WO2001021615A1 - Dérivés de benzimidazole - Google Patents

Dérivés de benzimidazole 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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English (en)
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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Priority to AU73142/00A priority Critical patent/AU7314200A/en
Publication of WO2001021615A1 publication Critical patent/WO2001021615A1/fr

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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

Cette invention concerne des composés des plus utiles dans le traitement de diverses maladies liées à la (poly (ADP-ribose) polymérase) (PARP), lesquels composés sont des dérivés de benzimidazole possédant des groupes hétérocycliques en position 2 et des groupes carbamoyles en position 4, comme représenté par la formule générale (I) ou (II), ou leurs sels. Dans cette formule (I ou II), R1 représente un hydrogène, un alkyle de faible poids moléculaire ou analogue, R2 représente un hydrogène, un alkyle de faible poids moléculaire ou analogue et A représente un groupe hétérocyclique éventuellement substitué ou analogue.
PCT/JP2000/006319 1999-09-17 2000-09-14 Dérivés de benzimidazole WO2001021615A1 (fr)

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