WO2002068407A1 - Benzimidazole compound - Google Patents

Benzimidazole compound Download PDF

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WO2002068407A1
WO2002068407A1 PCT/JP2002/001741 JP0201741W WO02068407A1 WO 2002068407 A1 WO2002068407 A1 WO 2002068407A1 JP 0201741 W JP0201741 W JP 0201741W WO 02068407 A1 WO02068407 A1 WO 02068407A1
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group
le
alkyl
compound
honoré
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PCT/JP2002/001741
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French (fr)
Japanese (ja)
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Kazuhisa Takayama
Takenori Kimura
Naoyuki Masuda
Ryo Naito
Yoshinori Okamoto
Yuji Koga
Yohei Okada
Makoto Takeuchi
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Yamanouchi Pharmaceutical Co., Ltd.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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

Abstract

A compound usable in treatments for various diseases in which poly(ADP-ribose) polymerase (PARP) participates. It is either a benzimidazole derivative represented by the following formula (1), which has a substituted heterocyclic group in the 2-position and a carbamoyl group in the 4-position, or a salt of the derivative. (I)

Description

Bright fine manual benzo I Mi imidazole compound art

The present invention relates to pharmaceutical, regarding useful benzo I Mi indazole derivatives as particularly PARP inhibitors. BACKGROUND

Riumachi arthritis (rheumatoid Riumachi, rheumatoid arthritis: RA) is a polyarthritis repeated relapse and remission, Kitaichi joint destruction, accompanied by extra-articular symptoms, is a disease life-threatening at the time. Infiltration of RA as the feature (1) mononuclear, (2) increase in synovial cells ingrowth, (3) as a result of tissue Yabu壌 the like (N. Engl. J. Med., 322, 1277 -1289 (1990)). Therefore purpose of drug therapy is the prevention of bone Yabu壌 observed by holding and X-ray of the joint function.

Poly (ADP-ribose) polymerase (Poly (ADP-ribose) polymerase: PARP) is a nuclear enzyme 113 kDa. Zn finger in two places at the N-terminus of PARP. Motifs recognizes damaged DNA strands, the vicinity of the histone and DNA topoisomerase I, various nuclear proteins in E Cochin adenine dinucleotide containing II (nicotinamide adenine dinucleotide: it is known that governs the reactions going polymerizing ADP- ribose portion of NAD). Therefore activation of excess PARP is thought to lead to cell death were 枯渴 intracellular NAD 及 Pi ATP content (J. Clin. Invest, 77, 1312-1330 (1986)). NO and active oxygen in a variety of inflammatory diseases or Peruokishi two birds bets is these reaction products, it is well known that a powerful mediators causing tissue damage. The tissue damage is, NO, reactive oxygen recognizes damaged DNA strand PARP is-activity I spoon generated Te cowpea to Peruokishi two birds bets, is believed to be the result of inviting 'energy 枯渴 ( Proc. Natl. Acad. Sci. USA 93 1753-1758 (1996)). The PARP of the cellular infiltration at inflammation is strongly suppressed by inhibiting the activation are also summer and clarified (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)), NCV ion amount of synovial fluid and serum is increased markedly being (Ann. Rheum. Dis., 51, 1219-1222 (1992)), the damage to the DNA strand is increased in peripheral mononuclear cells (Aim. Rheum. Dis, 51, 8-12 (1992) ), it NAD content is slightly reduced (Int. J. Clin. P arm. Res., 14, 57-63 (1994) from the facts, etc.), are active 个生 I ratio of PARP has been suggested, cell infiltration and tissue destruction is believed to that has been caused as a result.

Therefore, PARP inhibitors are believed to Ru useful der for the treatment of inflammatory diseases including RA. However, clinically effective PARP inhibitors is not been found, development of new PARP inhibitors with superior inhibitory activity has been desired.

Represented by the following formulas, the unsubstituted Karupamoiru group in the 4-position of the benzimidazole, PAR inhibitors with heterocycle at the 2-position to the nitrogen - containing saturated is disclosed in Japanese Patent WO00 / 32579.

(In the formula, A, having a substituent R 2及Pi R 3, shows a 4-8 membered saturated or mono-E Tenofovir I de hetero ring containing 1 or 2 N atoms. R 2 is H ; NR 26 R 27 or Okiso may be substituted with a group branched or linear C I-8 alkyl; C 3-7 Shikuroarukinore - C M alkyl le; CO-CNH ^ -R 21; C0 2 R 21; or optionally substituted Hue - Le (R 21 is C 3-7 cyclo alkyl, or Hue - show Le etc.), R 3 is, H; Hue - be substituted by Le group shows good branched or linear C 1-8 alkyl or the like, respectively. also, the NR 26 R 27 in R 2 may form a heterocyclic ring from 3 to 8-membered, said heterocycle C w alkyl or C 1-4 alkyl - may be substituted by phenyl details, reference can be made to the publication)..

The I arsenide Gobutsu has a hetero ring at the 2-position to the nitrogen-containing saturated may further combined with other rings said heterocycle via a bond, but a bond at that time, in Okiso group it may also be substituted Rere C 1-8 alkylene, CO-INH) (a u, C0 2 or a bond. the ring you bind to their connecting bonds, (1) may be substituted with Okiso group for C 1-8 alkylene, heterocyclic ring 3-8 membered nitrogen-containing you bond with N, (2) C 1-4 alkylene, CO-CNH; for ^ or C0 2, full Eniru or C 3-7 cycloalkyl, (3) C 5-8 when alkylene or a bond, phenyl, and disclosure of which is limited respectively. iNVENTION

The present inventors, as a result of intensive studies on compounds which inhibit PARP, unsubstituted force Rubamoiru group in the 4-position of the Benzoimida tetrazole, having a hetero ring at the 2-position to the nitrogen-containing saturated, to those nitrogen-containing saturated a heterocycle, further one or more ring group is attached through a specific bond, benzo I Mi indazole derivatives have good PARP inhibitory activity, in particular found that also have good activity in oral administration and prevention of diseases involving PARP, found to be useful as therapeutic or diagnostic agents, the present invention has been completed.

That is, according to the present invention, benzimidazole derivative represented by the following general formula (I) (hereinafter, referred to as "the present compound (I)".) Or a pharmaceutically acceptable salt thereof, and one of these pharmaceutical comprising as seeds or active ingredients of two or more, and particularly PARP inhibitors are provided.

(Symbols in the formula have the following meanings.

R 1: H, lower alkyl, halogen, or a lower alkyl group substituted with a halogen, R 2a and R 2b: H, lower alkyl or absent,

Dotted line: the presence or absence of a double bond in the ring,

A: nitrogen-containing heterocyclic ring saturated,

X: Okiso which may lower alkylene or a bond substituted with one,

Y 1及Pi Y 3: identical or different from each other, optionally substituted lower alk Killen in Okiso group, optionally substituted lower alkenylene optionally substituted with Okiso group, optionally substituted lower alkynylene optionally substituted with Okiso group or bond, Y 2: 0, S, SO, S0 2 or a bond (when伹and Y 1 is methylene or a bond, Upsilon 2 is shows the binding),

zeta: optionally substituted cycloalkyl, substituted to an optionally also good Ariru or substitution Hajime Tamaki (provided that heterocyclic group such via a carbon atom which is a ring atom Υ 3 binds to),

And伹, -Υ ^ Υ ^ Υ 3 - group represented by the, -CO-0-, C 1-8 alkylene or optionally substituted with Okiso group - CO-0-C 1-4 When alkylene , Z is Les yo be substituted, it indicates terrorist ring to, and if the bond Y 1 and Y 2 are both, Y 3 represents a group other than binding. Following the same like. )

Dotted lines in formula (I), in combination with R 2a及Pi R 2b, shows that benzimidazole ring portion is one of the following structures.

Hereinafter, the present invention will be described in detail.

As used herein, the term "alkyl", "alkylene", "Aruke two Ren" 及 Pi Γ Arukini Ren "means a straight or branched hydrocarbon chain," lower alkyl ", for example if an alkyl group of C Les 6, preferably an alkyl group of C 1-4, more preferably methyl, Echiru and Isopuropiru group. "Lower alkylene" is, for example, alkylene down of c 1-6, preferably is alkylene c 2-4, and more preferably ethylene及Pi Petit Ren. "Lower alkenylene", for example, means having any one or more double bonds at the position of alkyl C 2-6, "lower alkynylene", for example, any of § alkyl chains of C 2-6 It means having one or more triple bonds in position.

"Halogen", F, Cl, showed a Br and I, preferably, F, C1 and Br. "Lower alkyl substituted with C androgenic" and, for example, refers to C 1-6 alkyl substituted with one or more halogen, preferably C 1-6 alkyl substituted with one or more F Yes, - more preferably, Furuoromechiru, Jifuruoromechiru a triflate Ruo ii methyl and preparative Rifuruoroechiru. "Cycloalkyl group" is preferably a cycloalkyl group having 3 to 1 4 carbon atoms, it may be crosslinked. More preferably consequent opening pentyl, heptyl 及 Pi Adamanchiru group to consequent opening hexyl, the consequent opening.

"Ariru group" is preferably a monocyclic to tricyclic Ariru group having 6 to 1 to 4 carbon. More preferably, Hue - a le and naphthyl groups, more preferably a Hue group. Further, the cycloalkyl ring of 5 to 8 membered phenyl group is condensed, For example, may form a indanyl or tetrahydronaphthyl group.

The "heterocyclic group" refers to a heterocyclic group 0, S and monocyclic 5-8 membered containing four 1 乃 optimum heteroatoms selected or from N tricyclic as a ring atom. Any carbon atoms are ring atoms may be substituted with Okiso group, S or N may be oxidized to form an Okishido Ya-di O Kishido. Heterocyclic group said may be crosslinked, also may be formed a spiro ring (including Asetaru of 1,3 Jiokisoran ring, derived from Okiso group). In addition, the good which may have been a cycloalkyl ring or benzene ring is condensed,. Preferably, Pirijinore, Piridaji - Le, Pirimijininore, pyrazinyl, furyl, Choi two Honoré, pyrrolyl, Okisazoriru, Isokisazorinore, Okisajiazoriru, thiazolyl, thiadiazole Lil, Imidazoriru, Toriazoriru, tetrazolyl, benzofuranyl, Benzoche sulfonyl, benzo O hexa benzisoxazolyl, benzo I Mida sled Honoré, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pyrrolidinyl, piperidyl, mol Horiniru, piperazinyl, pyrazolidinyl, Imidazorijiniru, Homopiperaji - Le, Tetorahi Dorofuraniru, Tetorahi Dorobira two Honoré, chromanyl, Jiokisoraninore, 8 Azabishikuro 3.2 .1] octane - 3-I-le, 9-Azabishikuro [3.3.1] nonane - 3-I-le, 3 § The bicyclo [3.2.1] octane - 6 I le, 7- Azabishikuro [2.2.1] heptane - 2-I le, 2- Azato Rishikuro [3.3.1.1 3 '7] decane - 4-I le, 1- Azabishikuro [2.2.2] octane - 2 - I le, 1- Azabi [2.2.2] octane - 3-I le, 1- Azabishikuro [2.2.2] octane - 4-I le, 3- Azasupi port [5.5] Undekan - 9-I le, 2 - Azasupiro [4.5] decane - 8 I le, 2- Azasupiro [4.4] non emissions -7 I le and 8 Azasupiro [4.5] decan-2-I group, and the like. More preferably pyridyl, pyridazinyl, furyl, thienyl, Okisazoriru, isoxazolyl, O Kisajiazoriru, thiazolyl and base Nzocheniru group.

As "heterocyclic group nitrogen-containing saturated" has at least one N as a ring atom, a further one O or heterocyclic group S to have also be 5 to 8 membered saturated have ring any carbon atom is an atom that may be substituted with Okiso group, it may also form a Okishido Ya Jiokishido S or N is oxidized Rere. Terrorist ring to said (including Asetaru of 1,3 Jiokisoran ring, derived from Okiso group) may be crosslinked, also may be formed a spiro ring. Preferably, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrazolidinyl, formidacillin isoxazolidinyl Honoré, homopiperazinyl, 8 Azabi cyclo [3.2.1] octane - 3-I le, 9 Azabishikuro [3.3.1] nonane - 3- I Le, 3- Azabishiku port [3.2.1] octane - 6 I le, 7- Azabishikuro [2.2.1] heptane - 2-I le, 2- Azatorishiku port [3.3.1.13,7] decane - 4- I le 1- Azabishikuro [2.2.2] octane - 2-I le, 1- Azabishiku port [2.2.2] Okutan 3 I le, 1- Azabishikuro [2.2.2] Otatan 4 I le, 3- Azasupiro [5.5] Undekan - 9-I le, 2- Azasupiro [4.5] decane - 8 I le, 2- Azasupiro [4.4] nonane - 7-I le 及 Pi 8 Azasupiro [4.5] decane - 2-I le radical and is a more preferably pyrrolidinyl, piperidyl 及 Pi 8- Azabishikuro [3.2.1] Okutan -3- I le group.

The "heterocyclic group binds to Y 3 via a carbon atom which is a ring atom", are adjacent linker - YLY ^ Y 3 - group represented by (e.g., Y 2及Pi Y 3 are both ring atoms when bond binds to Y 1) indicates a heterocyclic group are carbon atoms. For example, 1-piperidyl is that does not contain is 2-, 3- or 4-piperidyl encompasses.

"Cycloalkyl which may be substituted", the substituent in the "optionally substituted Ariru" or "heterocyclic group to be substituted", a pharmaceutical, in particular of the PARP inhibitors ring of a substituent usable as substituents, it may have five of these substituents 1. Preferably a substituent, C 1-2 () hydrocarbon group, halogen, C 1-6 alkyl substituted by halogen, OH, 0- C 1-2 Q hydrocarbon group, SH, S one C 1-2 Q hydrocarbon radical, SO- C 1-2 g hydrocarbon group, S0 2 - C 1-2G hydrocarbon group, CO- C 1-2Q hydrocarbon group, a heterocyclic group, C0 2 H, COO_C 1-20 hydrocarbon group, CON¾, CONH- C 1-6 Al kill, CON CM alkyl) 2, NHCO- C 1-6 Arukinore, NHCO 2 - C 1-6 alkyl, NHCONH - C 1-6 Arukinore, NH 2, NH- C 1-6 alkyl, N (d-6 alkyl) 2, CN及Pi N0 is a group selected from the group consisting of 2 groups (where the alkyl is a "C 1-20 hydrocarbon group", Al Keninore, Anorekienore, cycloalkyl Anore keno les, Arinore, Anorekiren - cycloalkyl Anore Kino les, alkenylene - cycloalkyl, alkynylene - cycloalkyl, alkylene - Ari le, alkenyl Len - Ariru, alkynylene -. Encompasses Ariru like carbon reduction heterocyclic group hydrogen group and the may have a substituent, preferably as the substituent, C 1-6 alkyl, halogen, OH, 0- C 1-6 Arukinore, SH, S- C 1-6 alkyl, SO-C, -6 Ryo alkyl, S0 2 - C 1-6 alkyl, CO- C 1-6 alkyl, C0 2 H, COO- C 1-6 alkyl, CONH 2, C0NH- C 1-6 alkyl, C0N (C 1-6 alkyl) 2, NHCO- C 1-6 alkyl, NHC0 2 -C 1-6 alkyl, NHCONH-C 1-6 alkyl, NH 2, NH- C 1-6 alkyl, N (C 1-6 alkyl) 2, CN and N0 2 groups selected from the group consisting of radicals, have 1-4 the substituent it may be). More preferably, C 1-6 alkyl, cycloalkyl, Ariru, C 1-6 § alkylene - cycloalkyl, C 1-6 alkylene - Ariru, halogen, C 1-6 alkyl substituted by halogen, OH, 0- C 1-6 alkyl, 0-cycloalkyl, 0- Ariru, 0- C 1-6 alkylene - cycloalkyl, 0- C 1-6 alkylene - Ariru, S- C 1-6 alkyl Le, S- cycloalkyl, S- Ariru, S- C 1-6 alkylene - cycloalkyl, S- C 1-6 alkylene - Ariru, CO- C 1-6 alkyl, CO- cycloalkyl, CO- § Li one Le, CO- C 1- 6 alkylene - cycloalkyl, CO- C 1-6 alkylene - Ariru, hetero ring group, C0 2 H, C00_C 1-6 alkyl, C0NH 2, CONH- C 1-6 alkyl, C0N (C 1-6 al kill) 2, NHCO- C 1-6 alkyl, NHC0 2 - C 1-6 alkyl, NHC0NH_C 1-6 alkyl, NH 2, NH-C 1-6 alkyl , N (C 1-6 alkyl) 2, CN及Pi N0 is 2 groups selected from the group consisting of (said cycloalkyl, Ariru及Pi heterocyclic group, C 1-6 Anorekinore, Ha androgenic, 0H, 0- C 1-6 alkyl, SH, S_C 1-6 alkyl, CO- C 1-6 alkyl, C0 2 H, C00-C 1-6 alkyl, NH 2, NH-C 1-6 alkyl, N (C 1-6 alkyl) 2, CN and N0 2 it may also be a group selected from the group have 1 to 4 consisting of radicals Les). More preferably, C 1-6 alkyl, cycloalkyl, Ariru, C 1-6 alkylene - Ariru, halogen, C 1-6 alkyl substituted by halogen, 0H, 0-C 1-6 alkyl, 0- Ariru, 0- C 1-6 alkylene - Ariru, S- C 1-6 Anorekiru, S- Ariru, S- C 1-6 alkylene - § reel, CO- C 1-6 alkyl, CO- Ariru, heterocyclic group, C0 2 H, C00- d- 6 Al kill, C0NH 2, CONH- d- 6 alkyl, C0N (C 1-6 alkyl) 2, NHCO- C 1-6 alkyl, NHC0 2 - C 1-6 alkyl, N¾, NH- C 1-6 alkyl, N (C 1-6 alkyl) 2, a group selected from CN and the group consisting of N0 2 (said cycloalkyl, heterocyclic group Ariru and to, Ci -6 alkyl, halogen, 0H, 0- C 1-6 alkyl, S- C 1-6 alkyl, CO- C 1-fi alkyl, C0 2 H, COO-C 1-6 alkyl, N¾, NH- C 1-6 alkyl , N (C 1-6 alkyl) 2, a CN and N0 2 groups selected from the group consisting of groups which may have 1 to 4).

Preferred compounds of the present invention, R 1 is H, R 2a or R 2b is H, X is a bond or C 1-6 alkylene, A is pyrrolidinyl or piperidyl, Y 1 is C 1-6 alkylene, Y 2 is 0, S or a bond, Y 3 is C 1-6 alkylene or a bond, are compounds of the heterocyclic group Z is optionally substituted cycloalkyl le, to which may be also be Ariru or substituted optionally be substituted . More preferably, optionally substituted cycloalkyl, substituted to an optionally also good phenyl or substituted are compounds of heterocyclic group, further good Mashiku is the X及Pi Y 3 binding a compound, more preferably, (1)丫2 is 0 or 8, and optionally Z is substituted full We - le,及Pi (2) Y 2 is a bond, and even Z is substituted compounds of heterocyclic groups aromatic. Even more preferably, -X, - .psi. is a group selected from the following G group, 2- [1- (substituted) piperidine - 4 Inore]-1H-Benzoi imidazole-4-carboxamide compound it is.

Group G: 2- off enoki Chez Chino les, 3-phenoxyethanol propyl, 4-Fuenokishipuchiru, hexyl 6 Hue phenoxy, 2- (2-fluoro-phenoxyethanol) Echiru, 3- (2-unloading Leo Roff hackberry ) propyl, 4- (2-fluoro-phenoxyethanol) heptyl, 2- (3-fluoro-phenoxyethanol) Echiru,

3- (3-fluoro-phenoxyethanol) propyl, 4- (3-Furuorofue carboxymethyl) heptyl, 2- (4-full Orofuenokishi) Echiru, 3- (4-fluoro-phenoxyethanol) propyl, 4- (4-Furuorofe phenoxy) heptyl, 2- (2-Kurorofuenokishi) Echiru, 3- (2-Kurorofuenokishi) prop Honoré, 4- (2-Kurorofuenokishi) heptyl, 3- (3-Kurorofuenokishi) propyl, 3 - (4-click port Rofuenokishi) propyl, 3- (2-Puromofuenokishi) flop port pills, 3- (3-Buromofuenoki) propyl, 3- (4-Buromofuenokishi) propyl, 3- (2-preparative V Furuoro Mechirufueno carboxymethyl) propyl, 3- (3-Torifuruoromechi / Refuenokishi) propyl, 3- (4-Torifuruo b-methyl phenoxyethanol) propyl, 3- (2-Shianofuenokishi) propyl, 3- (3-Shianofu

'Enoxy) propyl, 3- (4-Shianofuenokishi) propyl, 3- (2-Nitorofuenokishi) flop port pills, 3- (3-two Torofuenokishi) propyl, 3- (4-Nitorofuenokishi) propyl,

2- (2,4-difluoromethyl O Mikhailov Enoki Shi) Echiru, 3- (2,4-difluoromethyl O Mikhailov Enoki) propyl,

4- (2,4-difluoromethyl O Mikhailov Enoki Shi) butyl, 3- (2,3-difluoromethyl O Mikhailov Enoki) propyl,

3- (2,5-difluoro-phenoxyethanol propyl, 3- (2,6-difluoro-phenoxyethanol) propyl, 3- (3,4-difluoro phenoxyethanol) propyl, 3- (3,5-Jifuruorofu enoxy) propyl, 3- (2,3-dichloro phenoxyethanol) propyl, 3- (2,4-dichloro-phenoxyethanol) propyl, 3- (2,5-dichloro phenoxyethanol) propyl, 3- ( 2,6-dichloro-phenoxyethanol) propyl,

3- (3,4-dichloro phenoxyethanol) propyl, 3- (3,5-dichlorobenzoyl port Rofuenokishi) propyl,

4- (naphthalene - 1 Iruokishi) butyl, 4- (naphthalene - 2 Iruokishi) butyl, 2-off Eniruchioechiru, 3 Hue E thio propyl, 4-phenylene Ruchiopuchiru, 2- (3-Hue nil -1, 2,4 Okisajiazoru 5 I le) Echiru, 3- (3-phenyl-1,2,4-Okisajiazo one Honoré - 5-I) propyl, 4- (3-Fuweniru 1,2,4 Okisajiazoru-5-I-le) butyl,

2- (5-phenyl-1,2,4-Okisajiazoru 3-I le) Echiru, 3- (5 Fe - Le 1,2,4 Okisa Jiazonore - 3-I) propyl, 4- (5 - full We - Le 1,2,4 Okisajiazoru 3-I le) Petit Le, 3- [3- (2-click every mouth phenyl) -1,2,4 Okisajiazo one Honoré - 5- I le ] propyl, 3- [3- (3-fluorophenyl) -1,2,4 Okisajiazoru -5- I le] propyl, 2- (2-phenylene Ruoki Sazonore - 4-I le) Echiru, 3- ( 2-phenylpropyl O benzoxazole-4-I) propyl, 4- (2-off E - Ruokisazo one Honoré - 4-I le) butyl, 2- (2-off We two Ruchiazoru 4-I le) Echiru ,

3- (2-Hue - Ruchiazonore - 4 Inore) propyl, 4- (2-phenylene Ruchiazoru 4 Inore) Bed chill, 2- (3-phenylene Ruisokisazoru 5-I le) Echiru, 3- ( 3-phenylene Ruisokisazo Lou 5- Inore) propyl, 4- (3-phenylene Ruisokisazoru 5-I le) butyl, 2- (5-phenylene Le thiophene - 2-I le) Echiru, 3- (5- Hue - Ruchiofuwen-2-I) propyl, 4- (5-phenylene Le thiophene - 2-I le) heptyl, 2- (5-phenylene Ruisokisazoru 3-I le) E Chi le, 3- (5 - phenylene Ruisokisazoru 3-I) propyl, 4- (5-phenylene Ruisokisazo Le _3- I Le) butyl 及 Pi {3- [5- (4-chlorophenyl) furan-2-I le] propyl group.

Among the compounds of the present invention, particularly preferred compounds are 2- [1- (6-phenoxy hexyl) Piperi Gin - 4-I le]-1H-benzo I Mi imidazole-4-Karubokisami de, 2- {1- [ 2- (4-Furuorofueno carboxymethyl) Echiru] piperidine - 4-I le} -1Ita- Benzoimidazo one Honoré - 4- force Rupokisami de, 2- {1- [4- (4-unloading Leo Mikhailov Enoki Shi) heptyl] Pi Bae lysine - 4 I le} -1Ita- benzo I Mi Dazo Honoré 4 Karubokisami de, 2- {1- [3- (3-phenyl-1,2,4-Okisajiazoru 5-I) propyl] piperidine - 4-Ino W-1H-benzimidazole-4-Karubokisami de 及 Pi 2- {1- [2- (2-off We - Ruokisazoru 4 I le) Echiru] piperidine - 4-pray} - 111- benzo I Mi imidazole-4-force Rupokisami de. Compound (I) of the present invention include, but are sometimes geometrical isomers and tautomers are present depending on the kind of substituents, those to the present invention has been separation of these isomers, or also a mixture. Further, the present compound (I) may have asymmetric carbon atoms, isomers based on asymmetric carbon atoms may be present. The present invention encompasses those mixture and an isolated form of these optical different 14 body. Further, the present invention encompasses present invention compound (I) is also a compound labeled with a radioactive isotope elemental.

Compound (I) of the present invention, the compound one of R 2a or R 2b is H is in relationship parallel to each other. Notation such as the structural formula and chemical name herein described in that only one, but includes a compound in the present invention in their equilibrium.

Compound (I) of the present invention, depending on the type of acid addition salts or substituents may also form salts with bases, force mowing salts are included in the present invention, as long as it is a pharmaceutically acceptable salt thereof that. Specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, and inorganic acids such as sulfuric, nitric, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, full circle acid, maleic acid, lactic acid, malic acid, tartaric acid, Kuen acid, methanesulfonic acid, E Tan sulfonic acid, Asuparagin acid, acid addition salts with organic acids glutamic acid ", sodium © beam, potassium, magnesium, calcium, inorganic aluminum bases, methyl Amin, Echinoreamin, ethacrylic no Honoré amine, lysine, and the like salts or Anmoyuumu salts with organic bases such as Onorenichin like. further, the present invention may be tolerated present invention compound (I) and its pharmaceutically also encompasses various hydrates and solvates and polymorphic substances of the salt.

Further, the present compound also includes prodrugs pharmacologically acceptable. The pharmacological acceptable prodrug, a I匕合having a book onset Ming NH 2, OH, C0 2 groups are converted to H, etc. In by solvolysis or under a physiological condition. The group that form a prodrug, Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990) include groups described in the seventh Certificates Molecular Design 163-198 It is.

(Production Method)

The present invention compound (I) and pharmaceutically acceptable salts may be its basic skeleton or using the characteristics based on the type of substituent is prepared by applying various known synthetic methods. At that time, depending on the type of functional groups, protect the functional groups with a suitable protecting group during the steps from starting materials to intermediates, or replaced easily rolling I arsenate groups to the functional groups and Okuko manufacturing techniques there is a case in above effective. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, etc., as their protecting groups such green (TW Greene) and U'tsu (PGM Wuts) al, "Protective Groups in Organic Synthesis (3rd edition, 1999) "can be exemplified protecting group as described, may be appropriately selected and used according to these reaction conditions. In this way, after one row the reaction by introducing the protecting group, by converting removing the protecting group as necessary, or desired group, it can be obtained Nozomu Tokoro compound.

Further, prodrugs of the present compounds (I) may be prepared by carrying out the reaction using the same manner as described above protecting groups, by introducing a specific group during the steps from starting materials to intermediates, or resulting present compound (I) . The reaction is usually esterification, amidation, dehydration and the like, it can be carried out by applying the method of publicly known by those skilled in the art.

Hereinafter will be described a typical process of the invention compound (I). R 2a or the compound of the present invention one of R 2b is a H (gamma) may be prepared according to the following route.

(Wherein, R A is CONH 2, or readily Utati匕groups to CONH 2 (C0 2 H, the carboxylic acid ester or CN, etc.), L is a leaving group, P 1 is H or C 1 -6 coercive Mamorumoto of C0 2 H such as an alkyl group, P 2 represents a protecting group for H or an amino group, a 'is of the a, respectively a group having a ring atom N in a position to bind Y 1 shown. Similarly below.)

A. The first recipe: Arukirui spoon

This production process is a method of obtaining the starting compounds ([pi) the invention by a subjected to an alkylation reaction the compound (I '). The leaving group illustrated L is, Cl, Br, a halogen atom such as I, methanesulfonic Ruhoniruokishi group, an alkyl sulfonyl Ruokishi group and benzene Sno Reho Nino Reo alkoxy groups such Etansuruho two Ruokishi group, toluene (particularly P- Toruen) such as sulfonyl Ruokishi group of which § Li one Le sulfonyl O carboxymethyl organic sulfonic acid residue group, and the like.

The reaction is benzene, aromatic hydrocarbons such as Toruen, Jefferies chill ether, tetra hydrofuran (THF), ethers such as Jiokisan, dichloromethane, Jikuroroetan, halogenated hydrocarbons such as chloroform, methanol one Honoré, such as ethanol alcohols, New, Nyu- dimethylformamidine de (DMF), in a solvent inert to the reaction of dimethyl sulfoxide (DMSO) or the like, using the compound ([pi) with the compound (III) equimolar or one with an excess amount of , under cooling one 7 8 ° C~0 ° C, under cooling to room temperature, optionally at room temperature or carried out under room temperature to heating. Further, sodium hydride, potassium hydride, lithium Jie Sopu port Piruamido, hexa hexamethyldisilazide, sodium methoxide to lithium, force Liu arm tert- butoxide, sodium Mizusani匕, potassium hydroxide, sodium carbonate, force preferably carried out in the presence of a base such as Riumu.

Further, the present invention compound (gamma) can also be prepared by reductive Arukirui spoon reaction. At that time, instead of starting compounds (Iotapai), the corresponding carbonylation Louis 匕合 was used to reductive alkylation reaction a conventional method (e.g., "Jikken Kagaku Koza (Maruzen)" (4th edition , vol. 20, the reaction is carried out according to the method) described in 1992, 300) or the like.

Furthermore, when R a starting compound (II) is other than CONH 2, at the stage of the raw material I匕合product ([pi), or after § alkylation reaction can be converted to the desired CON¾ group. If R a is C0 2 H, halogenation hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, in a solvent inert to the reaction such as pyridine, a condensing agent (e.g., hexyl Cal positive imide dicyclohexyl (DCC), Jie isopropyl carbonitrile Jie Mi de (DIPC) ヽ 1- Echiru 3- (3-dimethylaminopropyl § amino propyl) Cal Pojiimi de (WSC), iota, .gamma.-carbonyl bis - 1H-imidazole (CDI) or the like ), in some cases, further additives (e.g., Nyu- hydroxysuccinimide (HONSu), the presence of 1-hydroxy-base Nzotoriazoru (HOBt), etc.), Ru can be prepared by treatment with ammonia. When R a carboxylic acid ester, water, alcohols, DMF, inert solvent or without a solvent in the reaction such as THF, at room temperature or under heating, optionally under pressure, it can be prepared by reacting with ammonia. If R a is CN, directly CON¾ group by hydrolysis, or can be prepared via over且a C0 2 H. These reactions can also be applied in the preparation of other compounds, can be prepared a compound R a is CONH 2 in the same manner.

. B Second method: Amidation and cyclization

This production process intermediates subjected starting compounds (IV) 及 Pi (VII) to amidation reaction and (VIII), obtained was subjected compound (VIII) to cyclization reaction to give the present invention compound (gamma) it is a method. Incidentally, it is possible to obtain without isolation of intermediate (VIII) single, also present compound is subjected to conditions directly after Ami de reaction cyclization reaction (gamma).

(1) Ami Di匕

Reaction are aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, in a solvent inert to the reaction such as DMSO, DCC, DIPC, WSC, condensing agent CDI, etc., optionally further HONSu, HOBt the presence of additives like, using compound (IV) with the compound (VII) one equimolar there have is a an excess, one 7 8 ° C~0 under cooling in ° C, under cooling to room temperature, It carried out at room temperature to under heating in some cases at room temperature or. Toryechiruamin, diisopropyl E Chiruamin, N- methylmorpholine, N, N- Jimechirua diphosphate, pyridine, 4-(N, N- dimethyl Chiruamino) pyridine, picoline, to react in the presence of a base such as lutidine, and the reaction sometimes chromatic 禾 U of on to smoothly proceed.

Alternatively, it may be using a variety of reactive derivatives in place of the starting compound (VII). The the reflected refractory derivatives, acid anhydrides; methyl esters of carboxylic acids, which conventional esters Echiruesuteru; acid chloride, acid halides acid Puromaido; acid azide; P- two Torofuwenoru phenolic compounds such or HONSu, HOBt, etc. of N- arsenide Dorokishiru of compounds active ester obtained by reacting the like; alkyl Harokaru Bonn acid alkyl ester and Viva port Iruharaido such a reacted organic-acid-based mixed acid anhydrides or salts Ihijifu sulfonyl obtained by such carbonate Haraido mixed acid anhydrides such as phosphoric acid-based mixed acid anhydride obtained by reacting a phosphoryl can be applied.

(2) The cyclization reaction of the aromatic hydrocarbons with halogenated hydrocarbons, inert organic solvent or without a solvent in the reaction such as ethers, a catalytic amount of acid to the solvent amount one 7 8 ° C~0 cold rejection ° C, under cooling to room temperature, optionally at room temperature or carried out under room temperature to heating. As the acid to be used acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, P- toluenesulfonic acid, Torifuruoro acetic, and the like triflate Ruo b methanesulfonic acid. Preparation of C starting compound

Compound ([pi) are from the compound (IV) 及 Pi (V), it can be prepared by subjecting the above amidation 及 Pi cyclization and similar conditions. Compound (VII) is from the compound (IX) and (III), can be prepared by subjecting the above Arukirui spoon reaction condition similar to that of. Compound (IV) can be prepared by the method described in such as US5380719. Compound (V) and (IX) by the applying known reaction are commercially available and many other compounds Isonipekochin acid, or readily available compounds connexion, can be easily manufactured, for example, compound (V) or X is C 1-6 alkylene der Ru compound in (IX) (ΧΙΠ) can also be prepared by the following method. Reduction P 1 OOC R B

~~>

(XIII)

(Wherein, the R b - A'-P 2 or C 1-4 alkylene - A'-P 2, R c is H or C 1-4 alkyl, or, with the carbon atom to which R b and R e are bonded overall together -. showing the A'-P 2 R d represents a commonly available groups on the reaction, such as C 1-4 aralkyl kill group hereinafter the same)..

That can be prepared by catalytic reduction of a Horner Emmons (Horner-Emmons) after O Les fins by reaction Wittig-like reaction, etc., in the presence of a palladium carbon or the like. Alternatively, a commercially available preparative port Pinon (XlVa) or precision organic synthesis (L.-F. Tietze, T. Eicher al, Makoto Takano one, Ogasawara States Ichiro translation, Nankodo, 487-489) a method similar to that described in the compound which is produced by the compound (V) or a compound corresponding to (IX) (XIVe), is (XlVf) and (XlVg) can be produced.

Shiano reaction, it is preferable to use the like tosyl methyl isobutyl Xia Nido (TosMIC), specifically Synthetic Communication 25 (6), Ru method and the like according to 787-793 (1995). Others are prepared by known reactions to the person skilled in the art.

Compound (III) can be easily prepared from readily available force \ or commercially available compounds. Leaving group L can be easily manufactured in a conventional manner from the OH group or C0 2 H group. Y 2 is 0 or compounds S are Eterui匕又by esterification reaction, the compound Y 2 is SO or S0 2 can be easily produced respectively by Sani spoon the S. Further, compounds having various substituents on the ring group Z are readily prepared by known methods, as a hetero ring having a substituent, for example, 1,2,4-Okisajiazoru derivative N- hydroxyamidine derivative condensation of a carboxylic acid derivative of Sankuguchiri de like (J. Med. Chem. 29, 2174-2183 (1986)) by the like reaction (J. Med the Okisazoru derivative is 2- haloketone derivative and amide derivative . Chem. 39, the 237-245 (1996)) or the like, condensation with Isookisazoru derivatives 1,3-ketone derivative with heat Dorokishiruamin (J. Med. Chem. 31, 1659-1664 (1988)) or double Toriruokishido 1,3-dipolar addition reaction between the derivative and the acetylene derivative (J. Med. Chem. 10, 411-418 (1967)) by the like, the reaction of a thiazole derivative is 2- haloketone derivative and Ji Oamido derivative (Gazz. Chim . Ital. 92, by 1084-1092 (1962)) or the like, imidazole induction Body imidate derivative, 2-reaction of hydroxy ketone derivative 及 Pi ammonia (J. Med. Chem. 43, 1071-1084 (2000)) can be produced by such.

Further, the present invention compounds in which one of R 2a or R 2b is a lower alkyl, the intermediate (IV), in (VI) or (VIII), or Compound (gamma), prepared by subjecting the Arukirui spoon reaction it can. The reaction conditions can the same conditions as above Arukiruihi apply.

The compounds of the present invention even when the ring Α is other than A ', the process substantially similar, can be prepared by obvious to those skilled in the art.

The reaction product obtained by each method is a free compound, isolated as a solvate of a salt thereof or hydrates soil various, it can be purified. Salts can be prepared by subjecting the usual salt formation process.

Isolation and purification, extraction, concentration, distillation, crystallization, filtration, recrystallization, can be carried out by applying various chromatographic I, First general chemical operations.

Various isomers can be isolated by conventional methods using a physical I 匕学 differences between the isomers. For example, optical isomers general optical resolution method such can be separated by fractional crystallization or chromatography. The optical isomers can also be prepared from an appropriate optically active starting I arsenide compound. Industrial Applicability

Compounds of the present invention are useful as an active ingredient of pharmaceutical preparations. In particular because, PARP involvement of having a PARP inhibitory activity, inflammatory diseases (e.g., rheumatoid Riumachi, ulcerative colitis, Crohn's disease, peritonitis, pleuritis, nephritis, etc.), autoimmune diseases (e.g., I-type diabetes etc.), diseases associated with ischemia-reflux disorders (e.g., useful stroke, myocardial infarction, as a prophylactic or 'Osamu / iota Ryoyaku organ transplantation, etc.).

Effect of compounds of the present invention had it occurred confirmed pharmacological test below.

1. Cell-free PARP inhibitory activity Measurement Test (in vitro)

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- It was reacted 25 ° C, 3 hours in a reaction solution containing the NAD and 0.06 Unit human recombinant type PARP.

2) The reaction was stopped by adding 100 mM nicotinamidine de to the reaction solution.

3) The reaction solution is reacted with 0.5 mg anti Mausu IgG antibody conjugated SPA beads Top count (trade name, and enzyme activity was measured by Packard).

4) IC 50 was calculated for each compound as ADP-ribose polymerization activity of the test compound that inhibits 50% concentration of PARP.

Example 1, 6 2, 7 2, 7 A compound according to 7 and 8 8, showed an IC50 of each 16, 23, 17, 16 and 8.3 nM.

2.-Producing cell lines PARP inhibitory activity Measurement Test (in vitro)

1) J774.1 cells (murine monocyte / macrophage cell line) was adjusted to 5 X 10 5 cells / ml in 25 mM HEPES and 10% fetal bovine serum-containing DMEM medium, of 37 ° C, 5% C0 2 They were cultured for 24 hours under the conditions.

2) Test compound 28 mM chloride force helium, 28 mM sodium chloride, 2 mM chloride mugs Neshiumu, adjusted to the desired concentration in 56 mM HEPES (pH 7.5) solution containing 0.01% digitonin及Pi 26 nM 3 H-NAD then, it was the reaction solution.

3) DMEM medium was replaced with the above reaction solution and incubated 15 minutes at 37 ° C, 5% C0 2 conditions.

4) After washing the cells with cold 5% trichloroacetic port acetate, 2% SDS, it was measured dissolved radioactivity by 0.1 M NaOH.

5) IC 50 was calculated for each compound as ADP-ribose polymerization activity of the test compound that inhibits 50% concentration of PARP.

Example 1, 6 2, 7 2, 7 7 A compound according to及Pi 8 8, respectively 8.2, 47, 5.1, showed 10及Pi 6.1 nM of IC 50.

3. Zaimozan-induced peritonitis (in vivo)

1) 6-8 Shureiyu. Of Balb / c mice (Nippon Chiya one Rusuriba I) were subjected to the experiment.

2) mice fasted from the evening the day before the test, was free drinking water.

3) Each test compound was suspended or dissolved in 0.5% methylcellulose.

4) Each test compound suspension is Les, the solution was orally administered in way 5 ml / kg to obtain a desired dosage to mice N the Balb. The negative and positive control group was administered 0.5% Mechiruse Norerosu a solvent at 5 ml / kg.

5) Zaimozan (Sigma) was suspended in a 0.5 mg / ml with saline, was administered intraperitoneally at oral administration and at the same time 1 ml / mouse of the compound. The negative control group was administered intraperitoneally with saline at 1 ml / mouse.

6) Zaimozan administered four hours after the abdominal cavity of each Mausu to 0.1% 5 ml of washing with heparin-containing physiological saline to recover the cells in the peritoneal cavity.

7) recovered the number of cells was measured by Celltak (trade name, Nihon Kohden).

8) ED30 was calculated for each compound the number of cells infiltrated into by connexion ip Zaimozan as a 30% inhibiting test I arsenide compound doses.

4. Collagen-induced arthritis (in vivo)

1) 3 mg / ml © shea type II collagen (Collagen Workshop) 8 ml of the same amount of FCA (Freund complete adjuvant H37 Ra, DIFCO Laboratories) were fully mixed, male DBA / 1 J mice (Nippon Chiya one Rusuriba one) were immunized by 100 1 to the ridge in the skin.

2) 21 days after, it was boosted in the same manner as described above.

3) additional immune date and day 0, to determine the arthritis score § of body weight you Yopi each 胺 at a rate of 2 times per week. Arthritis score was set as follows. That is, 0 is normal, 1 is redness and mild swelling, 2 moderate swelling, Mel in ankylosis severe swelling or joint portion 3.

4) Test compound As the solvent 0.5% methylcellulose, 1, 3, 10 and suspended at a concentration of 30 mg / 5 ml, and administered orally once daily at a dose of 5 ml / kg was continued until day 21 . Note the negative contact Yopi positive control group was administered with 0.5% methylcellulose which is a solvent at 5 ml / kg. '

5) Measurement results Time first reaction area under the curve with expressed as daily are changes (AUC: expressed as area under the curve). The steel test with respect arthritic score, is related to weight fluctuation p value after Dunnett's test was significant in the case of 0.05 or less.

From the above experiments, the present invention compounds have PARP inhibitory activity, it was confirmed to be useful as a preventive or therapeutic drug for diseases involving PARP.

The present invention compound (I) or one or a pharmaceutical composition containing two or more as the effective component of a pharmaceutically acceptable salt, pharmaceutical responsible body commonly used in the art, shaping etc. Yore typically can be by connexion prepared methods used Te agents. Administration tablets, pills, capsules, granules, powders, oral administration by solutions such or, intraarticular, intravenous, injections such as intramuscular, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches may be in any form of parenteral administration by inhalant or the like.

As the solid composition for oral administration according to the present invention, as needed use tablets, powders and granules. In such a solid composition, one or more active ingredients, one inert excipient even without low, such as lactose, mannitol, Pudou sugar, hydroxy sheet cellulose, microcrystalline cellulose, starch, poly Bulle pyrrolidone, magnesium main Takei aluminometasilicate. Composition, according to a conventional method, inertness additives, such as lubricants and carboxymethyl disintegrating agent such as methyl Star over Ji sodium and magnesium stearate, it may also contain solubilizing agents les. Tablets or pills may be coated with sugar or a gastric or enteric coating agent required.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, white-up agent, elixirs and the like, generally used inert solvent such as purified water, ethanol including. The composition solubilizers In addition to the inert solvents, wetting agents, adjuvants, sweetening agents, such as suspending agents, flavoring agents, perfuming agents and preserving agents.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions including. The aqueous solvent includes 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 the like Porisonore base one DOO 80 (trade name). Such composition may further contain tonicity agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, it may also include a solubilizing agent les. These through a bacteria retaining full Iruta such as filtration, it is sterilized by blending of a germicide or irradiation. They also be manufactured in the form of sterile solid compositions, it may be dissolved in sterile water or a sterile solvent for injection, suspended prior to use.

Transmucosal agents such as transnasal agent solid, liquid, semi-solid ones are used, it can be prepared according to conventional known methods. For example, a known pH adjusting agents, preservatives, 增粘 and excipients are added appropriate, molded solid, a liquid or semi-solid. Transnasal preparations usual spray instrument, nasal drops containers, tubes, is administered using a nasal 內揷 input tool like.

In oral administration, the daily dose is from about body weight per 0.001 to 100 mg / kg, rather preferably is suitably 0.1 to 10 mg / kg, a divided manner or in 2 to 4 times once when c intravenously administered Te, the daily dose is suitably from about 0.0001 per weight 10 mg / kg, is administered in once to several times a day. For intraarticular administration, the daily dose is from about 0.0001 to 10 mg / kg per body weight is suitably administered by dividing into one to several times per day. Also, a transmucosal agent is administered at a dose of about 0.001 to 100 1¾ / 1¾ per body weight once or more times a day. BEST MODE FOR CARRYING OUT THE c invention is appropriately determined depending on the case dose in consideration symptoms, age, sex and the like of each

Hereinafter, the present invention will be described more specifically based on examples. The present invention compounds are not limited to the compounds described in the following Examples. Further illustrating the production processes for the starting compounds in Reference Examples. Reference Example 1

1-tert-butoxide Kishikarubo two Rupipe lysine DMF (500 ml) solution of 2,3 Jiamino acid Echiruesuteru (29.3 g) - 4- carboxylic acid (40.0 g), WSC -HC1 (40.0 g) and HOBt ( 1.5 g) was added and stirred overnight at room temperature. The reaction mixture was concentrated, water was added and extracted with acetic acid Echiru. The organic layer was dried, the solvent was distilled off, crude 2-Amino - 3 - was obtained - [(4-carbonyl l-tert Butokishikaruboyu Rubiperijin) Amino] Echiruesuteru benzoic acid (56.9 g). The crude preparations were dissolved in acetic acid (600 ml), was stirred on heating for 1 hour at 120 ° C. The reaction solution was concentrated, toluene was added to the residue, and concentrated under reduced pressure. The residue was diluted with black port Holm, washed with 1M hydroxide Na Toriumu aqueous further extracted with black port Holm from the aqueous layer, silica and the residue obtained by concentrating the combined organic layers force gel force ram chromatography purification in one, Echiru 2- (l-tert- butoxycarbonyl two Rupipe lysine - 4-I le) was obtained -1H- benzo I Mi imidazole-4-Kishireto (27.5 g).

Reference Example 2

Echinore 2- (l-tert- butoxycarbonyl two Rubiperijin - 4-I le)-1H-benzo I Mi indazole _4- carboxylate (27.5 g) in ethanol (400 ml) was added 1M hydroxide Natoriumu solution (250 ml) the mixture was stirred for 3 hours at 50 ° C. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, the precipitated crystals were collected by filtration, washed with water, 2- (l-tert- butoxycarbonyl two Rubiperijin - 4-I le)-1H-benzo I Mi Dazo Honoré - 4 - give the carboxylic acid (23.3 g).

Reference Example 3

2- (l-tert- butoxycarbonyl two Rupipe lysine - 4 Inore) -1H- THF (300 ml) benzo I Mi imidazole-4-Cal Pont acid (23.2 g) suspension in CDI (16.2 g) the mixture was stirred at room temperature for 3 hours. The reaction solution THF (200 ml) of Anmoyua saturated, and the mixture was stirred overnight at room temperature. The reaction mixture was reduced pressure concentrated, water was added to the residue, followed by extraction with acetic acid Echiru. The organic layer was washed with saturated brine, dried, the solvent was distilled off, tert- heptyl 4- (4-force Rubamoiru - 1H-benzoimidazol-2 Inore) piperidine - 1- Karubokishire DOO (18.9 g) was obtained.

Reference Example 4

2- (l-tert- butoxycarbonyl two Rupipe lysine - 4 Inore)-1H-benzo I Mi imidazole-4-Cal Pokisamido (14.1 g) in under ice-cooling Torifuruoro acetate (50 ml) was added, at room temperature overnight and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, was collected by filtration is that solid obtained was added to the residue acetic acid Echiru 及 Pi I isopropyl ether, and washed with acetic acid Echiru and isopropyl ether, 2-Piperidin-4-I le - give 1H- benzo I Mi imidazole-4-Karubokisami de 2 Torifuruoro acid salt (15.1 g).

Reference compounds of Reference Examples 5-8 shown in the following Table 1 in the same manner as in Reference Example 1, Reference Example 9-1 2 compound in Reference Example 2 in the same like manner, in the same manner as in Reference Example 3 the compound of example 1 3-1 6, the compound of reference example 1 7-2 0 in the same manner as in reference example 4 were synthesized. The structure of Example 1-2 0 compounds shown in Table 1. In the table, the compounds of the physicochemical data is empty column indicates that was used in the next reaction without purification.

Example 1

2-piperidine - 4-I le -1H- benzo I Mi imidazole-4-force Rubokisami de 2 Torifuruoro acetate (710 mg), 4- (4-fluoro-phenoxyethanol) Puchiruburomido (310 mg), carbonate power Riu beam (1.4 g), the mixture was stirred at room temperature overnight potassium iodide (129 mg) and DMF (10 ml). Water was added to the reaction solution, followed by extraction with acetic acid Echiru. The extract was dried over anhydrous magnesium sulfate, and purified the residue obtained by distilling off the solvent by silica gel column chromatography (click every mouth Holm one methanol), 2- {l- [4- (4- Furuo Rofuenokishi) heptyl] was obtained piperidines lysine down 4 Inore)-1H-benzo I Mi indazole-carboxamide (519 mg). The resulting reduction compound (519 mg) was dissolved in ethanol, was added 4M hydrogen chloride / acetic acid Echiru solution (4 ml). The solvent was recrystallized (ethanol monohydrate) crystals produced was concentrated under reduced pressure, 2- {1- [4- (4-off Ruorofuenokishi) butyl] piperidine - 4-I le} -1Ita- Benzoimidazo Honoré - 4 carboxyl Sami de 'to give the dihydrochloride (200 mg) (colorless powder).

Example 2

2-piperidine - 4-I le -1H- benzo I Mi imidazole-4-Karubokisami de 2 Torifuruoro acetate (860 mg), Chiofen - 2- aldehyde (1.1 g), acetic acid (5 ml) and 1, 2 Jikuroroe Tan Π5 ιη1) mixture added Toriasetokishi sodium borohydride (1.10 g), and stirred for 2 days. The reaction solution saturated bicarbonate Natoriumu solution and 1M aqueous sodium hydroxide solution was added, and the mixture was extracted with black port Holm. The organic layer was dried over anhydrous magnesium sulfate, and purified the residue obtained by distilling off the solvent by silica gel column chromatography (black port Hol beam one methanol), 2- [1- (Chiofen - 2 Irumechiru) pin Bae lysine - to give 4-I le]-1H-benzo I Mi imidazole-4-carboxamide (95 mg). The obtained compound was dissolved in methanol was added fumaric acid (30 mg). The resulting crystals recrystallized (2-propanol) to give 2- [1- (thiophene-2-Irumechiru) piperidine - 4-I le]-1H-benzo I Mi imidazole-4-carboxamide \ 12 fumarate It was obtained salt (10 8 mg) (colorless powder).

Example 3

2- {1- [4- (2-benzyl-O carboxymethyl phenoxyethanol) heptyl] piperidine - 4-I le} -1Ita- Benzoimi Dazonore - 4- carboxamide (344 mg), methanol (15 ml) and 10% palladium the Ichisumi element (90 mg) the mixture under a hydrogen atmosphere and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was concentrated. The residue was purified by silica gel column chromatography (black port Holm Ichime methanol), 2- {1- [4- (2-hydroxycarboxylic phenoxyethanol) heptyl] piperidine - 4-I Honoré} -1Ita- benzoyl imidazole -4-carboxamide (254 mg). The obtained compound was dissolved in methanol and added 4M hydrogen chloride Z acetate Echiru solution (4 ml). The solvent was recrystallized (ethanol monohydrate) crystals produced was concentrated under reduced pressure, 2- {1- [4- (2-Hidorokishifuweno carboxymethyl) heptyl] piperidine - 4-I le} -1Ita- benzimidazole 4- force Rupokisami de 2 to give the hydrochloride salt (244 mg) (colorless powder). -

The compound of Example 4-1 0 6 shown in the following Table 2-6 in the same manner as in Example 1, the compound of Example 1 0 7 and 1 0 8 shown in the following Table 6 in the same manner as in Example 2 It was synthesized. Structures and physicochemical data of Example compounds are shown in Table 2-6.

Also shows the structure of another compound of the invention in Table 7-9. These methods will be obvious to a method and the skilled person according to the above production method and examples or by Rukoto Using these variants, it can be readily synthesized.

In the table, the abbreviations below are used. Rex: Reference Example number, Ex: Example number, Cmpd: compound number, Me: methyl, Et: Echiru, Pr: 1-propyl, iPr: 2-propyl, tBu: tert Buchinore, Boc: tBu-0- CO-, Ac: Asechinore, Ph: Hue - le, Bn: benzyl, cHex: Kishinore to consequent opening, Ad: Readamanchiru, INaph: 1 - naphthyl, 2Naph: 2- naphthyl, 2Thi: 2- thienyl, 3Thi: 3 - Choi - le, 2Py: 2-pyridyl, 3Py ': 3- pyridyl, 4Py: 4- pyridyl, Dat: physicochemical data (F: FAB-MS [( M + H) +]; EI: EI-MS (M +); ES: ESI -MS [(M + H) +]; NMR: δ in ifiNMR in DMSO-d 6 (ppm)) ; Sal: salt (blank: free form; HC1: hydrochloride; Fu: fumarate;. numbers indicate the percentage of the acid component, for example, 2HC1 the meaning dihydrochloride) are shown, respectively. Also, the number before the substituent indicates the substitution position, which numbers are a plurality represents a plurality of substitutions. For example, 2-OMe-Ph 2-main Tokishifue two / Les, 2,4-F 2 -Ph is 2,4-difluoro Fe - show Le.

table 1

Table 2

Table 4

Ex n -Y 3 -Z Sal Dat

74 4 one Ph 2HC1 F: 419

F: 439; NMR: 1.65-2.05 (thigh, m), 2.54 (2H, t, J = 6.4 Hz), 3.22-3.36 (3H, m), 4.16 (2H, t, J = 6.4 Hz), 6.93 ( IH, dt, J = 1.0, 7.3 Hz), 7.16 (IH, d, J = 8.3 Hz), 7.25

75 three to (2-CI-Ph) 1.9HC1 (IH, t, J = 7.8 Hz), 7.28 (IH, t, J = 8.3 Hz), 7.41 (IH, dd,

J = 1.0, 8.3 Hz), 7.60 (IH, d, J = 7.8 Hz), 7.65 (IH, brs), 7.79 (IH, d, J = 7.3 Hz), 9.34 (IH, brs), 12.63 (IH, brs)

6Z

S 挲 雕 oar / E :) d 890/0 OAV οε

9 挲

I LlO / ZOdT / lDd 890/0 OAV

t

CO

Claims

The scope of the claims
1 -. Benzimidazole derivatives or salts thereof represented by the general formula (I).
(I)
(Symbols in the formula have the following meanings.
R 1: lower alkyl, halogen, or a lower alkyl group substituted with a halogen, R 2a及Pi R 2b: H, lower alkyl or absent,
Dotted line: the presence or absence of a double bond in the ring,
A: nitrogen-containing heterocyclic ring saturated,
X: Okiso which may lower alkylene or a bond substituted with one,
Y 1 and Y 3: identical or different from each other, optionally substituted lower alk Killen in Okiso group, optionally substituted lower alkenylene optionally substituted with Okiso group, which may lower alkynylene or bond substituted with Okiso group ,
Y 2: 0, S, SO , S0 2 or a bond (provided that when Y 1 is methylene or a bond, Upsilon 2 is shows the binding),
Zeta: optionally substituted cycloalkyl, substituted to an optionally also good Ariru or substitution Hajime Tamaki (provided that heterocyclic group such via a carbon atom which is a ring atom Υ 3 binds to),
And伹, -Υ Υ 23 - group represented by the, -CO-0-, C 1-8 alkylene or optionally substituted with Okiso groups - For CO-0-C M alkylene, Z is to optionally substituted indicates heterocyclic group, and when the bond Y 1 and Y 2 are both, Y 3 represents a group other than binding. )
. 2 2- [1- (6-phenoxy into Kishinore) piperidin - 4-Inore]-1H-Benzoimidazo one Honoré - 4- force Honoré Bokisami de, 2- {1- [2- (4-fluoro-phenoxyethanol) Echiru] piperidine - 4-pray} -111- Ben Zoimidazoru 4 Karubokisami de, 2- {1- [4- (4-full O Mikhailov Enoki Shi) butyl] Piperi Jin - 4 I le} -1Η- benzoimidazol over Honoré - 4 Karubokisami de, 2- {1- [3- (3-phenylene Honoré -1,2.4- Okisajiazo one Honoré - 5 Inore) propyl] piperidine - 4-I le} - 1Η- Benzoimida Zonore - 4 Karubokisami de 及 Pi 2- {1- [2- (2-Fe two Ruokisazo Ichiru 4-I le) Echiru] peak Perijin - 4 I le} -1Ita- Benzoimidazo Honoré - benzo I Mi indazole derivative or a salt thereof according to claim 1, wherein is selected from the group consisting of 4-force Rubokisamido.
. Benzo I Mi Dazo Honoré derivative according to claim 1, wherein the or its pharmaceutically acceptable salts, pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
. The pharmaceutical compositions of the range 3 according claims a PARP P 且害 agent.
. Range 4 The pharmaceutical composition according to claim which is a prophylactic or therapeutic agent for inflammatory diseases.
. Medicament range 5 according claims which is a prophylactic or therapeutic agent for rheumatoid Riumachi, 袓成 thereof.
PCT/JP2002/001741 2001-02-28 2002-02-26 Benzimidazole compound WO2002068407A1 (en)

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WO2003062234A1 (en) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Quinoxaline compounds
WO2004048363A1 (en) * 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited Imidazole derivative, process for producing the same, and use
JP2004182730A (en) * 2002-11-22 2004-07-02 Takeda Chem Ind Ltd Imidazole derivative, its manufacturing method and use
WO2006110683A1 (en) * 2005-04-11 2006-10-19 Abbott Laboratories 2-substituted-1h-benzimidazole-4-carboxamides are parp inhibitors
US7151102B2 (en) 2000-10-30 2006-12-19 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7449464B2 (en) 2003-03-12 2008-11-11 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US7462724B2 (en) 2005-11-15 2008-12-09 Abbott Laboratories Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US7470688B2 (en) 2005-10-19 2008-12-30 Maybridge Limited Phthalazinone derivatives
WO2009029375A1 (en) * 2007-08-27 2009-03-05 Lead Therapeutics, Inc. Novel inhibitors of poly(adp-ribose)polymerase (parp)
US7550603B2 (en) 2005-04-11 2009-06-23 Abbott Laboratories Inc. 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US7692006B2 (en) 2006-10-17 2010-04-06 Kudos Pharmaceuticals Limited Phthalazinone derivatives
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WO2011058367A2 (en) 2009-11-13 2011-05-19 Astrazeneca Ab Diagnostic test for predicting responsiveness to treatment with poly(adp-ribose) polymerase (parp) inhibitor
EP2336120A1 (en) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinations containing amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors
US7981890B2 (en) 2007-09-14 2011-07-19 Astrazeneca Ab Phthalazinone derivatives
JP2011521214A (en) * 2008-05-16 2011-07-21 セルゾーム アーゲー The method for the purification of identification and parp proteins Parp interacting molecules
US7999117B2 (en) 2006-05-02 2011-08-16 Abbott Lab Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
US8067613B2 (en) 2007-07-16 2011-11-29 Abbott Laboratories Benzimidazole poly(ADP ribose)polymerase inhibitors
US8093396B2 (en) 2009-01-19 2012-01-10 Abbott Laboratories Benzthiazole inhibitors of poly(ADP-ribose)polymerase
US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
JP2012532908A (en) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ 3-oxo-2,3-dihydro -1h- isoindole-4-carboxamide having selective parp-1 inhibition
JP2012532907A (en) * 2009-07-14 2012-12-20 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Parp inhibitor as the 3-oxo-2,3-dihydro -1h- isoindole-4-carboxamide
US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
US8475842B2 (en) 2008-10-07 2013-07-02 Astrazeneca Ab Immediate release pharmaceutical formulation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one
US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
CN104860919A (en) * 2015-03-26 2015-08-26 天津药物研究院有限公司 Piperidine-containing benzimidazole derivative, preparation method and uses thereof
WO2018197461A1 (en) 2017-04-28 2018-11-01 Akribes Biomedical Gmbh A parp inhibitor in combination with a glucocorticoid and/or ascorbic acid and/or a protein growth factor for the treatment of impaired wound healing

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WO2003062234A1 (en) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Quinoxaline compounds
US7196085B2 (en) 2002-04-30 2007-03-27 Kudos Pharmaceuticals Limited Phthalazinone derivatives
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US7745623B2 (en) 2004-05-21 2010-06-29 Takeda Pharmaceutical Company Limited Cyclic amide derivative, and its production and use
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US7728026B2 (en) 2005-04-11 2010-06-01 Abbott Laboratories, Inc. 2-substituted-1 h-benzimidazile-4-carboxamides are PARP inhibitors
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US7595406B2 (en) 2005-11-15 2009-09-29 Abbott Laboratories Inc. Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
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US7999117B2 (en) 2006-05-02 2011-08-16 Abbott Lab Substituted 1H-benzimidazole-4-carboxamides are potent PARP inhibitors
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US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
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