, chenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzochenyl, benzoxazolyl, benzimidazolyl, benzothiazonyl, benzothiazolyl, benzothiazolyl , Quinoxalinyl, cinnolinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, vilazolidinyl, imidazolidinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydroviranyl, chromanyl, dioxolanyl, 8-azabicyclo [3.2.1] cyclo-3-anyl-3-anilane-3-anilane-3-anilane ] Non-3-yl, 3-azabicyclo [3.2.1] octane-6-yl, 7-azabicyclo [2.2.1] heptane-2-yl, 2-azatricyclo [3.3.1.1 3 ' 7 ] Big -4-yl, 1-azabicyclo [2.2.2] octane-2-yl, 1-azabicyclo [2.2.2] octane-3-yl, 1-azabicyclo [2.2.2] octane-4-yl, 3-azaspiro [5.5] ゥ decane-9-yl, 2-azaspiro [4.5] decane-8-yl, 2-azaspi mouth ί4.4Ίnonane-7-yl and 8-azaspi [4.5] decane- And a 2-yl group. More preferred are a pyridyl, pyrazinyl, furyl, chenyl, thiazolyl, pyrrolidinyl, piperidyl, 8-azabicyclo [3.2.1] oct-3-yl group and the like.
「含窒素非芳香属ヘテロ環基」 とは、環原子として少なくとも 1つの Nを有し、 更に 0又は S原子を 1個有してもよいへテロ環基であって、 芳香属性を示さないへ テロ環基を示す。環原子である任意の炭素原子がォキソ基で置換されていてもよい。 好ましくは、 ピロリジニル、 ピペリジル、 モルホリニル、 ピペラジニル、 ピラゾリ ジニル、 イミダゾリジニル及びホモピペラジニル基であり、 更に好ましくはピロリ ジニル及びピペリジル基である。  "Nitrogen-containing non-aromatic heterocyclic group" refers to a heterocyclic group having at least one N as a ring atom and optionally having one or one S atom, and does not exhibit an aromatic attribute. Indicates a heterocyclic group. Any carbon atom that is a ring atom may be substituted with an oxo group. Preferred are pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl and homopiperazinyl groups, and more preferred are pyrrolidinyl and piperidyl groups.
「環原子である炭素原子で結合するへテロ環基」 とは、 隣接するリンカ一である Y1又は Y2で示される基と結合する環原子が炭素原子であるへテロ環基を示す。 例 えば、 1-ピペリジルは含まないが、 2-、 3-又は 4-ピペリジルは包含する。 The “heterocyclic group bonded at a carbon atom that is a ring atom” refers to a heterocyclic group whose carbon atom is bonded to a group represented by Y 1 or Y 2 which is an adjacent linker. For example, it does not include 1-piperidyl, but does include 2-, 3- or 4-piperidyl.
Aにおける 「置換基を有していてもよいへテロ環」 の置換基としては、 これらの 環の置換基として用いることができる基であれば特に制限はなく、 これらの置換基 を 1〜4個有していてもよい。 置換基として好ましくは、 下記 GQ群に示される基 であり、 該 GQ群は前記 G1群を包含する。 The substituent of the “heterocycle optionally having substituent (s)” in A is not particularly limited as long as it can be used as a substituent of these rings, and these substituents are 1 to 4 You may have one. Preferably as a substituent, a group represented by the following G Q group, said G Q groups include the Group G 1.
GG群：式— X— Y— Zで表される基。 G Group G : Group represented by the formula — X— Y— Z.
式中、 Xは、 結合、 C1-12アルキレン、 C2-12アルケニレン、 C2_12アルキニレン、 CO— C1-12アルキレン、 CO— C2-12 7ルケ二レン又は CO— C2-12アルキニレンを、 Yは、 結合、 CO、 N(R3)、 CON(R3)、 C02、 0、 S、 N(R3)CO、 0-CONH、 NHC〇2、 NHCO應、 NHCSNH、 CONHNH、 NHNHCO、 0-COC02、 0-COCONH、 NHCOC02、 NHCOCONH、 C(NH)NH、 C(N-CN)NH、 NHC(NH)亂 NHC(N-CN)NH、 S02-0、 S02NH、 S02NHNH、 P(0)(OR3)0、 SO、 S02、 0-CO、 N(R3)C02、 NHS02又は NHNHS02を、 Zは、 置換基を有していてもよい低級アルキル、 置換基を有して いてもよいシクロアルキル、 置換基を有していてもよいァリール、 置換基を有 していてもよいへテロ環基又は Hを示す。但し、 Yが、 SO、 S02、 0-CO、 N(R3)C02、 NHS02又は NHNHS02の場合、 Zは、 H以外の基を示す。 GQ群の置換基として より好ましくは、 式— X— Y— Zにおいて、 Xが CrC8アルキレンかつ Yが結合 又は N(R3)の場合、 Zは置換基を有していてもよいへテロ環基であり、 Xが Cr C8アルキレンかつ Yが 0又は Sの場合、 Zは置換基を有していてもよい低級ァ ルキル、 置換基を有していてもよいシクロアルキル、 置換基を有していてもよ ぃァリール又は置換基を有していてもよいへテロ環基であり、 Xが C9-C12アル キレン、 C2-C12アルケニレン又は C2-C12アルキニレンの場合、 Yは結合、 〇、 S 又は N(R3)、 かつ、 Zは H、 置換基を有していてもよい低級アルキル、 置換基を 有していてもよいシクロアルキル、 置換基を有していてもよいァリール又は置 換基を有していてもよいへテロ環基である。 GG群の置換基として更に好ましく は、 式一 X— Y— Zにおいて、 Xが CrC8アルキレンかつ Yが結合の場合、 Zは 置換基を有していてもよいへテロ環基であり、 Xが C!-Csアルキレンかつ Yが 0又は Sの場合、 Zは置換基を有していてもよい低級アルキル、 置換基を有し ていてもよいシクロアルキル、 置換基を有していてもよいァリール又は置換基 を有していてもよいへテロ環基であり、 Xが C9-C12アルキレン、 C2-C12ァルケ 二レン又は C2-C12アルキニレンの場合、 Yは結合、 0、 S又は N(R3)、 かつ、 Z は H、 置換基を有していてもよい低級アルキル、 置換基を有していてもよいシ クロアルキル、 置換基を有していてもよいァリール又は置換基を有していても よいへテロ環基が好ましい。 GG群の置換基として特に好ましくは、 式一 X— Y 一 Zにおいて、 Xが CrC8アルキレンかつ Yが結合の場合、 Zは置換基を有して いてもよいへテロ環基であり、 Xが C!-Csアルキレンかつ Yが 0又は Sの場合、 Zは置換基を有していてもよいァリール基であり、 Xが C9-C12アルキレン、 C2-C12 アルケニレン又は C2-C12アルキニレンの場合、 Yは結合、 かつ、 Zは置換基を 有していてもよい低級アルキル、 置換基を有していてもよいァリール基が好ま しい。 上記 GQ群の好ましい範囲は G1群にも適用される。 Wherein, X is a bond, C 1-12 alkylene, C 2-12 alkenylene, C 2 _ 12 alkynylene, CO- C 1-12 alkylene, CO- C 2-12 7 Luque two alkylene or CO- C 2- 12 alkynylene, Y is a bond, CO, N (R 3 ), CON (R 3 ), C 0 2 , 0, S, N (R 3 ) CO, 0-CONH, NHC〇 2 , NHCONH, NHCSNH, CONHNH, NHNHCO, 0-COC0 2 , 0-COCONH, NHCOC0 2, NHCOCONH, C (NH) NH, C (N-CN) NH, NHC (NH)亂NHC (N-CN) NH, S0 2 -0, S0 2 NH, S0 2 NHNH, the P (0) (oR 3) 0, SO, S0 2, 0-CO, N (R 3) C0 2, NHS0 2 or NHNHS0 2, Z has a substituent A lower alkyl which may be substituted, a cycloalkyl which may have a substituent, an aryl which may have a substituent, a heterocyclic group which may have a substituent or H. However, Y is, SO, S0 2, 0- CO, N (R 3) C0 2, when the NHS0 2 or NHNHS0 2, Z represents a group other than H. As more preferred substituents of G Q group, wherein - X- Y- in Z, when X is C r C 8 alkylene and Y is a bond or N (R 3), Z is an optionally substituted group a heterocyclic group optionally, when X is C r C 8 alkylene and Y is 0 or S, Z represents a lower § be substituted Alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group, wherein X is C 9 -C 12 alkyl In the case of kylene, C 2 -C 12 alkenylene or C 2 -C 12 alkynylene, Y is a bond, 〇, S or N (R 3 ), and Z is H, a lower alkyl which may have a substituent, A cycloalkyl which may have a substituent; an aryl which may have a substituent; or a heterocyclic group which may have a substituent. The more preferred substituents G G group, in the formula one X- Y- Z, when X is a bond C r C 8 alkylene and Y, Z to which may have a substituent heterocyclic group When X is C! -Cs alkylene and Y is 0 or S, Z is lower alkyl which may have a substituent, cycloalkyl which may have a substituent, and which has a substituent When X is C 9 -C 12 alkylene, C 2 -C 12 alkylene or C 2 -C 12 alkynylene, Y is A bond, 0, S or N (R 3 ), and Z is H, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), having substituent (s) And a heterocyclic group which may have a substituent. Particularly preferred as the substituent for G G group, in the formula one X- Y one Z, when X is a bond C r C 8 alkylene and Y, Z to which may have a substituent heterocyclic group When X is C! -Cs alkylene and Y is 0 or S, Z is an aryl group which may have a substituent, and X is C 9 -C 12 alkylene, C 2 -C 12 alkenylene or In the case of C 2 -C 12 alkynylene, Y is preferably a bond, Z is preferably a lower alkyl which may have a substituent, or an aryl group which may have a substituent. A preferred range of the G Q group applies to Group G 1.
「置換基を有していてもよい低級アルキル基」 の置換基としては、 置換基として 用いることができる基であれば特に制限はない力 好ましくは、 ハロゲン、 0H、 0 — Cwo炭化水素基、 SH、 S— C 2G炭化水素基、 CO— C1-2G炭化水素基、 C02H、 COO 一 d— 2Q炭化水素基、 C0NH2、 CONH—低級アルキル、 CON (低級アルキル )2、 NHCO —低級アルキル、 NHC02—低級アルキル、 NHCONH—低級アルキル、 NH2、 NH— 低級アルキル、 N (低級アルキル )2、 CN及び N02基からなる群より選択される基で ある。 これらの置換基を 1〜4個有していてもよい。 尚、 「C1-20炭化水素基」 とは アルキル、 アルケニル、 アルキニル、 シクロアルキル、 ァリール、 アルキレン-シ クロアルキル、 アルケニレン-シクロアルキル、 アルキニレン-シクロアルキル、 ァ ルキレン-ァリール、 アルケニレン-ァリール、 アルキニレン-ァリール等を包含し、 それらは更に置換基を有していてもよく、 該置換基として好ましくは、 ハロゲン、 OH、 0—低級アルキル、 SH、 S—低級アルキル、 CO—低級アルキル、 C02H、 COO 一低級アルキル、 CONH2、 CONH—低級アルキル、 CON (低級アルキル )2、 NHCO— 低級アルキル、 NHC02—低級アルキル、 NHCONH—低級アルキル、 NH2、 NH—低 級アルキル、 N (低級アルキル )2、 CN及び N02基からなる群より選択される基であ り、 該置換基を:！〜 4個有していてもよい。 The substituent of the “optionally substituted lower alkyl group” is not particularly limited as long as it can be used as a substituent. Preferably, halogen, 0H, 0—Cwo hydrocarbon group, SH, S—C 2G hydrocarbon group, CO—C 1-2G hydrocarbon group, C0 2 H, COO 1 d— 2 Q hydrocarbon group, C0NH 2 , CONH—lower alkyl, CON (lower alkyl) 2 , NHCO - lower alkyl, -NHCONH- lower alkyl, NH 2, NH- lower alkyl, N (lower-alkyl) 2, CN and groups selected from the group consisting of N0 2 group - lower alkyl, NHC0 2. These substituents may have 1 to 4 substituents. In addition, “C 1-20 hydrocarbon group” means alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylene- Chloroalkyl, alkenylene-cycloalkyl, alkynylene-cycloalkyl, alkylene-aryl, alkenylene-aryl, alkynylene-aryl, etc., which may further have a substituent. Halogen, OH, 0—lower alkyl, SH, S—lower alkyl, CO—lower alkyl, C0 2 H, COO lower alkyl, CONH 2 , CONH—lower alkyl, CON (lower alkyl) 2 , NHCO—lower alkyl, NHC0 2 - lower alkyl, -NHCONH- lower alkyl, NH 2, NH- lower alkyl, N Ri Oh by (lower alkyl) 2, a group selected from CN and the group consisting of N0 2 group, the substituents:! You may have up to four.
「置換基を有していてもよいシクロアルキル基」 の置換基としては、 これらの環 の置換基として用いることができる基であれば特に制限はないが、 好ましくは、 C^o炭化水素基、 0— d ^炭化水素基、 ハロゲン、 ハロゲンで置換された低級アル キル及びォキソ基 （ォキソ基より誘導される 1,3-ジォキソラン環等のァセ夕一ル体 を含む） からなる群より選択される基であり、 更に好ましくは低級アルキル基であ る。 これらの置換基を 1〜4個有していてもよい。  The substituent of the “optionally substituted cycloalkyl group” is not particularly limited as long as it can be used as a substituent of these rings, but is preferably a C ^ o hydrocarbon group. , 0-d ^ hydrocarbon group, halogen, lower alkyl substituted with halogen, and oxo group (including acetyl group such as 1,3-dioxolan ring derived from oxo group) It is a group selected, more preferably a lower alkyl group. These substituents may have 1 to 4 substituents.
「置換基を有していてもよいァリール基」 及び「置換基を有していてもよいへテ 口環基」 の置換基としては、 これらの環の置換基として用いることができる基であ れば特に制限はない力 好ましくは、 C1-20炭化水素基、 ハロゲン、 ハロゲンで置換 された低級アルキル、 OH、 0— d ^炭化水素基、 SH、 S— C1-2G炭化水素基、 CO— C1-2o炭化水素基、 C02H、 COO— C1-2()炭化水素基、 CONH2、 CONH—低級アルキル、 CON (低級アルキル )2、 NHCO—低級アルキル、 NHC02—低級アルキル、 NHCONH —低級アルキル、 NH2、 NH—低級アルキル、 N (低級アルキル )2、 CN及び N02基か らなる群より選択される基であり、 更に好ましくは、 低級アルキル、 ハロゲン及び 0—低級アルキルからなる群より選択される基である。 これらの置換基を 1〜 4個 有していてもよい。 The substituents of the "aryl group which may have a substituent" and the "heterocyclic group which may have a substituent" are groups which can be used as a substituent of these rings. If there is no particular limitation, preferably a C 1-20 hydrocarbon group, halogen, lower alkyl substituted with halogen, OH, 0-d ^ hydrocarbon group, SH, S—C 1-2G hydrocarbon group, CO- C 1-2 o hydrocarbon group, C0 2 H, COO- C 1-2 () hydrocarbon radical, CONH 2, CONH- lower alkyl, CON (lower alkyl) 2, NHCO- lower alkyl, NHC0 2 - lower alkyl, NHCONH - lower alkyl, NH 2, an NH- lower alkyl, N (lower-alkyl) 2, CN and N0 2 groups or Ranaru group selected from the group, more preferably, lower alkyl, halogen and 0 —A group selected from the group consisting of lower alkyl. These substituents may have 1 to 4 substituents.
本発明における好ましい化合物は、 R1としては H、 低級アルキル又はハロゲン、 R2としては H又は低級アルキル、 Aとしてはピリジル、 ピリダジニル、 ピリミジニ ル、 ピラジニル、 フリル、 チェニル、 ピロリル、 ォキサゾリル、 チアゾリル、 イミ ダゾリル、 テ卜ラゾリル、 ベンゾフラニル、 ベンゾチェ二ル、 ベンゾォキサゾリル、 ベンゾイミダゾリル、 ベンゾチアゾリル、 キノリニル、 キナゾリニル、 キノキサリ ニル、 シンノリニル、 ピロリジニル、 ピペリジル、 モルホリニル、 ピペラジニル、 ビラゾリジニル、 イミダゾリジニル、 ホモピペラジニル、 テトラヒドロフラニル、 テトラヒドロビラニル、 クロマニル及びジォキソラニル基から選択されるへテロ環 基であり、 該ヘテロ環基は置換基を有していてもよい。 該ヘテロ環基の置換基とし て好ましくは、 ノニル基、 ゥンデシル基、 フエニルェチル基、 フエニルブチル基、 ヘプテニル基、 フエニルェテニル基、 フエニルプロぺニル基、 4-メトキシフエニル プロぺニル基、 フエノキシェチル基、 2-クロロフエノキシェチル基、 フエノキシプ 口ピル基、 2-クロロフエノキシプロピル基、 2-シァノフエノキシプロピル基、 2-ブ ロモフエノキシプロピル基、 2-トリフルォロメチルフエノキシプロピル基、 2-メチ ルフエノキシプロピル基、 2-ニトロフエノキシプロピル基、 2-メトキシカルボニル フエノキシプロピル基、 2,6-ジクロロフエノキシプロピル基、 3-クロロフエノキシ プロピル基、 3-(2,3-ジヒドロべンゾ [1,4]ジォキシン- 6-ィル)ォキシプロピル基、 4- トリフルォロメチルフエノキシプロピル基、 4-ブロモフエノキシプロピル基、 4-二 トロフエノキシプロピル基、 4-メトキシフエノキシプロピル基、 4-メチルフエノキ シプロピル基、 フエノキシブチル基、 フエノキシペンチル基、 フエ二ルチオプロピ ル基、 テニルプロピル基、 ピリジルプロピル基、 メチルチアゾリルェチル基、 へキ シルァミノ基、 シクロへキシルメチルァミノ基、 フエネチルァミノ基、 フエニルプ 口ピルアミノ基、 フエノキシェチルァミノ基、 ベンジルォキシ基、 フエニルプロピ ルォキシ基、 ベンジルチオ基、 フエネチルチオ基、 フエニルプロピルチオ基である。 本発明化合物の内、 最も好ましい化合物としては以下の化合物が挙げられる： 2- (チォフェン- 2-ィル) -1H-ベンゾイミダゾール -4-カルボキサミド、 2-(2-メトキシピ リジン- 5-ィル) -1H-ベンゾイミダゾ一ル -4-カルボキサミド、 2-(2-ェチルァミノピリ ジン- 5-ィル) -1H-ベンゾィミダゾ一ル -4-カルボキサミド、 2- (ピリジン- 4-ィル) -1H- ベンゾイミダゾール- 4-カルボキサミド、 2-(1-ノニルビペリジン- 4-ィル] -1H-ベンゾ イミダゾール -4-カルボキサミド、 2-{1-[3- (チォフェン- 2-ィル)プロピル]ピぺリジン -4-ィル }-1Η-ベンゾイミダゾ一ル -4-カルボキサミド、 2-[1-(2-フエノキシェチル）ピぺ リジン- 4-ィル] -1H-ベンゾイミダゾ一ル -4-カルボキサミド、 2-[1-(3-フエノキシプロ ピル）ピペリジン- 4-ィル] -1H-ベンゾィミダゾ一ル -4-カルボキサミド、 2-{1-[3-(2-ク ロロフエノキシ）プロピリレ]ピぺリジン- 4-ィル}-111-ベンゾィミダゾ一ル -4-カルボキ サミド、 2- {1-[3-(2-ブロモフエノキシ）プロピル]ピぺリジン- 4-ィル }-1Η-ベンゾイミ ダゾール— 4-カルボキサミド、 2-{1-[3-(2-シァノフェノキシ）プロピリレ]ピぺリジン- 4- ィル }-1Η-ベンゾイミダゾール -4-カルボキサミド、 2-{1-[3-(2-トリフルォロメチルフ エノキシ）プロピル]ピペリジン- 4-ィル }-1Η-ベンゾイミダゾ一ル -4-カルボキサミド、 2-{1-[3-(2-メチルフエノキシ）プロピル]ピぺリジン -4-ィル}-111-ベンゾィミダゾ一ル -4-カルボキサミド、 2-{1- [3-(2-ニトロフエノキシ）プロピル]ピぺリジン- 4-ィル }-1Η- ベンゾイミダゾ一ル -4-カルボキサミド、 2-{1-[3-(3-クロロフエノキシ）プロピル]ピ ペリジン- 4-ィル }-1Η-ベンゾイミダゾール -4-カルボキサミド、 2-{1-[3-(4-クロロフエ ノキシ）プロピル]ピペリジン- 4-ィル }-1Η-ベンゾイミダゾ一リレ -4-力ルポキサミド、 2-{1-[3-(4-トリフルォロメチルフエノキシ）プロピル]ピペリジン- 4-イリ 1/}-1Η-ベンゾ イミダゾ一ル -4-カルボキサミド、 2-{1-[3-(4-ブロモフエノキシ）プロピル]ピベリジ ン—4-イリ -1H-ベンゾイミダゾ一ル -4-カルボキサミド、 2-{1-[3-(4-ニトロフエノキ シ）プロピル]ピペリジン- 4-ィル }-1Η-ベンゾイミダゾール -4-カルボキサミド、 2-{1- [3-(4-メトキシフエノキシ）プロピル]ピペリジン- 4イリ 1/}-1Η-ベンゾイミダゾ一ル -4- カルボキサミド、 2-{1-[3-(4-メチルフエノキシ)プロピル]ピぺリジン- 4-ィル }-1Η-ベ ンゾイミダゾ一ル -4-カルボキサミド、 2-[1-(4-フエノキシブチル）ピぺリジン- 4-ィ ル] -1H-ベンゾイミダゾ一ル -4-カルボキサミド、 2-[1-(3-フエ二ルチオプロピル）ピぺ リジン- 4-ィル] -1H-ベンゾイミダゾ一リレ -4-カルボキサミド、 2-[1- (3-フエニル -2-プロ ペン- 1-ィル）ピペリジン- 4-ィル] -1H-ベンゾイミダゾ一ル -4-カルボキサミド。 Preferred compounds of the present invention, as R 1 is H, lower alkyl or halogen, as R 2 is H or lower alkyl, as the A pyridyl, pyridazinyl, Pirimijini Le, pyrazinyl, furyl, thienyl, pyrrolyl, Okisazoriru, thiazolyl, Imi Dazolyl, tetrazolyl, benzofuranyl, benzochenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxali A heterocyclic group having a substituent selected from the group consisting of phenyl, cinnolinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, vilazolidinyl, imidazolidinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydroviranyl, chromanyl and dioxolanyl. May be. The substituent for the heterocyclic group is preferably a nonyl group, a benzyl group, a phenylethyl group, a phenylbutyl group, a heptenyl group, a phenylethenyl group, a phenylpropyl group, a 4-methoxyphenylpropyl group, a phenyloxyl group, Chlorophenoxethyl, phenoxypropyl pill, 2-chlorophenoxypropyl, 2-cyanophenoxypropyl, 2-bromophenoxypropyl, 2-trifluoromethylphenoxypropyl, 2-methylphenoxypropyl, 2-nitrophenoxypropyl, 2-methoxycarbonylphenoxypropyl, 2,6-dichlorophenoxypropyl, 3-chlorophenoxypropyl, 3- ( 2,3-dihydrobenzo [1,4] dioxin-6-yl) oxypropyl group, 4-trifluoromethylphenoxypropyl group, 4 -Bromophenoxypropyl, 4-2-trophenoxypropyl, 4-methoxyphenoxypropyl, 4-methylphenoxypropyl, phenoxybutyl, phenoxypentyl, phenylthiopropyl, and phenylpropyl , Pyridylpropyl group, methylthiazolylethyl group, hexylamino group, cyclohexylmethylamino group, phenethylamino group, phenylaminopropylamino group, phenoxethylamino group, benzyloxy group, phenylpropyloxy group, benzylthio group Phenylethylthio group and phenylpropylthio group. Among the compounds of the present invention, the most preferred compounds include the following compounds: 2- (thiophen-2-yl) -1H-benzimidazole-4-carboxamide, 2- (2-methoxypyridin-5-yl) ) -1H-benzimidazole-4-carboxamide, 2- (2-ethylaminopyridin-5-yl) -1H-benzimidazol-4-carboxamide, 2- (pyridine-4-yl) -1H- Benzimidazole-4-carboxamide, 2- (1-nonylbiperidin-4-yl) -1H-benzimidazole-4-carboxamide, 2- {1- [3- (thiophen-2-yl) propyl] piperidine -4-yl} -1Η-benzimidazole-4-carboxamide, 2- [1- (2-phenoxethyl) pyridin-4-yl] -1H-benzimidazole-4-carboxamide, 2 -[1- (3-Phenoxypropyl) piperidin-4-yl] -1H-benzoimidazole-4-carboxamide, 2- {1- [3- (2-k Lolophenoxy) propylyl] piperidin-4-yl} -111-benzoimidazole-4-carboxy Samide, 2- {1- [3- (2-bromophenoxy) propyl] piperidin-4-yl} -1Η-benzimidazole— 4-carboxamide, 2- {1- [3- (2-cyanophenoxy) ) Propyreyl] piperidin-4-yl} -1Η-benzimidazole-4-carboxamide, 2- {1- [3- (2-trifluoromethylphenoxy) propyl] piperidin-4-yl}- 1Η-benzimidazol-4-carboxamide, 2- {1- [3- (2-methylphenoxy) propyl] piperidin-4-yl} -111-benzimidazol-4-carboxamide, 2- {1 -[3- (2-Nitrophenoxy) propyl] piperidin-4-yl} -1Η-benzimidazole-4-carboxamide, 2- {1- [3- (3-chlorophenoxy) propyl] pi Peridin-4-yl} -1Η-benzimidazole-4-carboxamide, 2- {1- [3- (4-chlorophenoxy) propyl] piperidin-4-yl} -1Η-benzimidazolyl-4- Force Poxamide, 2- {1- [3- (4-trifluoromethylphenoxy) propyl] piperidine-4-yl 1 /}-1Η-benzoimidazole-4-carboxamide, 2- {1- [3 -(4-Bromophenoxy) propyl] piberidine-4-yl-1H-benzimidazole-4-carboxamide, 2- {1- [3- ( 4 -nitrophenoxy) propyl] piperidine-4-yl}- 1Η-benzimidazole-4-carboxamide, 2- {1- [3- (4-methoxyphenoxy) propyl] piperidine-4yl 1 /}-1Η-benzimidazol-4-carboxamide, 2- {1 -[3- (4-Methylphenoxy) propyl] piridin-4-yl} -1Η-benzoimidazole-4-carboxamide, 2- [1- (4-phenoxybutyl) piridin-4-yl ] -1H-benzimidazol-4-carboxamide, 2- [1- (3-phenylthiopropyl) pyridin-4-yl] -1H-benzimidazolyl-4-carboxamide, 2- [1- (3-Phenyl-2-propen-1-yl) piperidin-4-yl] -1H-benzimidazol-4-carboxamide.
本発明化合物は、 R2が Hである場合、 一般式 （ I ) 及び （Π) で示される化合物 は平衡にある。 本発明はそれら平衡の関係にある化合物を包含する。 In the compound of the present invention, when R 2 is H, the compounds represented by general formulas (I) and (Π) are in equilibrium. The present invention includes those compounds in equilibrium.
本発明化合物は、置換基の種類によっては幾何異性体や互変異性体が存在する場 合があるが、 本発明にはこれらの異性体の分離したもの、 あるいは混合物をも包含 する。 また、 本発明化合物は不斉炭素原子を有する場合があり、 不斉炭素原子に基 づく異性体が存在しうる。本発明にはこれら光学異性体の混合物や単離されたもの を包含する。 また、 本発明には、 本発明化合物を放射性同位元素でラベル化した化 合物も包含する。  The compound of the present invention may have a geometric isomer or a tautomer depending on the type of the substituent, but the present invention also includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and may have an isomer based on the asymmetric carbon atom. The present invention includes a mixture of these optical isomers and an isolated one. The present invention also includes a compound in which the compound of the present invention is labeled with a radioisotope.
また、 本発明化合物には、 薬理学的に許容されるプロドラッグも含まれる。 薬理 学的に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で本発 明の NH2、 OH、 C02H等に変換できる基を有する化合物である。 プロドラッグを形 成する基としては、 Prog. Med., 5， 2157-2161 (1985)や 「医薬品の開発」 （廣川書店、 1990年） 第 7卷 分子設計 163-198に記載の基が挙げられる。 The compounds of the present invention also include pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug is defined as a solvolysate or under physiological conditions. It is a compound having a group that can be converted to light NH 2 , OH, C 2 H, and the like. The group that form a prodrug, Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 19 1990) groups according to the seventh Certificates Molecular Design 163-198 No.
更に、 本発明化合物は、 酸付加塩又は置換基の種類によっては塩基との塩を形成 する場合もあり、かかる塩が製薬学的に許容され得る塩である限りにおいて本発明 に包含される。 具体的には、 塩酸、 臭化水素酸、 ヨウ化水素酸、 硫酸、 硝酸、 リン 酸等の無機酸や、 ギ酸、 酢酸、 プロピオン酸、 シユウ酸、 マロン酸、 コハク酸、 フ マル酸、 マイレン酸、 乳酸、 リンゴ酸、 酒石酸、 クェン酸、 メタンスルホン酸、 ェ 夕ンスルホン酸、 ァスパラギン酸、 グルタミン酸等の有機酸との酸付加塩、 ナトリ ゥム、 カリウム、 マグネシウム、 カルシウム、 アルミニウム等の無機塩基、 メチル ァミン、 ェチルァミン、 エタノールアミン、 リジン、 オル二チン等の有機塩基との 塩やアンモニゥム塩等が挙げられる。 さらに、 本発明は、 本発明化合物及びその製 薬学的に許容され得る塩の各種の水和物や溶媒和物及び結晶多形の物質をも包含 する。  Further, the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent, and is included in the present invention as long as such a salt is a pharmaceutically acceptable salt. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleene Acid addition salts with organic acids such as acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, disulfonic acid, aspartic acid, glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc. And a salt with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ordinine, and an ammonium salt. Furthermore, the present invention also includes various hydrates, solvates, and crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof.
(製造法） (Manufacturing method)
本発明化合物及びその製薬学的に許容される塩は、その基本骨格あるいは置換基 の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができ る。 その際、 官能基の種類によっては、 当該官能基を原料乃至中間体の段階で適当 な保護基 （容易に当該官能基に転化可能な基） に置き換えておくことが製造技術上 効果的な場合がある。 このような官能基としては例えばアミノ基、 水酸基、 カルボ キシル基等であり、 それらの保護基としては例えばグリーン （Greene) 及びウッツ (Wuts) 著、 「Protective Groups in Organic Synthesis (第 2版） 」 に記載の保護基を 挙げることができ、 これらを反応条件に応じて適宜選択して用いればよい。 このよ うな方法では、 当該保護基を導入して反応を行った後、 必要に応じて保護基を除去 することにより、 所望の化合物を得ることができる。  The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents. At this time, depending on the type of the functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage of a raw material or an intermediate. There is. Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group. Examples of such a protecting group include “Protective Groups in Organic Synthesis (2nd edition)” by Greene and Wuts. And the protecting groups described in (1) and (2) may be appropriately selected and used according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group as necessary.
以下、 本発明化合物の代表的な製造法を一般式 （I ) について説明するが、 一般 式 （II) で示される化合物も、 対応する原料を使用することで同様に製造すること ができる。 第 1製法 Hereinafter, a typical production method of the compound of the present invention will be described with reference to the general formula (I), but the compound represented by the general formula (II) can also be produced in the same manner by using the corresponding raw materials. First manufacturing method
Figure imgf000014_0001
Figure imgf000014_0001
(式中、 Rは H又は低級アルキル基を示す。 他の記号は前記の意味を有する。 ） 第 1製法 （R=低級アルキル基の場合）  (Wherein, R represents H or a lower alkyl group. Other symbols have the same meanings as described above.) First production method (when R = lower alkyl group)
本製法は、 エステル化合物である （III) をアンモニアと反応させアミド化し、 本 発明化合物 （ I ) を製造する方法である。 反応は水、 メタノール、 エタノール等の アルコール類、 Ν,Ν-ジメチルホルムアミド （DMF) 、 テトラヒドロフラン （THF) 等の反応に不活性な溶媒中または無溶媒中、 室温乃至加熱下で行われる。 場合によ り加圧下にて行うのが反応に有利な場合がある。  This production method is a method for producing the compound (I) of the present invention by reacting an ester compound (III) with ammonia to amidate it. The reaction is carried out in a solvent inert to the reaction, such as water, alcohols such as methanol and ethanol, Ν, Ν-dimethylformamide (DMF), and tetrahydrofuran (THF), or in a solvent-free condition from room temperature to under heating. In some cases, performing the reaction under pressure may be advantageous for the reaction.
第 2製法 （R= Hの場合）  Second manufacturing method (R = H)
本製法は、 カルボン酸化合物である （Ilia) を縮合剤 （例えば、 ジシクロへキシル カルボジイミド （DCC) 、 ジイソプロピルカルボジイミド （DIPC) 、 1-ェチル -3-(3- ジメチルァミノプロピル)カルポジイミド （WSC) 、 Ι,Γ-カルボニルビス- 1H-イミダ ゾール （CDI) 等） 、 場合によっては、 更に添加剤 （例えば、 Ν-ヒドロキシスクシ ンイミド （HONSu) 、 1-ヒドロキシベンゾトリアゾ一ル （HOBt) 等） の存在下、 ァ ンモニァで処理することにより本発明化合物 （ I ) を製造する方法である。 カルボ ン酸化合物 （Ilia) がヒドロキシ基、 アミノ基等の反応に活性な官能基を有する場合 には、 これらの官能基を予め保護基で保護しておき、 本反応を実施し、 所望により、 保護基を除去して、 本発明化合物 （ I ) を得ることができる。  In this production method, a carboxylic acid compound (Ilia) is condensed with a condensing agent (eg, dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) , Ι, Γ-carbonylbis-1H-imidazole (CDI), etc., and in some cases, further additives (eg, Ν-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), etc.) )), Wherein the compound of the present invention (I) is produced by treating with ammonia. When the carboxylic acid compound (Ilia) has a functional group active in a reaction such as a hydroxy group or an amino group, these functional groups are protected with a protecting group in advance, and this reaction is carried out. By removing the protecting group, the compound (I) of the present invention can be obtained.
溶媒としては、 ジクロロメタン、 1,2-ジクロロェタン、 クロ口ホルム等のハロゲン 化炭化水素類、 ベンゼン、 トルエン、 キシレン等の芳香族炭化水素類、 ジェチルェ 一テル、 THF、 1,4-ジォキサン等のェ一テル類、 DMF、ジメチルスルホキシド（DMSO)、 ピリジン等の反応に不活性な溶媒が使用できる。 これらの溶媒は単独で、 又は 2種 以上混合して用いることができる。  Examples of the solvent include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethyl ether, THF, and 1,4-dioxane. Inert solvents such as monotells, DMF, dimethyl sulfoxide (DMSO) and pyridine can be used. These solvents can be used alone or in combination of two or more.
第 3製法 （環基 A上の置換基又はその側鎖の変換） 本発明化合物を原料として、 更に反応に付すことにより、 種々の本発明化合物を 製造することができる。 Third production method (conversion of substituent on ring group A or its side chain) Various compounds of the present invention can be produced by using the compound of the present invention as a raw material and subjecting it to a reaction.
( 1 ) 求核置換反応によるアルキル化  (1) Alkylation by nucleophilic substitution
OH基を有する化合物を、 塩化チォニル等との反応で得られるアルキルクロリ ド 等のアルキルハラィド又は塩化メタンスルホニル又は塩化 P-トルエンスルホニル等 との反応で得られる有機スルホン酸エステルとし、求核試薬と反応して使用できる。 あるいは、 光延反応に付すことによつても製造できる。 反応はハロゲン化炭化水素 類、 芳香族炭化水素類、 エーテル類、 DMF等の反応に不活性な有機溶媒中または無 溶媒下、 冷却下〜加熱下に行われる。 水素化ナトリウム、 水素化カリウム、 リチウ ムジイソプロピルアミド、 リチウムへキサメチルジシラジド、 ナトリウムメトキシ ド、 カリウム tert-ブトキシド、 水酸化ナトリウム、 水酸化カリウム、 炭酸ナトリウ ム、 炭酸カリウム等の塩基の存在下に反応させるのが、 反応を円滑に進行させる上 で有利な場合がある。  A compound having an OH group is converted into an alkyl halide such as alkyl chloride obtained by reaction with thionyl chloride or the like, or an organic sulfonate obtained by reaction with methanesulfonyl chloride or P-toluenesulfonyl chloride, and reacted with a nucleophile. Can be used. Alternatively, it can also be produced by subjecting it to the Mitsunobu reaction. The reaction is carried out in an organic solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF and the like, or without solvent, under cooling to heating. In the presence of bases such as sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. In some cases, it is advantageous to make the reaction proceed smoothly.
( 2 ) 還元的アルキル化  (2) Reductive alkylation
一級若しくは二級ァミンを有する化合物と、 ケトンゃアルデヒド等のカルボニル 化合物とを反応させることにより、 アルキル化を行うことができる。 反応は還元的 アルキル化 (カルボニル化合物から見れば還元的ァミノ化)の常法を用いることがで き、 例えば日本化学会編 「実験化学講座 (第 4版)」 20卷 （1992年） （丸善)等に記載 の方法が挙げられる。  Alkylation can be performed by reacting a compound having a primary or secondary amine with a carbonyl compound such as a ketone-aldehyde. For the reaction, a conventional method of reductive alkylation (reductive amination from the viewpoint of a carbonyl compound) can be used. For example, “Experimental Chemistry Course (4th edition)” edited by The Chemical Society of Japan, 20 volumes (1992) (Maruzen ) And the like.
( 3 ) アミド化、 スルホンアミド化及びエステル化  (3) Amidation, sulfonamidation and esterification
カルボン酸若しくはスルホン酸化合物を、 縮合剤の存在下あるいはそれらの反応 性誘導体を使用することにより製造できる。 カルボン酸又はスルホン酸化合物の反 応性誘導体は、 酸ハライド、 酸無水物、 活性エステルを示す。 反応は、 例えば日本 化学会編 「実験化学講座 (第 4版)」 22巻 （1992年） （丸善） 等に記載の方法により 行うことができる。  The carboxylic acid or sulfonic acid compound can be produced in the presence of a condensing agent or by using a reactive derivative thereof. The reactive derivative of a carboxylic acid or sulfonic acid compound includes an acid halide, an acid anhydride and an active ester. The reaction can be carried out, for example, according to the method described in “Experimental Chemistry Lecture (4th edition)”, edited by The Chemical Society of Japan, Vol.
( 4 ) 力ルバマート化及びウレァ化  (4) Conversion to urebamart and urea
カルボン酸の反応性誘導体とアジ化ナトリゥム等のアジ化物塩との反応若しく はアジ化ジフエニルホスホリル （DPPA) との反応によって得られる酸アジドを Curtius転位することにより、 あるいは、 一級アミドの Hofmann転位等により得ら れるイソシァネ一ト体を、 OH基を有する化合物又はアミン化合物と反応すること により製造できる。 The reaction of a reactive derivative of a carboxylic acid with an azide salt such as sodium azide or diphenylphosphoryl azide (DPPA) or Curtius rearrangement of an acid azide obtained by reaction with DPPA, or the primary amide Hofmann Obtained by dislocation, etc. The isocyanate compound can be produced by reacting the compound with an OH group or an amine compound.
反応は、 八ロゲン化炭化水素類、 芳香族炭化水素類、 エーテル類、 DMF等の反応 に不活性な有機溶媒中又は無溶媒下、冷却下〜加熱下に行われる。反応に際しては、 当量若しくは一方を過剰に用いることができる。  The reaction is carried out in an organic solvent inert to the reaction such as octogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, or the like, or without a solvent, under cooling to heating. In the reaction, an equivalent amount or one of them can be used in excess.
原料化合物の製法  Production method of raw material compounds
本発明化合物の原料化合物 （III) 及び （Ilia) は、 例えば下記合成経路図に示さ れる公知の反応を用いて常法により製造できる。  The starting compounds (III) and (Ilia) of the compound of the present invention can be produced by a conventional method using, for example, a known reaction shown in the following synthetic scheme.
Figure imgf000016_0001
Figure imgf000016_0001
(Ilia) (ΙΠ)  (Ilia) (ΙΠ)
(式中、 L2-CO-A はカルボン酸 （L2 = OH) 又はその反応性誘導体を示す。 他の記 号は前記の意味を有する。 ） (In the formula, L 2 -CO-A represents a carboxylic acid (L 2 = OH) or a reactive derivative thereof. Other symbols have the meanings described above.)
ァシル化 Acylation
本製法はジァミノ安息香酸エステル化合物 （V) に化合物 （Vic) を反応させてァ ミド誘導体 （VII) を得る方法である。 反応は、 前記第 3製法 （3 ) アミド化、 スル ホンアミド化及びエステル化の条件を適用して同様に行うことができる。  In this production method, the diaminobenzoic acid ester compound (V) is reacted with the compound (Vic) to obtain the amide derivative (VII). The reaction can be performed in the same manner by applying the conditions of the third production method (3) amidation, sulfonamidation and esterification.
環化 Cyclization
(環化 A) 本製法は一般式 （VII) で示されるアミド誘導体を分子内で閉環するこ とによりエステル化合物 （III) を得る方法である。 反応はハロゲン化炭化水素類、 芳香族炭化水素類、 エーテル類等の反応に不活性な有機溶媒中または無溶媒下、 触 媒量乃至溶媒量の酸を用い、 -78°C〜0°Cの冷却下、 冷却下乃至室温下、 室温下又は 場合によっては室温下乃至加熱下に行われる。 用いられる酸としては酢酸、 硫酸、 塩酸、 リン酸、 メタンスルホン酸、 P-トルエンスルホン酸、 トリフルォロ酢酸、 ト リフルォロメ夕ンスルホン酸などが挙げられる。 (Cyclization A) This production method is a method for obtaining an ester compound (III) by cyclizing the amide derivative represented by the general formula (VII) in a molecule. The reaction is halogenated hydrocarbons, In an organic solvent inert to the reaction of aromatic hydrocarbons, ethers, etc., or in the absence of a solvent, using an acid of a catalytic amount or a solvent amount, cooling at -78 ° C to 0 ° C, under cooling to room temperature The reaction is performed at room temperature, at room temperature, or in some cases, at room temperature to under heating. Examples of the acid used include acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, P-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
(環化 本製法はジァミノ安息香酸化合物 （IV) をアルデヒド化合物 （Via) と を酸化的に閉環させカルボン酸化合物 （Ilia) を得る方法である。 反応は水、 アルコ ール類、 ァセトニトリル、 芳香族炭化水素類、 エーテル類などの反応に不活性な溶 媒中、 ジァミノ安息香酸化合物 （IV) とアルデヒド化合物 （Via) とを等モルまたは 一方を過剰量として用い、酸化剤の存在下、 室温または加熱下で行うことができる。 酸化剤としては銅化合物 （酢酸銅、 塩化銅など） 、 鉄化合物 （酢酸鉄など） 、 マン ガン化合物 （二酸化マンガン、 過マンガン酸カリウムなど） 、 クロム化合物 （酸化 クロムなど） 、 ルテニウム化合物 （テトラプロピルアンモニゥムパールテネートな ど） 、 銀化合物 （酸化銀など） 、 セリウム化合物 （硝酸セリウムなど） 、 ジメチル スルホキシド、 ベンゾフロキサン、 ニトロベンゼン、 キノン化合物 （クロラニルな ど） などが挙げられる。  (Cyclization This method is a method of oxidatively closing a diaminobenzoic acid compound (IV) with an aldehyde compound (Via) to obtain a carboxylic acid compound (Ilia). The reaction is carried out with water, alcohols, acetonitrile, and aroma. Diaminobenzoic acid compound (IV) and aldehyde compound (Via) in equimolar or excess amounts in a solvent inert to the reaction of aromatic hydrocarbons, ethers, etc., and in the presence of an oxidizing agent at room temperature Oxidizing agents include copper compounds (copper acetate, copper chloride, etc.), iron compounds (iron acetate, etc.), manganese compounds (manganese dioxide, potassium permanganate, etc.), chromium compounds (oxidation, etc.). Chromium), ruthenium compounds (such as tetrapropylammonium pearl tenate), silver compounds (such as silver oxide), cerium compounds (such as cerium nitrate) Dimethyl sulfoxide, benzofuroxan, nitrobenzene, quinone compounds (eg, chloranil).
(環化 C) 本製法はジァミノ安息香酸エステル化合物 （V) を一般式 （VIb) で示 されるカルボン酸化合物と縮合させ、 エステル化合物 （III) を得る方法である。 反 応はジァミノ安息香酸エステル化合物 （V) とカルボン酸化合物 （VIb) とを等モル または一方を過剰に用い、 硫酸、 トリフルォロ酢酸、 トリフルォロメ夕ンスルホン 酸、 無水トリフルォロ酢酸、 無水トリフルォロメ夕ンスルホン酸、 リン酸、 ポリリ ン酸等の酸性条件下に行う。 好ましくはポリリン酸中、 氷冷下〜加熱下で行う。 また、 ジァミノ安息香酸エステル化合物 （V) を、 前記 （環化 B) に記載の条件 に付すことによつても、 対応するエステル化合物 （III) を製造することができる。 エステル化及び加水分解  (Cyclization C) In this production method, the diaminobenzoic acid ester compound (V) is condensed with the carboxylic acid compound represented by the general formula (VIb) to obtain the ester compound (III). The reaction was carried out using an equimolar amount or one of the diaminobenzoic acid ester compound (V) and the carboxylic acid compound (VIb) in excess or one of them. Perform under acidic conditions such as acid and polyphosphoric acid. It is preferably carried out in polyphosphoric acid under ice-cooling to heating. The corresponding ester compound (III) can also be produced by subjecting the diaminobenzoic acid ester compound (V) to the conditions described in the above (Cyclization B). Esterification and hydrolysis
一般的な、 カルボン酸のエステル化 ·加水分解反応が適用できる。 具体的には、 前記 「Pro ctive Groups in Organic Synthesis (第 2版） 」 に記載されたカルボキシル 基の保護 ·脱保護の反応を適用することができる。  General esterification and hydrolysis of carboxylic acid can be applied. Specifically, the carboxyl group protection / deprotection reaction described in the above “Proctive Groups in Organic Synthesis (second edition)” can be applied.
その他、 前記第 3製法に記載のアミド化、 スルホンアミド化及びエステル化等の 各反応は原料化合物の製造にも適用可能である。 同様の条件を上記原料化合物（III) に適用することにより、 種々の原料化合物を製造することができる。 Others, such as amidation, sulfonamidation and esterification described in the third production method, Each reaction can be applied to the production of a starting compound. Various starting compounds can be produced by applying the same conditions to the starting compound (III).
上記各製法により得られた反応生成物は、 遊離化合物、 その塩あるいは水和物な ど各種の溶媒和物として単離、 精製することができる。 塩は通常の造塩処理に付す ことにより製造できる。  The reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate. The salt can be produced by subjecting the salt to a usual salt formation treatment.
単離、 精製は、 抽出、 濃縮、 留去、 結晶化、 濾過、 再結晶、 各種クロマトグラフ ィ一等通常の化学操作を適用して行うことができる。  Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
各種異性体は異性体間の物理化学的な差を利用して常法により単離できる。 例え ば、 光学異性体は一般的な光学分割法、 例えば分別結晶化又はクロマトグラフィー 等により分離できる。 また、 光学異性体は、 適当な光学活性な原料化合物より製造 することもできる。 産業上の利用可能性  Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. The optical isomer can also be produced from a suitable optically active starting compound. Industrial applicability
本発明化合物は医薬製剤の活性成分として有用である。特に PARP阻害作用を有す るため、 PARPの関与する、 炎症性疾患 （例えば、慢性関節リウマチ、 潰瘍性大腸炎、 クローン病、 腹膜炎、 胸膜炎、 腎炎等） 、 自己免疫疾患 （例えば、 I型糖尿病等） 、 虚血再還流障害に伴う疾患 （例えば、 脳卒中、 心筋梗塞、 臓器移植等） の予防 ·治 療薬として有用である。  The compounds of the present invention are useful as active ingredients in pharmaceutical preparations. In particular, it has PARP inhibitory activity, so PARP is involved in inflammatory diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.), autoimmune diseases (eg, type I diabetes) Etc.), and is useful as a prophylactic / therapeutic agent for diseases associated with ischemia reperfusion disorder (eg, stroke, myocardial infarction, organ transplantation, etc.).
本発明化合物の作用は以下の薬理試験によって確認された。  The effects of the compound of the present invention were confirmed by the following pharmacological tests.
1 . 無細胞系 PARP阻害活性測定試験 （in vitro)  1. Cell-free PARP inhibitory activity assay (in vitro)
1 ) 試験化合物は所望の濃度を、 82.5 mM トリス -HC1 (pH 8.0)、 50 mM塩化力リゥ ム、 10 mM塩化マグネシウム、 5 mMジチオスレィトール、 100 g/mlヒストン、 26 nM 3H-NADおよび 0.06 unitヒト組み替え型 PARPを含有している反応液中で 25° (：、 3時間反応させた。 1) Test compound desired concentration, 82.5 mM Tris -HC1 (pH 8.0), 50 mM chloride force Riu arm, 10 mM magnesium chloride, 5 mM dithiothreitol I torr, 100 g / ml histone, 26 nM 3 H- The reaction was performed at 25 ° (:, 3 hours) in a reaction solution containing NAD and 0.06 unit human recombinant PARP.
2 ) 反応液に 100 mMニコチンアミドを添加することにより反応を停止させた。  2) The reaction was stopped by adding 100 mM nicotinamide to the reaction solution.
3 ) 反応液を 0.5 mg抗マウス IgG抗体結合型 SPAビーズと反応させ Top count (Packard社） により酵素活性を測定した。  3) The reaction solution was reacted with 0.5 mg of anti-mouse IgG antibody-bound SPA beads, and the enzyme activity was measured by Top count (Packard).
4 ) IC5。は PARPの ADP-ribose重合化活性を 50%阻害する試験化合物濃度として 各化合物について算出した。 実施例 2、 10、 1 3、 16、 22、 39、 41、 50、 53、 56、 6 1、 6 3、 66、 67、 72、 92に記載の化合物は、 7〜50 nMの IC50を示した。 一方、 比較化合物 N'-[2-(N,N-ジメチルァミノ）ェチル ]-2-(4'-メトキシフエ二ル) -1H-ベンゾ イミダゾール -4-力ルポキサミド (J. Med. Chem" 33, 814-819 (1990)， no.21の化合 物） は 1000 nMで阻害活性を示さなかった。 4) IC 5. Was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%. Example 2, 10, 1 3, 16, 22, 39, 41, 50, 53, 56, 6 1, 6 3, 66, 67, 72, compounds described in 92, IC 50 of 7 to 50 nM Indicated. On the other hand, a comparative compound N '-[2- (N, N-dimethylamino) ethyl] -2- (4'-methoxyphenyl) -1H-benzoimidazole-4-potassium lipoxamide (J. Med. Chem "33, 814) -819 (1990), no.21) showed no inhibitory activity at 1000 nM.
2. 生細胞系 PARP阻害活性測定試験 （in vitro) 2. Live cell line PARP inhibitory activity assay (in vitro)
1) J774.1細胞 （マウス単球/マクロファ一ジ細胞株） を 25mMHEPESおよび 10% 牛胎児血清含有 DMEM培地にて 5xl05個/ mlに調整し、 37°C、 5%C02の条件下で 24時間培養した。 1) at J774.1 cells (murine monocyte / macrophage temporary cell line) were 25mMHEPES and 10% fetal bovine serum-containing DMEM medium and adjusted to 5Xl0 5 cells / ml, 37 ° C, 5 % C0 2 under the conditions of For 24 hours.
2) 試験化合物は 28 mM塩化カリウム、 28 mM塩化ナトリウム、 2 mM塩化マグ ネシゥム、 0.01%ジギトニン及び 26nM3H-NADを含む 56 mM HEPES (pH 7.5)溶液 にて所望の濃度に調整し、 反応溶液とした。 2) Test compound 28 mM potassium chloride, 28 mM sodium chloride, 2 mM chloride Mug Neshiumu, adjusted to a desired concentration in 56 mM HEPES (pH 7.5) solution containing 0.01% digitonin and 26 nM 3 H-NAD, reaction The solution was used.
3) DMEM培地を上記反応溶液と置換し、 37°C、 5 %C02条件下で 15分培養した。3) DMEM medium was replaced with the above reaction solution and incubated 15 minutes at 37 ° C, 5% C0 2 conditions.
4) 細胞を冷 5%トリクロ口酢酸にて洗浄後、 2%SDS、 0.1M NaOHにより溶解し 放射活性を測定した。 4) After washing the cells with cold 5% trichloroacetic acid, the cells were lysed with 2% SDS and 0.1 M NaOH and the radioactivity was measured.
5 ) IC5Qは PARPの ADP-ribose重合化活性を 50%阻害する試験化合物濃度として 各化合物について算出した。 5) IC 5Q was calculated for each compound as the concentration of the test compound that inhibited the ADP-ribose polymerization activity of PARP by 50%.
本発明化合物は、 上記 in vitro試験においても良好な阻害活性を示した。  The compound of the present invention also showed good inhibitory activity in the above in vitro test.
3. ザィモザン誘発腹膜炎 （in vivo)  3. Zymosan-induced peritonitis (in vivo)
1) 6〜8週令雄性 Balb/cマウス （日本チヤ一ルスリバ一） を実験に供した。  1) Male Balb / c mice (Nippon Charlsliver) of 6 to 8 weeks of age were subjected to the experiment.
2) マウスは試験前日夕方より絶食、 自由飲水とした。  2) The mice were fasted and had free access to water from the evening before the test.
3) 各試験化合物は 0.5%メチルセルロースにて懸濁あるいは溶解した。  3) Each test compound was suspended or dissolved in 0.5% methylcellulose.
4 )各試験化合物懸濁液あるレゝは溶液を上記 Balb/cマウスに所望の用量となるよう に 5 ml/kgにて経口投与した。 陰性および陽性対照群には溶媒である 0.5%メチルセ ルロ一スを 5 ml/kgにて投与した。  4) For each test compound suspension, the solution was orally administered to the above Balb / c mice at a desired dose of 5 ml / kg. The negative and positive control groups received 0.5% methylcellulose as a solvent at 5 ml / kg.
5) ザィモザン （Sigma) は生理食塩水により 0.5 mg/mlとなるように懸濁し、 化合 物の経口投与と同時に 1 ml/mouseにて腹腔内投与した。陰性対照群には生理食塩水 を 1 ml/mouseにて腹腔内投与した。  5) Zymozan (Sigma) was suspended in physiological saline to a concentration of 0.5 mg / ml, and the compound was orally administered and intraperitoneally at 1 ml / mouse. To the negative control group, physiological saline was intraperitoneally administered at 1 ml / mouse.
6 ) ザィモザン投与 4時間後に各マウスの腹腔を 5 mlの 0.1%へパリン含有生理食 塩水にて洗浄し腹腔内の細胞を回収した。 6) Four hours after the administration of Zymozan, 5 ml of 0.1% heparin-containing physiological diet After washing with saline, cells in the peritoneal cavity were collected.
7 ) 回収した細胞数は celkak (日本光電） にて測定した。  7) The number of collected cells was measured with celkak (Nihon Kohden).
8 ) ED30はザィモザンによって腹腔に浸潤した細胞数を 30%抑制する試験化合物 用量として各化合物について算出した。  8) ED30 was calculated for each compound as the dose of test compound that inhibited the number of cells infiltrated into the peritoneal cavity by 30% by Zymozan.
実施例 2、 1 0、 4 1、 5 0、 6 1、 7 2に記載の化合物は、 3〜： 15 mg/kgの ED 30を示した。 一方、 比較化合物 2-(4'-ニトロフエニル) -1H-ベンゾイミダゾーリレ -4-力 ルポキサミド （WO97/04771, 実施例 11の化合物） は、 30 mg/kgで作用を示さなか つ /こ。  The compounds described in Examples 2, 10, 41, 50, 61, 72 exhibited an ED 30 of 3 to: 15 mg / kg. On the other hand, the comparative compound 2- (4'-nitrophenyl) -1H-benzimidazolyl-4-force lipoxamide (compound of WO97 / 04771, Example 11) showed no effect at 30 mg / kg.
4 . コラーゲン誘発関節炎 （in vivo)  4. Collagen-induced arthritis (in vivo)
1 ) 3 mg/mlゥシ II型コラーゲン （コラーゲン研修会） 8 mlと同量の FCA (Freund complete adjuvant H37 Ra、 DIFCO Laboratories) を十分に混合し、 雄性 DBA/IJマウ ス （日本チヤ一ルスリバ一） 尾根部皮内に 100 1ずつ免疫した。  1) 3 mg / ml ゥ type II collagen (collagen workshop) Fully mix the same amount of FCA (Freund complete adjuvant H37 Ra, DIFCO Laboratories) as 8 ml and mix with male DBA / IJ mouse (Nippon Chillers River). 1) Immunization was carried out 100 to the ridge skin.
2 ) 21日後、 上記と同様に追加免疫した。  2) After 21 days, a booster immunization was performed as described above.
3 ) 追加免疫日を 0日目とし、 1週間に 2回の割合で体重および各肢の関節炎スコ ァを測定した。 関節炎スコアは以下のように設定した。 すなわち、 0は正常、 1 は 発赤および軽度の腫脹、 2は中程度の腫脹、 3は重度の腫脹または関節部の強直で ある。  3) The booster day was set as day 0, and the body weight and arthritis score of each limb were measured twice a week. The arthritis score was set as follows. 0 is normal, 1 is redness and mild swelling, 2 is moderate swelling, 3 is severe swelling or joint stiffness.
4 )試験化合物は 0.5 %メチルセルロースを溶媒として、 1、 3、 10および 30 mg 5 ml の濃度で懸濁し、 5 ml/kgの用量にて 1日 1回経口投与を 21日目まで行った。 なお 陰性および陽性対照群には溶媒である 0.5 %メチルセルロースを 5 ml/kgにて投与し た。  4) The test compound was suspended at a concentration of 5 ml of 1, 3, 10, and 30 mg in 0.5% methylcellulose as a solvent, and orally administered once daily at a dose of 5 ml / kg until the 21st day. To the negative and positive control groups, 0.5% methylcellulose as a solvent was administered at 5 ml / kg.
5 ) 測定結果は経日的な変化として表すと共に時間一反応曲線下面積 （AUC : area under the curve) として表した。 関節炎スコアに関しては steel検定を、 体重変動に 関しては Dmrnett検定を行い p値が 0.05以下の場合を有意とした。  5) The measurement results were expressed as changes over time and as area under the curve (AUC). A steel test was used for arthritis score, and a Dmrnett test was used for weight change, and a case where the p value was 0.05 or less was considered significant.
本発明化合物は、 上記 in vivo試験において良好な活性を示した。  The compound of the present invention showed good activity in the above in vivo test.
上記 1〜 4の実験結果より、 本発明化合物は PARP阻害作用を有する事が確認さ れ、 PARPの関与する疾患の予防 ·治療薬として有用である事が明らかである。 本発明化合物 （I ) 又はその製薬学的に許容され得る塩の 1種又は 2種以上を有 効成分として含有する医薬組成物は、 当分野において通常用いられている薬剤用担 体、 賦形剤等を用いて通常使用されている方法によって調製することができる。 投与は錠剤、 丸剤、 カプセル剤、 顆粒剤、 散剤、 液剤等による経口投与、 又は、 関節内、 静脈内、 筋肉内等の注射剤、 坐剤、 点眼剤、 眼軟膏、 経皮用液剤、 軟膏剤、 経皮用貼付剤、 経粘膜液剤、 経粘膜貼付剤、 吸入剤等による非経口投与のいずれの 形態であってもよい。 From the above experimental results 1 to 4, it was confirmed that the compound of the present invention has a PARP inhibitory activity, and it is clear that the compound is useful as a prophylactic / therapeutic agent for PARP-related diseases. Pharmaceutical compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be a pharmaceutical carrier commonly used in the art. It can be prepared by a commonly used method using a body, excipients and the like. For oral administration, tablets, pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant and the like may be used.
本発明による経口投与のための固体組成物としては、 錠剤、 散剤、 顆粒剤等が用 いられる。 このような固体組成物においては、 1種又は 2種以上の有効成分を、 少 なくとも 1種の不活性な賦形剤、 例えば乳糖、 マンニトール、 ブドウ糖、 ヒドロキ シプロピルセルロース、 微結晶セルロース、 デンプン、 ポリビニルピロリ ドン、 メ タケイ酸アルミン酸マグネシウム等と混合される。 組成物は、 常法に従って、 不活 性な添加剤、例えばステアリン酸マグネシウム等の潤滑剤やカルボキシメチルス夕 ーチナトリウム等の崩壊剤、 溶解補助剤を含有していてもよい。 錠剤又は丸剤は必 要により糖衣又は胃溶性若しくは腸溶性コ一ティング剤で被膜してもよい。  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients may be combined with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinyl pyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain an inactive additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl sodium salt, or a solubilizing agent, according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or a gastric or enteric coating agent.
経口投与のための液体組成物は、 薬剤的に許容される乳剤、 液剤、 懸濁剤、 シロ ップ剤、エリキシル剤等を含み、一般的に用いられる不活性な溶剤、例えば精製水、 エタノールを含む。 この組成物は不活性な溶剤以外に可溶化剤、 湿潤剤、 懸濁化剤 のような補助剤、 甘味剤、 矯味剤、 芳香剤、 防腐剤を含有していてもよい。  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including. The composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
非経口投与のための注射剤は、 無菌の水性又は非水性の液剤、 懸濁剤、 乳剤を含 む。 水性の溶剤としては、 例えば注射用蒸留水及び生理食塩液が含まれる。 非水性 の溶剤としては、 例えばプロピレングリコール、 ポリエチレングリコール、 オリー ブ油のような植物油、 エタノールのようなアルコール類、 ポリソルべ一ト 80 (商品 名） 等がある。 このような組成物は、 さらに等張化剤、 防腐剤、 湿潤剤、 乳化剤、 分散剤、 安定化剤、 溶解補助剤を含んでもよい。 これらは例えばバクテリア保留フ ィルターを通す濾過、 殺菌剤の配合又は照射によって無菌化される。 また、 これら は無菌の固体組成物を製造し、 使用前に無菌水又は無菌の注射用溶媒に溶解、 懸濁 して使用することもできる。  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (trade name). Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile injection solvent before use.
経鼻剤等の経粘膜剤は固体、 液体、 半固体状のものが用いられ、 従来公知の方法 に従って製造することができる。例えば公知の pH調整剤、 防腐剤、 増粘剤や賦形剤 が適宜添加され、 固体、 液体若しくは半固体状に成形される。 経鼻剤は通常のスプ レー器具、 点鼻容器、 チューブ、 鼻腔内挿入具等を用いて投与される。 Transmucosal preparations such as nasal preparations are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods. For example, known pH adjusters, preservatives, thickeners and excipients are appropriately added, and the mixture is shaped into a solid, liquid or semi-solid. Nasal pills are normal sp The drug is administered using a laser device, nasal drop container, tube, intranasal insert, etc.
通常経口投与の場合、 1日の投与量は、 体重当たり約 0.001〜100 mg/kg、 好まし くは 0.1〜10 mg/kgが適当であり、これを 1回であるいは 2〜4回に分けて投与する < 静脈投与される場合は、 1日の投与量は、体重当たり約 0.0001から 10 mg/kgが適当 で、 1日 1回〜複数回に分けて投与する。 関節内投与の場合は、 1日の投与量は、 体重当たり約 0.0001〜： 10 mg/kgが適当で、 1日 1回〜複数回に分けて投与する。 ま た、 経粘膜剤としては、 体重当たり約0.001〜100
Figure imgf000022_0001
を 1日 1回〜複数回に分け て投与する。 投与量は症状、 年令、 性別等を考慮して個々の場合に応じて適宜決定 される。 発明を実施するための最良の形態 Usually, for oral administration, the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg per body weight, which is divided into single doses or 2 to 4 doses. In the case of intravenous administration, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and the dose is administered once to several times a day. In the case of intra-articular administration, the daily dose is about 0.0001 to 10 mg / kg per body weight, and it is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 per body weight
Figure imgf000022_0001
Is administered once to several times a day. The dose is determined as appropriate for each individual case, taking into account symptoms, age, sex, and the like. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実施例に基づき本発明を更に詳細に説明する。 本発明化合物は下記実施例 に記載の化合物に限定されるものではない。また原料化合物の製法を参考例に示す。 なお、 2,3-ジァミノ安息香酸メチルエステルは US5380719に記載の方法により製造 した。  Hereinafter, the present invention will be described in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following examples. The production methods of the starting compounds are shown in Reference Examples. In addition, 2,3-diaminobenzoic acid methyl ester was produced by the method described in US5380719.
参考例 1 Reference example 1
6-メチルニコチン酸メチルエステル、 ケィ皮アルデヒド、 無水酢酸及び氷酢酸の 混合物を外温 120°Cで 12時間攪拌した。 以下、 常法により後処理、 精製して、 6-(4- フエニル -1,3-ブ夕ジェニル)ニコチン酸メチルエステルを無色固体として得た。 FAB-MS(M+H)+： 266。 A mixture of 6-methylnicotinic acid methyl ester, caeshy aldehyde, acetic anhydride and glacial acetic acid was stirred at an external temperature of 120 ° C for 12 hours. Thereafter, post-treatment and purification were carried out by a conventional method to give methyl 6- (4-phenyl-1,3-butenyl) nicotinic acid as a colorless solid. FAB-MS (M + H) <+> : 266.
参考例 2 Reference example 2
(E)-6-スチリルニコチン酸メチルエステルの酢酸ェチル溶液に 10%パラジウム-炭 素を加え、 常圧水素雰囲気下、 室温で 5時間攪拌した。 反応液をろ過し、 溶媒を留 去して、粗製の 6-(2-フエネチル)ニコチン酸メチルエステルを無色固体として得た。 FAB-MS(M+H)+： 242。 10% palladium-carbon was added to a solution of (E) -6-styrylnicotinic acid methyl ester in ethyl acetate, and the mixture was stirred at room temperature under a normal pressure hydrogen atmosphere for 5 hours. The reaction solution was filtered and the solvent was distilled off to obtain crude 6- (2-phenethyl) nicotinic acid methyl ester as a colorless solid. FAB-MS (M + H) + : 242.
参考例 3 Reference example 3
6-(4-フエニル- 1，3-ブ夕ジェニル)二コチン酸メチルエステルを用いて参考例 2と 同様にして、 粗製の 6-(4-フエニルブチル)ニコチン酸メチルエステルを淡黄色油状 物として得た。 FAB-MS(M+H)+： 270。 参考例 4 Crude 6- (4-phenylbutyl) nicotinic acid methyl ester was obtained as a pale yellow oil in the same manner as in Reference Example 2 using methyl 6- (4-phenyl-1,3-butenyl) dicotinate. Obtained. FAB-MS (M + H) +: 270. Reference example 4
6-(2-フエネチル)ニコチン酸メチルエステルのエタノール溶液に 1M 水酸化ナト リウム水溶液を加え、 室温で 2時間攪拌した。 反応溶液を減圧下留去し、 6M塩酸 で pHを 3〜4とした後、 分液処理して、 粗製の 6-(2-フエネチル)ニコチン酸を無色 固体として得た。 FAB-MS(M+H)+： 228。 A 1M aqueous sodium hydroxide solution was added to an ethanol solution of 6- (2-phenethyl) nicotinic acid methyl ester, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, the pH was adjusted to 3 to 4 with 6M hydrochloric acid, and the mixture was separated to give crude 6- (2-phenethyl) nicotinic acid as a colorless solid. FAB-MS (M + H) + : 228.
参考例 5 Reference example 5
(E)- 6-スチリルニコチン酸メチルエステルを用いて参考例 4と同様にして、 粗製 の (E)-6-スチリルニコチン酸を無色固体として得た。 FAB-MS(M+H)+： 226。  Crude (E) -6-styrylnicotinic acid was obtained as a colorless solid in the same manner as in Reference Example 4 using (E) -6-styrylnicotinic acid methyl ester. FAB-MS (M + H) +: 226.
参考例 6 Reference example 6
6-(4-フエニルブチル)ニコチン酸メチルエステルを用いて参考例 4と同様にして、 粗製の 6-(4-フエニルブチル)ニコチン酸を無色固体として得た。 FAB-MS(M+H)+： 256。  Crude 6- (4-phenylbutyl) nicotinic acid was obtained as a colorless solid in the same manner as in Reference Example 4 using 6- (4-phenylbutyl) nicotinic acid methyl ester. FAB-MS (M + H) +: 256.
参考例 7 Reference Example 7
5-ク口口- 3-二トロアントラニル酸のメタノール溶液に濃硫酸を加え、 16時間加熱 還流後、 常法により精製して、 5-クロ口- 3-ニトロアントラニル酸メチルエステルを 黄色固体として得た。 FAB-MS(M+H)+： 231。  Concentrated sulfuric acid is added to a methanol solution of 5-cyclobut-3-nitroanthranilic acid, and the mixture is heated and refluxed for 16 hours.Purification is performed by a conventional method, and methyl 5-chloro-3-nitroanthranilate is obtained as a yellow solid Obtained. FAB-MS (M + H) +: 231.
参考例 8 Reference Example 8
5-クロ口- 3-ニトロアントラニル酸メチルエステルをエタノール及び酢酸ェチル 混合溶媒中、 10%パラジウム一炭素存在下、 水素雰囲気下に接触還元して、 2，3-ジ ァミノ- 5-クロ口安息香酸メチルエステルを茶褐色固体として得た。 EI-MS(M+)： 200。 参考例 9  2,3-Diamino-5-chloromethylbenzoate is obtained by catalytic reduction of methyl 5-nitro-3-nitroanthranilate in a mixed solvent of ethanol and ethyl acetate in the presence of 10% palladium-carbon under a hydrogen atmosphere. The acid methyl ester was obtained as a brown solid. EI-MS (M +): 200. Reference Example 9
2,3-ジァミノ安息香酸メチルエステルを THF中、 トリェチルァミン及び 4-ジメチ ルァミノピリジン存在下、 チォフェン- 2-カルボニルクロリドと反応後、 常法により 精製して、 2-ァミノ- 3- [(チォフェン- 2-ィルカルボ二リレ)ァミノ]安息香酸メチルエス テルを淡灰色粉末として得た。  2,3-Diaminobenzoic acid methyl ester is reacted with thiophene-2-carbonyl chloride in THF in the presence of triethylamine and 4-dimethylaminopyridine, and purified by a conventional method to give 2-amino-3-[(thiophene-2 Methyl [benzoylyl) amino] benzoate was obtained as a pale gray powder.
参考例 1 0  Reference example 10
ニコチン酸を、 トリェチルァミン及び THFの混合溶媒中、 クロロギ酸イソプチ ルと反応後、 2,3-ジァミノ安息香酸メチルエステルと反応させ、 以下、 常法により 精製して、 2-ァミノ- 3- [(ピリジン- 3-ィルカルボ二リレ)ァミノ]安息香酸メチルエステ ルを淡褐色粉末として得た。 Nicotinic acid is reacted with isobutyl chloroformate in a mixed solvent of triethylamine and THF, followed by reaction with 2,3-diaminobenzoic acid methyl ester, followed by purification by a conventional method to give 2-amino-3-[( Pyridine-3-ylcarbonylyl) amino] methyl benzoate Was obtained as a light brown powder.
参考例 1 1 Reference example 1 1
2,3-ジァミノ安息香酸メチルエステルの DMF 溶液に、 6-クロ口ニコチン酸、 WSC · HC1及び HOBTを加え反応後、 常法により精製して 2-ァミノ- 3-[(2-クロロピ リジン- 5-ィルカルボ二リレ)ァミノ]安息香酸メチルエステルを淡緑色粉末として得 た。  To a DMF solution of 2,3-diaminobenzoic acid methyl ester is added 6-chloronicotinic acid, WSCHC1 and HOBT, and the mixture is reacted and purified by a conventional method to give 2-amino-3-[(2-chloropyridine- [5-ylcarbonyl) amino] benzoic acid methyl ester was obtained as a pale green powder.
参考例 1 2 Reference example 1 2
2—ァミノ—3-[(2-クロロピリジン -5-ィルカルボニル)ァミノ ]安息香酸メチルエステ ル及び酢酸を加熱下反応後、 常法により精製して、 メチル 2-(2-クロ口ピリジン- 5-ィル) -1H-ベンゾィミダゾ一ル -4-力ルポキシラートを淡褐色粉末として得た。 参考例 1 3 2 -Amino-3-[(2-chloropyridine-5-ylcarbonyl) amino] Methyl ester of benzoate and acetic acid are reacted under heating and purified by a conventional method to give methyl 2- (2-chloropyridine-5 -Yl) -1H-Benzimidazole-4-hexanoloxylate was obtained as a light brown powder. Reference Example 1 3
2,3-ジァミノ安息香酸メチルエステル及び 3-チォフェンカルボン酸を、 五酸化二 リン及びリン酸より調製したポリリン酸中、 加熱下反応し、 以下、 常法により精製 して、 メチル 2- (チォフェン- 3-ィル) -1H-ベンゾイミダゾ一ル -4-カルボキシラート を褐色粉末として得た。  2,3-Diaminobenzoic acid methyl ester and 3-thiophenecarboxylic acid are reacted under heating in polyphosphoric acid prepared from diphosphorus pentoxide and phosphoric acid, and purified by a conventional method. Thiophen-3-yl) -1H-benzimidazole-4-carboxylate was obtained as a brown powder.
参考例 1 4 Reference example 1 4
チアゾ一ル -2-カルボキシアルデヒド及び 2,3-ジァミノ安息香酸メチルエステル をメタノール中反応後、 ベンゾフロキサンのァセトニ卜リル溶液で処理し、 常法に より精製して、 メチル 2-チアゾ一ル -2-ィル- 1H-ベンゾイミダゾ一ル -4-カルボキシ ラートを淡黄色固体として得た。  After reacting thiazol-2-carboxaldehyde and 2,3-diaminobenzoic acid methyl ester in methanol, the mixture is treated with benzofuroxane in acetonitrile and purified by a conventional method to give methyl 2-thiazol. 2-yl-1H-benzimidazole-4-carboxylate was obtained as a pale yellow solid.
参考例 1 5 Reference example 1 5
2,3-ジァミノ安息香酸メチルエステルおよび 1H-ピロ一ル -2-カルバルデヒドのメ 夕ノール溶液に酢酸、 酢酸銅 （II) 水和物及び水を加え、 加熱した。 沸騰するとす ぐに銅塩を濾取し、 減圧下乾燥させた。 得られた銅塩のエタノールおよび濃塩酸懸 濁液に二硫化ナトリウム九水和物の水溶液を加え、 加熱し沸騰させ、 すぐに濾過し た。 濾液に 1M水酸化ナトリウム水溶液を加え、 pHを 6にした。 水を加えた後、 液量が半分程度になるまで溶媒を減圧濃縮した。 生じた沈殿物を濾取後、 常法によ り精製して、メチル 2-(1Η-ピ口一ル -2-ィル) -1H-ベンゾィミダゾール -4-力ルポキシ ラートを茶褐色固体として得た。 参考例 1 6 a及び b Acetic acid, copper (II) acetate hydrate and water were added to a methanol solution of 2,3-diaminobenzoic acid methyl ester and 1H-pyrrol-2-carbaldehyde and heated. Upon boiling, the copper salt was filtered off and dried under reduced pressure. An aqueous solution of sodium disulfide nonahydrate was added to the suspension of the obtained copper salt in ethanol and concentrated hydrochloric acid, and the mixture was heated to boiling and filtered immediately. A 1M aqueous sodium hydroxide solution was added to the filtrate to adjust the pH to 6. After adding water, the solvent was concentrated under reduced pressure until the liquid volume became about half. The resulting precipitate was collected by filtration and purified by a conventional method to give methyl 2- (1Η-piper-2-yl) -1H-benzoimidazole-4-hexyloxylate as a brown solid As obtained. Reference Example 16 a and b
メチル 2-ベンゾ [b]チォフェン- 2-ィル -1H-ベンゾイミダゾ一ル -4-力ルポキシラ —ト及びジメチルホルムアミドジメチルァセタールを、 トルエン中 3時間加熱環流 して反応後、 常法により精製して、 メチル 2-ベンゾ [b]チォフェン- 2-ィル小メチ ル -1H-ベンゾイミダゾール -4-カルボキシラート （1 6 a ) 及びメチル 2-ベンゾ [b] チォフェン- 2-ィル -3-メチル -1H-ベンゾイミダゾール -4-カルボキシラート （1 6 b ) を無色固体として得た。 FAB-MS(M+H)+： ( 1 6 a及び b共に） 323。  Methyl 2-benzo [b] thiophen-2-yl-1H-benzimidazol-4-hexylpropoxylate and dimethylformamide dimethyl acetal are heated under reflux in toluene for 3 hours, reacted and purified by a conventional method. To give methyl 2-benzo [b] thiophen-2-yl small methyl-1H-benzimidazole-4-carboxylate (16a) and methyl 2-benzo [b] thiophen-2-yl-3 -Methyl-1H-benzimidazole-4-carboxylate (16b) was obtained as a colorless solid. FAB-MS (M + H) +: 323 (both 16a and b).
参考例 1 7 Reference Example 1 7
メチル 2-(2-クロロピリジン -5-ィル) -1H-ベンゾィミダゾ一ル -4-力ルポキシラ一 トをエタノ一ル及び 1M水酸化ナトリゥム水溶液中 50°Cで加水分解して、 2-(2-ク口 口ピリジン- 5-ィル) -1H-ベンゾィミダゾール -4-カルボン酸を淡褐色粉末として得た。 参考例 1 8  Methyl 2- (2-chloropyridin-5-yl) -1H-benzoimidazole-4-hydroxypropylate was hydrolyzed in ethanol and a 1 M aqueous sodium hydroxide solution at 50 ° C to give 2- ( 2-kuguchi pyridine-5-yl) -1H-benzoimidazole-4-carboxylic acid was obtained as a pale brown powder. Reference Example 1 8
メチル 6-クロ口 -2-チオフェン -2-ィル -1H-ベンゾィミダゾール -4-カルボキシラ 一トをメタノ一ル及び 1M水酸化ナトリゥム水溶液中加水分解して、 6-クロ口- 2-チ ォフェン- 2-ィル -1H-ベンゾイミダゾ一ル -4-カルボン酸を無色固体として得た。 参考例 1 9  Methyl 6-chloro-2-thiophen-2-yl-1H-benzoimidazole-4-carboxylate is hydrolyzed in methanol and 1M aqueous sodium hydroxide solution to give 6-chloro-2 -Thiophene-2-yl-1H-benzimidazole-4-carboxylic acid was obtained as a colorless solid. Reference Example 1 9
6-メチルアントラニル酸を DMF 中、 N-プロモコハク酸イミドと反応させて、 5- ブロモ -6-メチルアントラニル酸を無色固体として得た。 EI-MS(M+)： 229。  6-Methylanthranilic acid was reacted with N-bromosuccinimide in DMF to give 5-bromo-6-methylanthranilic acid as a colorless solid. EI-MS (M +): 229.
参考例 2 0 Reference Example 20
5-ブロモ -6-メチルアントラニル酸より文献 (J, Med. Chem., 33, 814-819 (1990)) に 記載の方法により、 5-ブロモ -6-メチル -3-ニトロアントラニル酸を得た。 EI- MS(M+)： 274。  5-Bromo-6-methyl-3-nitroanthranilic acid was obtained from 5-bromo-6-methylanthranilic acid by the method described in the literature (J, Med. Chem., 33, 814-819 (1990)). . EI-MS (M +): 274.
参考例 2 1 Reference Example 2 1
5-ブロモ -4-メチル -3-ニトロアントラニル酸 （文献 （J. Med. Chem., 30， 843-851 (1987)) に記載の方法と同様にして、 4-ブロモ -3-メチルァニリンより製造） を水酸 化ナトリウム水溶液中、 10%パラジウム -炭素存在下、 水素雰囲気下に接触還元し た。 反応液を濾過後酢酸で酸性とし、 メタノール中、 酢酸銅 （II) 水和物存在下、 2-チォフェンカルバルデヒドと加熱下反応させた。 銅塩を濾取し、 エタノール、 濃 塩酸及び二硫化ナトリゥム九水和物の水溶液を加え、加熱沸騰させた後すぐに濾過 した。 濾液に 1M水酸化ナトリウム水溶液を加え、 常法により精製して、 7-メチル -2-チォフェン- 2-ィル -1H-ベンゾイミダゾ一ル -4-カルボン酸を無色固体として得た。 参考例 2 2 5-bromo-4-methyl-3-nitroanthranilic acid (prepared from 4-bromo-3-methylaniline in the same manner as described in the literature (J. Med. Chem., 30, 843-851 (1987)). ) Was catalytically reduced in an aqueous sodium hydroxide solution in the presence of 10% palladium-carbon under a hydrogen atmosphere. The reaction solution was filtered, acidified with acetic acid, and reacted with 2-thiophenecarbaldehyde in methanol in the presence of copper acetate (II) hydrate under heating. The copper salt is collected by filtration, and an aqueous solution of ethanol, concentrated hydrochloric acid and sodium disulfide nonahydrate is added. did. The filtrate was added with a 1M aqueous sodium hydroxide solution and purified by a conventional method to obtain 7-methyl-2-thiophen-2-yl-1H-benzimidazol-4-carboxylic acid as a colorless solid. Reference Example 2 2
2,3-ジァミノ安息香酸メチルエステルの DMF溶液に 1-tert-ブトキシカルボ二ルビ ペリジン- 4—カルボン酸、 WSC ' HCl及び HOBtを加え、 室温下一夜攪拌した。 反応 液を濃縮後、 水を加え、 酢酸ェチルで抽出した。 抽出液を乾燥 （無水硫酸マグネシ ゥム） 後、 留去して得た粗生成物と酢酸の混合物を、 120°Cで 1時間加熱攪拌した。 反応液を濃縮後、 クロ口ホルムを加え、 1 M水酸化ナトリウム水溶液で洗浄、 乾燥 (無水硫酸マグネシウム） 、 濃縮後、 シリカゲルカラムクロマトグラフィーで精製 し、 メチル 2- (1-tert-ブトキシカルボニルピペリジン- 4-ィル) -1H-ベンゾイミダゾー ル 4-カルボキシラートを淡桃色粉末として得た。  To a DMF solution of 2,3-diaminobenzoic acid methyl ester was added 1-tert-butoxycarbylbiperidine-4-carboxylic acid, WSC'HCl and HOBt, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried (anhydrous magnesium sulfate), the mixture of the crude product obtained by evaporation and acetic acid was heated and stirred at 120 ° C. for 1 hour. After concentrating the reaction solution, add chloroform and wash with 1 M aqueous sodium hydroxide solution, dry (anhydrous magnesium sulfate), concentrate and purify by silica gel column chromatography to obtain methyl 2- (1-tert-butoxycarbonylpiperidine). -4-yl) -1H-benzimidazole 4-carboxylate was obtained as a pale pink powder.
参考例 2 3 Reference Example 2 3
2-(l-tert-ブトキシカルボニルピペリジン- 4-ィル) -1H-ベンゾィミダゾ一ル 4-カル ボン酸及び THFの混合物に CDIを加え、 室温下 3時間攪拌した。 反応液にアンモ ニァ飽和の THF を加え、 室温下終夜攪拌した。 反応液を減圧濃縮し、 残渣に水を 加え、 酢酸ェチルで抽出した。 有機層を飽和食塩水で洗浄後、 乾燥 （無水硫酸マグ ネシゥム） 後、 溶媒をに留去して、 2-(l-tert-ブトキシカルボ二ルビペリジン- 4-ィ ル) -1H-ベンゾイミダゾール 4-カルボキサミ ドを白色粉末として得た。 FAB- MS(M+H)+： 360。 CDI was added to a mixture of 2- (l-tert-butoxycarbonylpiperidin-4-yl) -1H-benzoimidazole 4-carboxylic acid and THF, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added ammonia-saturated THF, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and the solvent was distilled off to give 2- (l-tert-butoxycarbonylbiperidine-4-yl) -1H-benzimidazole. -Carboxamide was obtained as a white powder. FAB-MS (M + H) + : 360.
参考例 2 4 Reference example 2 4
2-(l-tert-ブトキシカルボ二ルビペリジン- 4-ィル) -1H-ベンゾィミダゾ一ル 4-カル ボキサミド及びトリフルォロ酢酸の混合物を、 室温下終夜攪拌した。 反応液を濃縮 後、残渣に酢酸ェチル及びイソプロピルエーテルを加えて得られる固体を濾取しィ ソプロピルェ一テルで洗浄して、 2- (ピペリジン- 4-ィル) -1H-ベンゾイミダゾ一ル 4- カルボキサミド · 2 トリフルォロ酢酸塩粗生成物 (26.6 g)を白色粉末として得た。 FAB-MS(M+H)+： 245。 A mixture of 2- (l-tert-butoxycarbonylbiperidin-4-yl) -1H-benzoimidazole 4-carboxamide and trifluoroacetic acid was stirred at room temperature overnight. After concentrating the reaction mixture, ethyl acetate and isopropyl ether were added to the residue, and the resulting solid was collected by filtration and washed with isopropyl ether to give 2- (piperidin-4-yl) -1H-benzimidazole 4 -A crude product of carboxamide · 2 trifluoroacetate (26.6 g) was obtained as a white powder. FAB-MS (M + H) + : 245.
以下、 市販の化合物あるいは文献等で公知の化合物を用い、 上記の参考例 9の方 法と同様にして表 1に示す参考例 2 5及び 2 6の化合物を、参考例 1 0の方法と同 様にして表 1に示す参考例 2 7〜3 1の化合物を、参考例 1 1の方法と同様にして 表 1に示す参考例 3 2〜4 3の化合物を、参考例 1 2の方法と同様にして表 3に示 す参考例 4 4〜 6 5の化合物を、参考例 1 3の方法と同様にして表 3に示す参考例 6 6の化合物を、参考例 1 5の方法と同様にして表 3に示す参考例 6 7の化合物を、 参考例 2 1の方法と同様にして表 4に示す参考例 7 4の化合物を、参考例 2 2の方 法と同様にして表 3に示す参考例 6 8の化合物を、参考例 1 7の方法と同様にして 表 4に示す参考例 6 9〜7 3、 7 5 - 8 7の化合物及び表 2に示す参考例 8 8〜 8 9の化合物を、 それぞれ対応する原料を使用して製造した。 参考例化合物の構造及 び物理化学的データを、 参考例 9〜 1 1及び 2 5〜4 3の化合物は表 1に、 参考例 1 6 a、 1 6 b , 8 8及び 8 9の化合物は表 2に、 参考例 1 2〜： L 5、 2 2、 4 4 〜6 8の化合物は表 3に、 参考例 1 7、 1 8、 2 1、 6 9〜 8 7の化合物は表 4に それぞれ示す。 Hereinafter, the compounds of Reference Examples 25 and 26 shown in Table 1 were used in the same manner as in the method of Reference Example 9 above, using commercially available compounds or compounds known in the literature. The compounds of Reference Examples 27 to 31 shown in Table 1 in the same manner as in the method of Reference Example 11 The compounds of Reference Examples 32 to 43 shown in Table 1 were treated in the same manner as in Reference Example 12, and the compounds of Reference Examples 44 to 65 shown in Table 3 were treated in the same manner as in Reference Example 13. The compound of Reference Example 66 shown in Table 3 was treated in the same manner as in Reference Example 15, and the compound of Reference Example 67 shown in Table 3 was treated in the same manner as in Reference Example 15. The compound of Example 74 was used in the same manner as in Reference Example 22 to obtain the compound of Reference Example 68 shown in Table 3 in the same manner as in the method of Reference Example 22. The compounds of 3, 75-87 and the compounds of Reference Examples 88 to 89 shown in Table 2 were produced using the corresponding raw materials. Table 1 shows the structures and physicochemical data of the compounds of Reference Examples.The compounds of Reference Examples 9 to 11 and 25 to 43 are shown in Table 1, and the compounds of Reference Examples 16a, 16b, 88 and 89 are shown in Table 1. In Table 2, Reference Examples 12 to: The compounds of L5, 22 and 44 to 68 are shown in Table 3, and the compounds of Reference Examples 17, 18, 21 and 69 to 87 are shown in Table 4. Shown respectively.
実施例 1 Example 1
2-(2-クロロピリジン- 5-ィル) -1H-ベンゾィミダゾーリレ -4-カルボン酸 (549 mg)の THF(20 ml)懸濁液に CDI(350 mg)を加え、 室温下 1時間攪拌した。反応液にアンモニ ァ飽和の THF(15 ml)を加え、 室温下一夜攪拌した。 反応液を減圧濃縮し、 残渣を水 洗して 2-(2-クロロピリジン- 5-ィル) -1H-ベンゾィミダゾ一ル -4-カルボキサミド (420 mg)を白色粉末として得た。  CDI (350 mg) was added to a suspension of 2- (2-chloropyridine-5-yl) -1H-benzoimidazolyl-4-carboxylic acid (549 mg) in THF (20 ml), and the mixture was added at room temperature. Stir for 1 hour. Ammonia-saturated THF (15 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was washed with water to give 2- (2-chloropyridine-5-yl) -1H-benzoimidazole-4-carboxamide (420 mg) as a white powder.
実施例 2 Example 2
金属封管中、 —50°C以下に冷却した液体アンモニア (35 ml)にメチル 2- (ピリジン -4-ィル) -1H-ベンゾイミダゾ一ル -4-カルボキシラート（3.58 g)を加え、 140°Cで 3日間 加熱した。 反応容器を一 50°C以下に冷却して開封後、 反応液を濃縮し、 DMF-酢酸ェ チルから再結晶して 2- (ピリジン- 4-ィル) -1H-ベンゾイミダゾール -4-カルボキサミド (2.58 mg)を淡褐色粉末として得た。  In a sealed metal tube, add methyl 2- (pyridine-4-yl) -1H-benzimidazol-4-carboxylate (3.58 g) to liquid ammonia (35 ml) cooled to -50 ° C or lower. Heated at 140 ° C for 3 days. After the reaction vessel is cooled to below 50 ° C and opened, the reaction mixture is concentrated and recrystallized from DMF-ethyl acetate to give 2- (pyridine-4-yl) -1H-benzimidazole-4-carboxamide. (2.58 mg) was obtained as a light brown powder.
実施例 3 Example 3
金属封管中、 一 50°C以下に冷却した液体アンモニア (15 ml)にメチル 2-(2-クロ口 ピリジン- 5-ィル) -1H-ベンゾイミダゾール -4-カルボキシラ一ト（640 mg)を加え、 140°Cで 3日間加熱した。反応容器を— 50°C以下に冷却して開封後、 反応液を濃縮し、 残渣をシリカゲルカラムクロマトグラフィー （クロ口ホルム—メタノール） で精製 し、 次いでエタノールから再結晶して、 2ィ 2-アミノピリジン- 5ィル) -1H-ベンゾイミ ダゾール—4-カルボキサミド (312 mg)を淡褐色粉末として得た。 In a sealed metal tube, add methyl 2- (2-chloropyridine-5-yl) -1H-benzimidazole-4-carboxylate (640 mg) to liquid ammonia (15 ml) cooled to below 50 ° C. ) And heated at 140 ° C. for 3 days. After the reaction vessel is cooled to below -50 ° C and opened, the reaction solution is concentrated, the residue is purified by silica gel column chromatography (form-methanol), and then recrystallized from ethanol to give 2- (Aminopyridine-5yl) -1H-benzoimid Dazole-4-carboxamide (312 mg) was obtained as a light brown powder.
実施例 4 Example 4
2-(2-クロ口ピリジン- 5-イリレ) -1H-ベンゾイミダゾ一ル -4-力ルポキサミド（250 mg) 及びフエニルプロピルアミン (2 ml)を 100でで一夜攪拌した。 反応混合物をクロロホ ルムで希釈した後、 シリカゲルカラムクロマトグラフィー（へキサン—酢酸ェチル） で精製し、 次いでイソプロパノールから再結晶して、 2-(2-フエニルプロピルアミノ ピリジン- 5-ィル) -1H-ベンゾイミダゾール -4-カルボキサミド (215 mg)を無色粉末と して得た。  2- (2-Chloropyridine-5-iryl) -1H-benzimidazole-1-carboxoxamide (250 mg) and phenylpropylamine (2 ml) were stirred at 100 overnight at 100. The reaction mixture was diluted with chloroform, purified by silica gel column chromatography (hexane-ethyl acetate), and then recrystallized from isopropanol to give 2- (2-phenylpropylaminopyridin-5-yl)- 1H-benzimidazole-4-carboxamide (215 mg) was obtained as a colorless powder.
実施例 5 Example 5
2-(2-クロロピリジン- 5-ィル)- 1H-ベンゾィミダゾール -4-カルボン酸 (200 mg)及び 40%メチルァミン水溶液 (2 ml)を、 封管中 100°Cで 8時間加熱した。 反応混合物を水 で希釈後、 1M 水酸化ナトリウム水溶液を加えた。 水層をクロ口ホルムで洗浄後、 1M塩酸水を加えて pH5 とし、 析出した固体を濾取、 乾燥して、 粗生成物 (189 mg) を得た。 得られた粗生成物 (157 mg)に THF(10 ml)及び CDI(148 mg)を加え、 室温で 5 時間攪拌した。 反応液にアンモニアを飽和した THF(20 ml)を加え、 室温で一夜攪拌 した。 反応液に水を加え、 析出した固体を濾取、 水洗して、 2-(2-メチルァミノピリ ジン- 5-ィル) -1H-ベンゾイミダゾール -4-カルボキサミド (78 mg)を淡褐色粉末として 得た。  Heat 2- (2-chloropyridine-5-yl) -1H-benzimidazole-4-carboxylic acid (200 mg) and 40% aqueous methylamine solution (2 ml) in a sealed tube at 100 ° C for 8 hours did. After the reaction mixture was diluted with water, a 1 M aqueous sodium hydroxide solution was added. After the aqueous layer was washed with chloroform, the pH was adjusted to 5 by adding 1M aqueous hydrochloric acid, and the precipitated solid was collected by filtration and dried to obtain a crude product (189 mg). THF (10 ml) and CDI (148 mg) were added to the obtained crude product (157 mg), and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added THF saturated with ammonia (20 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water to give 2- (2-methylaminopyridin-5-yl) -1H-benzimidazole-4-carboxamide (78 mg) as a pale brown powder. Was.
実施例 6 Example 6
2- (2-クロロピリジン- 5-ィル) -1H-ベンゾィミダゾ一ル -4-カルボキサミド (600 mg)、 フエネチルメル力プ夕ン (609 mg)の DMF(6 ml)溶液に、 ナトリウムメトキシド (357 mg)を加え、 65°Cで 1.5時間攪拌した。 反応混合物を水で希釈した後、 1M塩酸水を 加え、 pH4 とした。 析出した固体を濾取後、 THF—メタノールより再結晶し、 2-(2- フエネチルスルファニルピリジン- 5-ィル) -1H-ベンゾイミダゾール -4 -カルボキサミ ド (466 mg)を無色針状晶として得た。  To a solution of 2- (2-chloropyridine-5-yl) -1H-benzoimidazole-4-carboxamide (600 mg) and phenethylmercaptan (609 mg) in DMF (6 ml) was added sodium methoxide ( 357 mg) and stirred at 65 ° C for 1.5 hours. After the reaction mixture was diluted with water, 1M hydrochloric acid was added to adjust the pH to 4. The precipitated solid was collected by filtration and recrystallized from THF-methanol to give 2- (2-phenethylsulfanylpyridine-5-yl) -1H-benzimidazole-4-carboxamide (466 mg) as a colorless needle. Obtained as crystals.
実施例 7  Example 7
2-(2-クロロピリジン- 5-ィル) -1H-ベンゾィミダゾ一ル- 4-力ルポキサミド (600 mg)、 ベンジルアルコール (595 mg)、 18-crown-6(71 mg)の DMF(6 ml)溶液に、 力リゥム tert- ブトキシド (tBuOK, 740 mg)を加え、 95°Cで 8 時間攪拌した。 反応混合物に、 18- crown-6(291 mg)及び tBuOK(246 mg)を加え、 95°Cで 14 時間攪拌し、 更に、 18- crown-6(291 mg)及び tBuOK(246 mg)を加え、 95°Cで 5時間攪拌した。 反応混合物を 水で希釈した後、 1M塩酸水を加え、 pH4とした。 析出した固体を濾取後、 THF—メ 夕ノールより再結晶し、 2- (2-ベンジルォキシピリジン -5-ィル) -1H-ベンゾィミダゾ一 ル— 4-力ルポキサミド (324 mg)を無色針状晶として得た。 2- (2-Chloropyridine-5-yl) -1H-benzoimidazole-1-4-hexanoloxamide (600 mg), benzyl alcohol (595 mg), 18-crown-6 (71 mg) in DMF (6 ml ) To the solution was added potassium tert-butoxide (tBuOK, 740 mg), and the mixture was stirred at 95 ° C for 8 hours. 18- Add crown-6 (291 mg) and tBuOK (246 mg), stir at 95 ° C for 14 hours, add 18-crown-6 (291 mg) and tBuOK (246 mg), and add Stirred for hours. After diluting the reaction mixture with water, 1M aqueous hydrochloric acid was added to adjust the pH to 4. The precipitated solid was collected by filtration and recrystallized from THF-methanol to give 2- (2-benzyloxypyridin-5-yl) -1H-benzoimidazole- 4-hexanoloxamide (324 mg) as colorless Obtained as needles.
実施例 8 Example 8
メチル 2- (2-クロ口ピリジン- 5-ィル) -1H-ベンゾイミダゾ一ル -4-カルボキシラー ト (767 mg)及び 28%ナトリゥムメトキシド—メタノール溶液 (10 ml)を、封管中 140°C で一夜加熱した。 反応混合物を濃縮後、 水で希釈し、 1M塩酸水を加えて pH6 とし た。 析出した固体を濾取、 乾燥して、 粗生成物 (287 mg)を得た。 得られた粗生成物 に THF(10 ml)及び CDI(280 mg)を加え、 室温で 2時間攪拌した。 反応液にアンモニ ァを飽和した THF(20 ml)を加え、 室温で 2日間攪拌した。 反応液を濃縮し、 水を加 えて得られた固体を濾取後、 シリカゲルカラムクロマトグラフィー （クロ口ホルム —メタノール） で精製し、 次いで DMF-酢酸ェチルから再結晶して、 2-(2-メトキシ ピリジン- 5-ィル) -1H-ベンゾイミダゾ一ル -4-カルボキサミド（128 mg)を淡褐色粉末 として得た。  Methyl 2- (2-chloropyridine-5-yl) -1H-benzimidazole-4-carboxylate (767 mg) and 28% sodium methoxide-methanol solution (10 ml) were sealed. Heated in a tube at 140 ° C overnight. The reaction mixture was concentrated, diluted with water, and adjusted to pH 6 with 1M aqueous hydrochloric acid. The precipitated solid was collected by filtration and dried to give a crude product (287 mg). THF (10 ml) and CDI (280 mg) were added to the obtained crude product, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added THF (20 ml) saturated with ammonia, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, water was added, and the obtained solid was collected by filtration, purified by silica gel column chromatography (form: methanol), and recrystallized from DMF-ethyl acetate to give 2- (2- Methoxypyridine-5-yl) -1H-benzimidazole-4-carboxamide (128 mg) was obtained as a pale brown powder.
実施例 9 Example 9
2- (ピペリジン- 4-ィル) -1H-ベンゾイミダゾ一ル 4-カルボキサミド · 2 トリフルォロ 酢酸塩粗生成物 (767 mg)、 ドデカナール (0.54 ml),酢酸 (5滴)及び 1,2-ジクロロェタン (10 ml)の混合物にトリァセトキシ水素化ホウ素ナトリゥム (1.20 g)を加え、 室温下 1 時間攪拌した。 反応液に飽和炭酸水素ナトリウム水溶液を加え、 クロ口ホルムで抽 出後、 有機層を乾燥 （無水硫酸マグネシウム） し、 濃縮して得られた残渣をシリカ ゲルカラムクロマトグラフィー （クロ口ホルム一メタノール） で精製し、 2-(1-ドデ シルピペリジン- 4-ィル) -1H-ベンゾイミダゾ一ル 4-カルボキサミド (554 mg)を得た。 得られた化合物をメタノールに溶解し、 フマル酸 117 mgを加えた。 生じた結晶を 再結晶 （メタノール—酢酸ェチル） し、 2-(1-ドデシルビペリジン- 4-ィル) -1H-ベンゾ イミダゾール 4-カルボキサミド 1/2フマル酸塩 (510 mg)を白色粉末として得た。 実施例 1 0  2- (piperidin-4-yl) -1H-benzimidazole 4-carboxamide2 trifluoroacetate crude product (767 mg), dodecanal (0.54 ml), acetic acid (5 drops) and 1,2-dichloroethane (10 ml), sodium triacetoxyborohydride (1.20 g) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried (anhydrous magnesium sulfate) and concentrated. The residue obtained was silica gel column chromatography (chloroform-methanol). To give 2- (1-dodecylpiperidin-4-yl) -1H-benzimidazole 4-carboxamide (554 mg). The obtained compound was dissolved in methanol, and fumaric acid (117 mg) was added. The resulting crystals were recrystallized (methanol-ethyl acetate), and 2- (1-dodecylbiperidin-4-yl) -1H-benzoimidazole 4-carboxamide 1/2 fumarate (510 mg) as a white powder As obtained. Example 10
2- (ピペリジン- 4-ィル) -1H-ベンゾイミダゾ一ル 4-カルボキサミド · 2 トリフルォロ 酢酸塩粗生成物 (700 mg)、 3-フエノキシプロピルブロミド (215 mg)、炭酸カリウム (1.4 g)、 ヨウ化カリウム (150 mg)及び DMF(13 ml)の混合物を室温下終夜攪拌した。 反応 液に水を加え、 酢酸ェチルで抽出後、 有機層を飽和食塩水で洗浄した。 抽出液を乾 燥 （無水硫酸マグネシウム） 、 濃縮後、 シリカゲルカラムクロマトグラフィー （ク ロロホルム一メタノール） で精製し、 2-[1-(3-フエノキシプロピル）ピぺリジン- 4-ィ ル] -1H-ベンゾイミダゾール 4-カルボキサミド (289 mg)を白色粉末として得た。 2- (piperidin-4-yl) -1H-benzimidazole 4-carboxamide2 trifluoro A mixture of crude acetate (700 mg), 3-phenoxypropyl bromide (215 mg), potassium carbonate (1.4 g), potassium iodide (150 mg) and DMF (13 ml) was stirred overnight at room temperature. . Water was added to the reaction solution, and after extraction with ethyl acetate, the organic layer was washed with saturated saline. The extract is dried (anhydrous magnesium sulfate), concentrated and purified by silica gel column chromatography (chloroform-methanol) to give 2- [1- (3-phenoxypropyl) piperidin-4-yl] -1H-benzimidazole 4-carboxamide (289 mg) was obtained as a white powder.
実施例 1 1 Example 1 1
2- (ピペリジン- 4-ィル) -1H-ベンゾイミダゾール 4-カルボキサミド · 2 トリフルォロ 酢酸塩粗生成物 (483mg)のジク口ロメ夕ン (10 ml)懸濁液に N，N-ジィソプロピルェチ ルァミン （1 ml) および P-トルエンスルホニルクロリ ド (264mg)を加え、 室温下 30 分間攪拌した。反応液に炭酸水酸ナトリウム水溶液を加え、 クロ口ホルムで抽出後、 有機層を乾燥した。 減圧下で溶媒を留去し、 残渣をシリカゲルシリカゲルカラムク 口マトグラフィ一(クロロホルム-メ夕ノール)で精製後、 再結晶（ク口口ホルム-メ夕 ノール-酢酸ェチル)することにより 2-(1-トルエン- 4-スルホニルピペリジン- 4-ィル) - 1H-ベンゾイミダゾール 4-カルボキサミド (152 mg)を得た。 を白色粉末として得た。 以下、上記実施例 1〜1 1に記載の方法と同様にして表 5〜 8に示す実施例 1 2 〜9 3の化合物を、 それぞれ対応する原料を使用して製造した。 実施例化合物の構 造を表 5〜 8に、 物理化学的デ一夕を表 9にそれぞれ示す。  2- (Piperidin-4-yl) -1H-benzimidazole 4-carboxamide · 2 Trifluoroacetic acid salt (483 mg) Ethylamine (1 ml) and P-toluenesulfonyl chloride (264 mg) were added, and the mixture was stirred at room temperature for 30 minutes. An aqueous solution of sodium carbonate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel silica gel column chromatography (chloroform-methanol) and then recrystallized (crop-mouth form-methanol-ethyl acetate) to give 2- ( 1-Toluene-4-sulfonylpiperidine-4-yl) -1H-benzimidazole 4-carboxamide (152 mg) was obtained. Was obtained as a white powder. Hereinafter, the compounds of Examples 12 to 93 shown in Tables 5 to 8 were produced using the corresponding raw materials in the same manner as in the methods described in Examples 1 to 11 above. Tables 5 to 8 show the structures of the compounds of the examples, and Table 9 shows the physicochemical data.
また、 表 1 0〜1 3に本発明の別の化合物の構造を示す。 これらは、 上記の製造 法や実施例に記載の方法及び当業者にとって自明である方法、 又はこれらの変法を 用いることにより、 容易に合成することができる。  Tables 10 to 13 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-mentioned production methods, the methods described in the examples, methods obvious to those skilled in the art, or modifications thereof.
表中、 次に示す略号を用いる。 Rex :参考例番号、 Ex :実施例番号、 Cmpd :化合 物番号、 Str：構造式、 Me：メチル、 Et：ェチル、 tBu： tert-ブチル、 Boc： tBuO-CO-、 Ph :フエニル、 Bn :ベンジル、 cHex :シクロへキシル、 Ac :ァセチル。 Sa 塩（HC1： 塩酸塩； Ox：シユウ酸塩； Fu： フマル酸塩；無記載：フリ一体） 、 Syn：製造法 （数 字は同様に製造した実施例番号を示す） 、 Dat :物理化学的データ （F : FAB- MS(M+H)+； FN： FAB-MS(M-H)"； NMR： DMSO-d6中の 1HNMRにおけるピークの δ (PPm)) 。 6ZIn the table, the following abbreviations are used. Rex: Reference example number, Ex: Example number, Cmpd: Compound number, Str: Structural formula, Me: Methyl, Et: Ethyl, tBu: tert-butyl, Boc: tBuO-CO-, Ph: Phenyl, Bn: Benzyl, cHex: cyclohexyl, Ac: acetyl. Sa salt (HC1: hydrochloride salt; Ox: oxalate salt; Fu: fumarate salt; no description: monolithic); Syn: production method (numbers indicate the example numbers produced in the same manner); Dat: physical chemistry data (F: FAB- MS (M + H) +; FN: FAB-MS (MH) "; NMR: DMSO-d during peaks in 1HNMR of 6 δ (PPm)). 6Z
Figure imgf000031_0002
Figure imgf000031_0002
s拏
Figure imgf000031_0003
halla
Figure imgf000031_0003
Figure imgf000031_0001
Figure imgf000031_0001
ie90/00df/XDd SI9IZ/10 OAV
Figure imgf000032_0001
ie90 / 00df / XDd SI9IZ / 10 OAV
Figure imgf000032_0001
ε拏 /00dr/XDJ S191Z/10 OA ella / 00dr / XDJ S191Z / 10 OA
Figure imgf000033_0001
Figure imgf000033_0001
拏 90/00df/13J SX9II/I0 O
Figure imgf000034_0001
Figure imgf000034_0003
表 6
Figure imgf000034_0002
Halla 90 / 00df / 13J SX9II / I0 O
Figure imgf000034_0001
Figure imgf000034_0003
Table 6
Figure imgf000034_0002
Figure imgf000035_0001
f/X3d SX9TZ/X0 OAV 表 8
Figure imgf000035_0001
f / X3d SX9TZ / X0 OAV Table 8
Figure imgf000036_0001
Figure imgf000037_0001
表 9
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000036_0001
Figure imgf000037_0001
Table 9
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0002
Figure imgf000044_0004
Figure imgf000044_0004
表 1 3 Table 13
Figure imgf000044_0003
Figure imgf000044_0003

Claims

請 求 の 範 囲  The scope of the claims
-般式 （ I ) 又は （II) で示されるベンゾイミダゾ一ル誘導体又はその塩。 -A benzimidazole derivative represented by the general formula (I) or (II) or a salt thereof.
Figure imgf000045_0001
Figure imgf000045_0001
(式中の記号は以下の意味を有する- R1 ： Η、 低級アルキル、 「、置換された低級アルキル基、(The symbols in the formula have the following meanings: R 1 : Η, lower alkyl, “, a substituted lower alkyl group,
R2 ： Η、 低級アルキル又は CO—低級アルキル基、 R 2 : Η, lower alkyl or CO—lower alkyl group,
A：置換基を有していてもよいへテロ環基、 但し、 該ヘテロ環が含窒素非芳香属へ テロ環の場合、 該ヘテロ環は G1群から選択される基を 1〜4個有する、 A: a heterocyclic group which may have a substituent, provided that when the heterocyclic ring is a nitrogen-containing non-aromatic heterocyclic ring, the heterocyclic ring has 1 to 4 groups selected from Group G1 Have,
Gi群：式 (i) _X0_Y2— Z (ii)一 X0 - Y3 - Z3、 (iii)— X0— Y5— Z2、 (iv) - X1— Y1 -Ζ (ν) - X1— Υ4_Ζ3、 (v — Xi— Y5— Ζ2、 （vii)_X2— Υ6— Ζ3又は (viii)— X2— Y5— z2で表される基、 Gi group: Formula (i) _X 0 _Y 2 — Z (ii) one X 0 -Y 3 -Z 3 , (iii) — X 0 — Y 5 — Z 2 , (iv)-X 1 — Y 1 -Ζ (ν)-X 1 — Υ 4 _Ζ 3 , (v — Xi— Y 5 — Ζ 2 , (vii) _X 2 — Υ 6 — Ζ 3 or (viii) — X 2 — Y 5 — z 2 Group,
入 · ロロ、  · Lolo,
X1 ： C1-8アルキレン又は CO— C1-7アルキレン、 X 1 : C 1-8 alkylene or CO—C 1-7 alkylene,
X2 ： C9-12アルキレン、 CO— C8-12アルキレン、 C2-12 7ルケ二レン、 C2-12アル キニレン、 CO— C2-12アルケニレン又は CO— C2-12アルキニレン、 X 2: C 9-12 alkylene, CO- C 8-12 alkylene, C 2-12 7 Luque two alkylene, C 2-12 aralkyl Kiniren, CO- C 2-12 alkenylene or CO- C 2-12 alkynylene,
Y1 ： CO、 N(R3)、 CON(R3)又は結合、 Y 1 : CO, N (R 3 ), CON (R 3 ) or a bond,
R3 ： H、 低級アルキル又は CO—低級アルキル基、 R 3 : H, lower alkyl or CO—lower alkyl group,
Y2 ： C02又は Y1に記載の基、 Y 2: C0 2 or a group described in Y 1,
Y3 ： 0、 S、 N(R3)CO、 0-CONH、 NHC02、 NHCONH、 NHCS亂 CONH亂 NHNHCO、 0-COC02、 0-COCO亂 NHCOC02、 NHCOCO亂 C(NH)NH、 C(N-CN)NH、 NHC(NH)NH、 NHC(N-CN)NH、 S02-0、 S02NH、 S02NHNH 又は P(0)(OR3)0、 Y 3: 0, S, N (R 3) CO, 0-CONH, NHC0 2, NHCONH, NHCS亂CONH亂NHNHCO, 0-COC0 2, 0 -COCO亂NHCOC0 2, NHCOCO亂C (NH) NH, C (N-CN) NH, NHC (NH) NH, NHC (N-CN) NH, S0 2 -0, S0 2 NH, S0 2 NHNH or P (0) (oR 3) 0,
Y4 ： C02又は Y3に記載の基、 Y 4: C0 2 or a group described in Y 3,
Y5 : S0、 S02、 0-C0、 N(R3)C02、 NHS02又は NHNHS02、 Y 5: S0, S0 2, 0-C0, N (R 3) C0 2, NHS0 2 or NHNHS0 2,
Y6 ： Y1又は Y4に記載の基、 z1：環原子である炭素原子で結合する置換基を有していてもよいへテロ環基、 Z2：置換基を有していてもよい低級アルキル、 置換基を有していてもよいシ クロアルキル、 置換基を有していてもよいァリール又は置換基を有してい てもよいへテロ環基、 Y 6 : a group described in Y 1 or Y 4 z 1 : a heterocyclic group which may have a substituent bonded at a carbon atom which is a ring atom, Z 2 : lower alkyl which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heterocyclic group which may have a substituent,
Z3： H又は Z2に記載の基。 ）Z 3 : H or the group described in Z 2 . )
. 2- (チォフェン- 2-ィル) -1H-ベンゾイミダゾ一ル -4-カルポキサミド、 2-[1-(3-フエ ノキシプロピル）ピぺリジン -4-ィル] -1H-ベンゾィミダゾ一ル -4-力ルボキサミド、 2- (ピリジン- 4-ィル) -1H-ベンゾイミダゾール -4-カルボキサミド、 2-{1-[3- (チォフエ ン -2-ィル）プロピル]ピペリジン- 4-ィル }-1Η-ベンゾイミダゾール -4-カルボキサミ ド、 2-{1-[3-(2-クロロフエノキシ]プロピリレ）ピぺリジン -4-ィル}-111-ベンゾィミダ ゾール—4-カルボキサミド、 2-[1-(3-フヱニル -2-プロペン- 1-ィル）ピぺリジン- 4-ィ ル] -1H-ベンゾィミダゾ一ル -4-カルボキサミドからなる群から選択される請求の 範囲 1記載のベンゾイミダゾール誘導体又はその塩。 2- (thiophen-2-yl) -1H-benzimidazole-4-carboxamide, 2- [1- (3-phenoxypropyl) piperidin-4-yl] -1H-benzimidazol- 4-carboxamide, 2- (pyridine-4-yl) -1H-benzimidazole-4-carboxamide, 2- {1- [3- (thiophen-2-yl) propyl] piperidine-4-yl } -1Η-benzimidazole-4-carboxamide, 2- {1- [3- (2-chlorophenoxy] propylyl) piperidin-4-yl} -111-benzimidazole-4-carboxamide, 2- The benzo according to claim 1, which is selected from the group consisting of [1- (3-phenyl-2-propen-1-yl) piperidin-4-yl] -1H-benzoimidazole-4-carboxamide. An imidazole derivative or a salt thereof.
. 請求の範囲 1記載のベンゾイミダゾール誘導体又はその塩と、 製薬学的に許容 される担体とからなる医薬組成物。 A pharmaceutical composition comprising the benzimidazole derivative according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.
. PARP阻害剤である請求の範囲 3記載の医薬組成物。 4. The pharmaceutical composition according to claim 3, which is a PARP inhibitor.
. 炎症性疾患の予防又は治療剤である請求の範囲 4記載の医薬組成物。  The pharmaceutical composition according to claim 4, which is an agent for preventing or treating an inflammatory disease.
. 慢性関節リゥマチの予防又は治療剤である請求の範囲 5記載の医薬組成物。  6. The pharmaceutical composition according to claim 5, which is an agent for preventing or treating rheumatoid arthritis.
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