WO2002068407A1 - Benzimidazole compound - Google Patents

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

 Description Benzimidazole compounds Technical field

 The present invention relates to medicaments, particularly to benzimidazole derivatives useful as PARP inhibitors. Background art

 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) infiltration of monocytes, (2) proliferation of synovial cells, and (3) consequent tissue rupture (N. Engl. J. Med., 322, 1277). -1289 (1990)). Therefore, the purpose of pharmacotherapy is to maintain joint function and prevent bone fractures observed by X-rays.

Poly (ADP-ribose) polymerase (PARP) is a 113 kDa nuclear enzyme. The two Zn fingers at the N-terminus of PARP.The motif recognizes DNA strand damage and places nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) on various nuclear proteins, including histones and DNA topoisomerases I and II. It is known to control the polymerization of the ADP-ribose moiety of dinucleotide (NAD). Therefore, it is thought that excessive activation of PARP depletes intracellular NAD and ATP contents and leads to cell death (J. Clin. Invest, 77, 1312-1330 (1986)). It is widely known that in various inflammatory diseases, NO, active oxygen, or their reaction product, peroxynitrite, is a potent mediator causing tissue damage. This tissue damage is thought to be the result of PARP recognizing and activating the DNA strand damage caused by NO, active oxygen, and peroxynitrite, leading to 'energy depletion' ( Proc. Natl. Acad. Sci. USA 93 1753-1758 (1996)). It has also been clarified that inhibition of PARP activation strongly suppresses cell invasion during inflammation (J. Exp. Med., 186, 1041-1049 (1997), Immunology, 93, 96). -101 (1998)).

 In RA patients, synovial fluid cells have an increased ability to produce active oxygen (Z. Rheumatol., 46, 227-232 (1987)), and the amount of NCV ions in synovial fluid and serum is markedly increased. (Ann. Rheum. Dis., 51, 1219-1222 (1992)), increased DNA strand damage in peripheral mononuclear cells (Aim. Rheum. Dis, 51, 8-12 (1992)) ) And the fact that the NAD content was reduced (Int. J. Clin. Parm. Res., 14, 57-63 (1994)). It is thought that as a result, cell invasion and tissue destruction are caused.

 Therefore, PARP inhibitors are considered to be useful as therapeutic agents for inflammatory diseases such as RA. However, no clinically effective PARP inhibitor has been found, and the development of a novel PARP inhibitor having excellent inhibitory activity is eagerly desired.

 WO 00/32579 discloses a PAR inhibitor having an unsubstituted carpamoyl group at the 4-position of a benzimidazole and a nitrogen-containing saturated heterocycle at the 2-position, as shown in the following formula.

(Wherein, A represents a 4- to 8-membered saturated or monoethenoid heterocycle having substituents R ² and R ³ and containing one or two 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 an optionally substituted phenol (R ²¹ represents C _3-7 cycloalkyl or phenyl, etc.); R ³ is H; even if it is substituted with a phenyl group, A good branched or straight-chain C _1-8 alkyl, etc. NR ²⁶ R ²⁷ in R ² may form a 3- to 8-membered hetero ring, and the hetero ring is C _w It may be substituted by alkyl or C _1-4 alkyl-phenyl.

The ehich compound has a nitrogen-containing saturated hetero ring at the 2-position, and the hetero ring can be further bonded to another ring via a bond. In this case, the bond is an oxo group. it may also be substituted Rere C _1-8 alkylene, CO-iNH) (u, C0 2 or a bond. Further to bind to their bond The ring is (1) a C _1-8 alkylene which may be substituted with an oxo group, a 3- to 8-membered nitrogen-containing hetero ring bonded with N, (2) a C _1-4 alkylene, CO- CNH; ^ or in the case of C0 _2, full Eniru or C _3-7 cycloalkyl, (3) C _5-8 when alkylene or a bond, are limited respectively phenyl, and. Disclosure of the invention

 The present inventors have conducted intensive studies on compounds that inhibit PARP.As a result, the benzimidazole has an unsubstituted rubamoyl group at the 4-position and a nitrogen-containing saturated hetero ring at the 2-position. A benzimidazole derivative in which one or more ring groups are further bonded to a terrorist ring via a specific bond has been found to have good PARP inhibitory activity, especially when administered orally. Furthermore, they have found that they are useful as agents for preventing, treating or diagnosing diseases involving PARP, and completed the present invention.

 That is, according to the present invention, a benzimidazole derivative represented by the following general formula (I) (hereinafter, referred to as “the compound (I)” of the present invention) or a pharmaceutically acceptable salt thereof, There is provided a drug, particularly a PARP inhibitor, containing one or more species as active ingredients.

 (The symbols in the formula have the following meanings.

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

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

A: nitrogen-containing saturated heterocycle,

 X: lower alkylene or a bond optionally substituted with an oxo group,

Y ¹ and Y ³ : the same or different, and a lower alkylene optionally substituted with an oxo group, a lower alkenylene optionally substituted with an oxo group, a lower alkynylene optionally substituted with an oxo group, or Join, ^{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),

ζ: cycloalkyl which may be substituted, aryl which may be substituted or heterocyclic group which may be substituted (provided that the heterocyclic group is bonded via a carbon atom which is a ring atom. ³ ),

場合, when the group represented by -Υ ^-^ Υ ³ -is -CO-0-, C _1-8 alkylene or -CO-0-C _1-4 alkylene which may be substituted by an oxo group And Z represent a heterocyclic group which may be substituted, and when Y ¹ and Y ² are both a bond, Y ³ represents a group other than a bond. The same shall apply hereinafter. )

The dotted line in the formula (I) indicates that the benzimidazole ring has one of the following structures in combination with R ^2a and R ^2b .

 Hereinafter, the present invention will be described in detail.

In the present specification, “alkyl”, “alkylene”, “alkenylene” and “alkynylene” mean a straight or branched hydrocarbon chain, and “lower alkyl” is, for example, 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, c _1-6 alkylene, preferably c _2-4 alkylene, and more preferably ethylene and butylene. “Lower alkenylene” means having one or more double bonds at any position of, for example, C _2-6 alkyl, and “lower alkynylene” means, for example, any of the C _2-6 alkyl chain. It means having one or more triple bonds at the position.

“Halogen” refers to F, Cl, Br and I, preferably F, C1 and Br. The term "lower alkyl substituted with halogen" means, for example, C _1-6 alkyl substituted with one or more halogen, preferably C _1-6 alkyl substituted with one or more F. Yes-more preferred are fluoromethyl, difluoromethyl, trifluoromethyl and trifluoroethyl. The “cycloalkyl group” is preferably a cycloalkyl group having 3 to 14 carbon atoms, and may be crosslinked. More preferred are pentyl, neck hexyl, neck heptyl and adamantyl groups.

 The “aryl group” is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms. More preferred are phenyl and naphthyl groups, and still more preferred are phenyl groups. Further, a 5- to 8-membered cycloalkyl ring may be condensed to the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.

The term "heterocyclic group" refers to a 5- to 8-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N as ring atoms. Any carbon atom that is a ring atom may be substituted with an oxo group, and S or N may be oxidized to form an oxoxide dioxide. The heterocyclic group may be cross-linked or may form a spiro ring (including an acetal derivative such as a 1,3-dioxolane ring derived from an oxo group). Also, a cycloalkyl ring or a benzene ring may be condensed. Preferably, pyridinole, pyridazinol, pyrimidininole, pyrazinyl, furyl, cheninole, pyrrolyl, oxazolyl, isoxazolinole, oxadizazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, benzozolyl, benzozolyl, benzozolyl, benzozolyl, benzozolyl Benzimidazolinole, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, homopiperazyl, tetrahydrodolofranil, tetrahydrodoloniloma .1] Octane-3-yl, 9-azabicyclo [3.3.1] Nonane-3-yl, 3-azabicyclo [3.2.1] octane- 6-yl, 7-azabicyclo [2.2.1] heptane-2-yl, 2-azatricyclo [3.3.1.1 ³ ' ⁷ ] decane-4-yl, 1-azabicyclo [2.2.2] octane-2 -Yl, 1-azabicyclo [2.2.2] octane-3-yl, 1-azabicyclo [2.2.2] octane-4-yl, 3-azaspi mouth [5.5] indecane-9-yl, 2 -Azaspiro [4.5] decane-8-yl, 2-azaspiro [4.4] nonan-7-yl and 8-azaspiro [4.5] decane-2-yl groups. More preferred are a pyridyl, pyridazinyl, furyl, chenyl, oxazolyl, isoxazolyl, oxaziazolyl, thiazolyl and benzozoenyl group.

“Nitrogen-containing saturated heterocyclic group” has at least one N as a ring atom, Further, it is a 5- to 8-membered saturated heterocyclic group which may have one O or S, and any carbon atom which is a ring atom may be substituted with an oxo group, and S or N is oxidized. The oxide may form a dioxide. The heterocyclic group may be cross-linked or may form a spiro ring (including an acetal derivative such as a 1,3-dioxolane ring derived from an oxo group). Preferably, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinole, homopiperazinyl, 8-azabicyclo [3.2.1] octane-3-yl, 9-azabicyclo [3.3.1] nonane-3-y 3-azabisic mouth [3.2.1] octane-6-yl, 7-azabicyclo [2.2.1] heptane-2-yl, 2-azatrisic mouth [3.3.1.13,7] decane-4-yl , 1-azabicyclo [2.2.2] octane-2-yl, 1-azabisik mouth [2.2.2] octane-3-yl, 1-azabicyclo [2.2.2] otatan-4-yl, 3-azaspiro [5.5] decane-9-yl, 2-azaspiro [4.5] decane-8-yl, 2-azaspiro [4.4] nonane-7-yl and 8-azaspiro [4.5] decane-2-yl And more preferably a pyrrolidinyl, piperidyl and 8-azabicyclo [3.2.1] octan-3-yl group.

“Heterocyclic group bonded to Y ³ via a carbon atom that is a ring atom” refers to a group represented by an adjacent linker represented by —YLY ^ Y ³ — (for example, when Y ² and Y ³ are both In the case of a bond, it represents a heterocyclic group in which the ring atom bonded to Y ¹ ) is a carbon atom. For example, it does not include 1-piperidyl, but does include 2-, 3- or 4-piperidyl.

Examples of the substituent in the “optionally substituted cycloalkyl”, the “optionally substituted aryl” or the “optionally substituted heterocyclic group” include those rings in a drug, particularly a PARP inhibitor. Is a substituent that can be used as a substituent of the above, and may have 1 to 5 of these substituents. As the substituent, a C _{1-2 ()} hydrocarbon group, halogen, C _1-6 alkyl substituted with halogen, OH, 0—C _1-2 Q hydrocarbon group, SH, S-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 alkyl, CON CM alkyl) ₂ , NHCO—C _1-6 alkynole, NHCO ₂ — C _1-6 alkyl, NHCONH—C _1-6 alkynole, 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, Cycloanorequinore, Arinore, Anorekilen-cycloanolequinole, Alkenylene-cycloalkyl, Alkynylene-cycloalkyl, Alkylene-ary And alkenylene-aryl, alkynylene-aryl and the like. The hydrocarbon group and the heterocyclic group may further have a substituent, and the substituent is preferably C _1-6 alkyl, halogen, OH, 0—C _1-6 alkynole, SH, S—. C _1-6 alkyl, SO-C, _-6 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 may have one to four the substituents). 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-aryl, 0—C _1-6 alkylene-cycloalkyl, 0—C _1-6 alkylene-aryl, S—C _1-6 alkyl, S-cycloalkyl, S—aryl, S—C _1-6 alkylene-cycloalkyl, S—C _1-6 alkylene-aryl, CO—C _1-6 alkyl, CO—cycloalkyl, CO—aryl, CO—C _{1- 6} alkylene-cycloalkyl, CO—C _1-6 alkylene-aryl, heterocyclic group, C0 ₂ H, C00_C _1-6 alkyl, C0NH ₂ , CONH—C _1-6 alkyl, C0N (C _1-6 alkyl) _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 , may have 1 to 4 groups selected from the group consisting of CN and NO ₂ groups)). More preferably, C _1-6 alkyl, cycloalkyl, aryl, C _1-6 alkylene-aryl, halogen, C _1-6 alkyl substituted with halogen, 0H, 0-C _1-6 alkyl, 0-aryl, 0—C _1-6 alkylene-aryl, S—C _1-6 alkylene, S—aryl, S—C _1-6 alkylene-aryl, CO—C _1-6 alkyl, CO—aryl, 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 , CN and N0 ₂ You may have four).

Preferred compounds in 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 a C _1-6 alkylene or a bond, Z is an optionally substituted cycloalkyl, an optionally substituted aryl or a substituted heterocyclic compound. . More preferably, it is a compound of an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, and further preferably, X and Y ³ are a bond. More preferably, (1) a compound in which 丫² is 0 or 8, and Z is optionally substituted, and (2) a compound in which Y ² is bonded and Z is substituted It is a compound of a good aromatic heterocyclic group. Still more preferably, 2- [1- (substituted) piperidin-4-inole] -1H-benzoimidazole-4-carboxamide compound, wherein -X and -Ψ- are groups selected from the following group G: It is.

 Group G: 2-phenoxyshetinole, 3-phenoxypropyl, 4-phenoxybutyl, 6-phenoxyhexyl, 2- (2-fluorophenoxy) ethyl, 3- (2-phenolelophenol) B) propyl, 4- (2-fluorophenoxy) butyl, 2- (3-fluorophenoxy) ethyl,

3- (3-fluorophenoxy) propyl, 4- (3-fluorophenoxy) butyl, 2- (4-fluorophenoxy) ethyl, 3- (4-fluorophenoxy) propyl, 4- (4-fluorophenyl) Noxy) butyl, 2- (2-chlorophenoxy) ethyl, 3- (2-chlorophenoxy) propynole, 4- (2-chlorophenoxy) butyl, 3- (3-chlorophenoxy) propyl, 3 -(4-chlorophenoxy) propyl, 3- (2-bromophenoxy) propyl pill, 3- (3-bromophenoxy) propyl, 3- (4-bromophenoxy) propyl, 3- (2-trifluorophenoxy) propyl (Methylphenoxy) propyl, 3- (3-trifluoromethylphenoxy) propyl, 3- (4-trifluoromethylphenoxy) propyl, 3- (2-cyanophenoxy) propyl, 3- (3-cyanophen)

'' Enoxy) propyl, 3- (4-cyanophenoxy) propyl, 3- (2-nitrophenoxy) propyl pill, 3- (3-ditrophenoxy) propyl, 3- (4-nitrophenoxy) propyl,

2- (2,4-difluorophenoxy) ethyl, 3- (2,4-difluorophenoxy) propyl,

4- (2,4-difluorophenoxy) butyl, 3- (2,3-difluorophenoxy) propyl,

3- (2,5-difluorophenoxypropyl, 3- (2,6-difluorophenoxy) propyl, 3- (3,4-difluorophenoxy) propyl, 3- (3,5-difluorophenoxy) propyl, 3- (2,3-dichlorophenoxy) propyl, 3- (2,4-dichloro Phenoxy) propyl, 3- (2,5-dichlorophenoxy) propyl, 3- (2,6-dichlorophenoxy) propyl,

3- (3,4-dichlorophenoxy) propyl, 3- (3,5-dichlorophenoxy) propyl,

4- (naphthalene-1-yloxy) butyl, 4- (naphthalen-2-yloxy) butyl, 2-phenylthioethyl, 3-phenylthiopropyl, 4-phenylthiobutyl, 2- (3-phenyl-1, 2,4-oxaziazol-5-yl) ethyl, 3- (3-phenyl-1,2,4-oxaziazo-mono-5-yl) propyl, 4- (3-phenyl-1,2,4- Oxaziazol-5-yl) butyl,

2- (5-phenyl-1,2,4-oxaziazol-3-yl) ethyl, 3- (5phenyl-1,2,4-oxaziazolone-3-yl) propyl, 4- (5 -Phenyl -1,2,4-oxaziazol-3-yl) butyl, 3- [3- (2-octaphenyl) -1,2,4-oxaziazolinole-5-yl ] Propyl, 3- [3- (3-fluorophenyl) -1,2,4-oxaziazol-5-yl] propyl, 2- (2-phenyloxazonole-4-yl) ethyl, 3- ( 2-phenyloxazole-4-yl) propyl, 4- (2-phenylazozinole-4-yl) butyl, 2- (2-phenylthiazol-4-yl) ethyl ,

3- (2-phenylthiazolone-4-ynole) propyl, 4- (2-phenylthiazole-4-ynole) butyl, 2- (3-phenylisoxazole-5-yl) ethyl, 3- ( 3-phenylisoxazole-5-inole) propyl, 4- (3-phenylisoxazole-5-yl) butyl, 2- (5-phenylthiophen-2-yl) ethyl, 3- (5- Phenylthiophen-2-yl) propyl, 4- (5-phenylthiophen-2-yl) butyl, 2- (5-phenylisoxazol-3-yl) ethyl, 3- (5 -Phenylisoxazole-3-yl) propyl, 4- (5-phenylisoxazol_3-yl) butyl and {3- [5- (4-chlorophenyl) furan-2-yl] propyl group.

Among the compounds of the present invention, particularly preferred compounds are 2- [1- (6-phenoxyhexyl) piperidin-4-yl] -1H-benzimidazole-4-carboxamide, 2- {1- [ 2- (4-Fluorophenoxy) ethyl] piperidin-4-yl} -1 ベ ン ゾ -benzoimidazo-mono--4-propanolamide, 2- {1- [4- (4-funolelophenoxy) butyl] pi {Lysin-4-yl} -1} -benzimidazonole-4-carboxamide, 2- {1- [3- (3-phenyl-1,2,4-oxaziazol-5-yl) propyl] Piperidine-4-ino-W-1H-benzimidazole-4-carboxamide and 2- {1- [2- (2-phenyl-oxazole-4-yl) ethyl] piperidine-4-inole}- 111-Benzimidazole-4-potassium lipoxamide. The compound (I) of the present invention may have a geometrical isomer or a tautomer depending on the kind of the substituent, and the present invention also includes a separated form or a mixture of these isomers. The compound (I) 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 14 optical isomers and isolated ones. The present invention also includes a compound obtained by labeling the compound (I) of the present invention with a radioisotope.

In the compound (I) of the present invention, compounds in which one of R ^{2a and} R ^2b is H are in equilibrium with each other. In the present specification, the notation of a structural formula, a compound name, or the like is described using only one of them, but the present invention includes compounds in such an equilibrium relationship.

 The compound (I) 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 the strong salt is a pharmaceutically acceptable salt. You. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleene Acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and other organic acids and acid addition salts, sodium, potassium, magnesium, calcium, aluminum and other inorganic acids Bases, salts with organic bases such as methylamine, ethynoleamine, ethanolanolamine, lysine, and onolenitine, and ammonium salts, etc. Further, the present invention provides the compound (I) of the present invention and pharmaceutically acceptable salts thereof. Various hydrates and solvates of salts and polymorphic substances are also included.

The compounds of the present invention also include pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug is a conjugate having a group that is converted to NH ₂ , OH, CO ₂ H or the like of the present invention by solvolysis or under physiological conditions. Prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. Can be

(Manufacturing method)

The compound (I) 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 type of the substituent. Can be. At that time, depending on the type of the functional group, it is necessary to protect the functional group with an appropriate protecting group at the stage of raw materials or intermediates, or to replace it with a group that can be easily transferred to the functional group. May be effective. Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups include, for example, "Protective Groups in Organic Synthesis (Third Edition, TW Greene) and PGM Wuts (Third Edition, 1999)], and these may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group or converting it to a desired group, if necessary.

 Further, the prodrug of the compound (I) of the present invention can be produced by introducing a specific group at the stage of a raw material or an intermediate, or performing a reaction using the obtained compound (I) of the present invention, similarly to the above-mentioned protective group. . The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.

Hereinafter, a typical production method of the compound (I) of the present invention will be described. The compound (Γ) of the present invention in which one of R ^2a or R ^2b is H can be produced 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 of C0 ₂ H and alkyl groups P ² represents a protecting group for H or an amino group, and A ′ represents a group having a ring atom N at the position where A is bonded to Y ¹ . The same applies hereinafter. )

A. First production method: Alky-Dai

 The present production method is a method for obtaining the compound (I ′) of the present invention by subjecting the starting compound (Π) to an alkylation reaction. Examples of the leaving group represented by L include halogen atoms such as Cl, Br, and I; alkylsulfonyloxy groups such as methanesulfonyloxy group and ethanesulfonyloxy group; benzenesnolephoninoleoxy group; and toluene (particularly, P-toluene). Examples include organic sulfonic acid residues such as arylsulfonyloxy groups such as sulfonyloxy groups.

 Reactions include aromatic hydrocarbons such as benzene and toluene, ethers such as dimethyl ether, tetrahydrofuran (THF), and dioxane; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; methanol, ethanol, and the like. In a solvent inert to the reaction of alcohols, Ν, Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc., equimolar amounts of compound (Π) and compound (III) or an excess amount of one of them is used. The reaction is performed under cooling at a temperature of 178 ° C to 0 ° C, under cooling to room temperature, at room temperature, or in some cases at room temperature to heating. In addition, sodium hydride, potassium hydride, lithium disopyl pyramide, lithium hexamethyldisilazide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, carbon dioxide It is preferable to carry out the reaction in the presence of a base such as lime.

 The compound (III) of the present invention can also be produced by a reductive alkylidation reaction. In this case, instead of the starting compound (ΙΠ), the corresponding carbonyl disulfide is used, and the conventional method of reductive alkylation is used (for example, “The Experimental Chemistry Course (Maruzen)” edited by The Chemical Society of Japan (4th edition) , Vol. 20, 1992, 300)).

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), diisopropylpropylcarbodiimide (DIPC) ヽ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), Ι, Γ-carbonylbis-1H-imidazole (CDI), etc. ), And in some cases, further additives (for example, ヒ ド ロ キ シ -hydroxysuccinimide (HONSu), 1-hydroxy Nzotriazole (HOBt)) in the presence of ammonia. When ^Ra is a carboxylic acid ester, it can be produced by reacting with ammonia in a solvent inert to a reaction such as water, alcohols, DMF, THF or the like, or at room temperature or under heating, and optionally under pressure, in a solvent without solvent. When ^Ra is CN, it can be produced directly to the CON group by hydrolysis or via CO ₂ H. These reactions can be applied to a method for producing another compound, and a compound in which ^Ra is CONH ₂ can be produced in the same manner.

B. Second production method: amidation and cyclization

 In this production method, the starting compounds (IV) and (VII) are subjected to an amidation reaction to obtain an intermediate (VIII), and the obtained compound (VIII) is subjected to a cyclization reaction to obtain the present compound (Γ) Is the way. The compound of the present invention (III) can also be obtained without isolating the intermediate (VIII) and subjecting it to the cyclization reaction conditions after the amidation reaction.

 (1) Ami Doi

 The reaction is carried out in a solvent inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, etc., a condensing agent such as DCC, DIPC, WSC, CDI, etc., and optionally HONSu, HOBt Compound (IV) and Compound (VII) are used in an equimolar amount or an excess amount in the presence of an additive, etc., under cooling at 178 ° C to 0 ° C, under cooling to room temperature, The reaction is performed at room temperature or, in some cases, at room temperature or under heating. Reacting in the presence of bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline and lutidine makes the reaction In some cases, it may be necessary to make progress smoothly.

 Alternatively, various reactive derivatives may be used in place of the starting compound (VII). Examples of the reactive derivative include: acid anhydrides; ordinary esters such as carboxylic acid methyl ester and ethyl ester; acid chlorides, acid halides of acid promide; acid azides; phenolic compounds such as P-ditrophenol, HONSu, HOBt and the like. Ester obtained by reacting with N-hydroxyl compound of organic acid; organic acid-based mixed acid anhydride or salt obtained by reacting with halocarbonic acid alkyl ester such as alkyl carbonate halide or Viva ethyl halide; A mixed acid anhydride such as a phosphoric acid mixed acid anhydride obtained by reacting phosphoryl can be used.

(2) Cyclization The reaction is carried out in an organic solvent inert to the reaction of aromatic hydrocarbons, halogenated hydrocarbons, ethers, etc., or in the absence of a solvent, using a catalytic amount or a solvent amount of acid, at a temperature of 78 ° C to 0 ° C The reaction is carried out under cooling, under cooling to room temperature, at room temperature, or in some cases at room temperature to 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. C Production of raw material compounds

Compound (II) can be produced from compound (IV) and (V) by subjecting it to the same conditions as in the above amidation and cyclization reaction. Compound (VII) can be produced from compounds (IX) and (III) under the same conditions as in the above alkylidation reaction. Compound (IV) can be produced by the method described in US5380719 and the like. Many compounds such as isisonipecotic acid are commercially available as compounds (V) and (IX), or readily available compounds can be easily produced by applying a known reaction. Alternatively, the compound (ΧΙΠ) in which X is C _1-6 alkylene in (IX) can also be produced by the following method. Reduction P ¹ OOC _R ^B

 ~~>

(XIII)

(In the formula, R ^b is -A'-P ² or C _1-4 alkylene-A'-P ² , R ^c is H or C _1-4 alkyl, or a carbon atom to which R ^b and R ^e are bonded. Together, they represent -A'-P ^2. R ^d represents a group generally usable for the reaction, such as a C _1-4 alkyl group.

That is, it can be produced by olefination by a Wittig-like reaction such as the Horner-Emmons reaction and then catalytic reduction in the presence of palladium carbon or the like. Alternatively, commercially available toguchi pinone (XlVa) or a method similar to that described in L.-F.Tietze, T. Eicher, translated by Seiichi Takano and Kunio Ogasawara, Nanedo, 487-489) (XIVe), (XlVf) and (XlVg) corresponding to compound (V) or (IX) can be produced using the compound produced by the above as a raw material.

For the cyanation reaction, it is preferable to use tosylmethyl isocyanide (TosMIC) or the like, and specific examples include the method described in Synthetic Communication 25 (6), 787-793 (1995). Others are produced by reactions known to those skilled in the art.

Compound (III) can be easily prepared from commercially available compounds or commercially available compounds. The leaving group for L can be easily produced from an OH group or a CO ₂ H group by an ordinary method. 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. Compounds having various substituents on the ring group Z can be easily produced by a known method. As a heterocyclic ring having a substituent, for example, a 1,2,4-oxadiazole derivative is an N-hydroxyamidine derivative Oxazole derivatives react with 2-haloketone derivatives and amide derivatives by condensation of oxazoles with carboxylic acid derivatives such as acid oxalates (J. Med. Chem. 29, 2174-2183 (1986)). Chem. 39, 237-245 (1996)), isoxazole derivatives can be condensed with 1,3-diketone derivatives and hydroxylamine (J. Med. Chem. 31, 1659-1664 (1988)) or nitritoloxide. Thiazole derivatives can be converted to 2-haloketone derivatives and thioamide derivatives (Gazz. Chim.) By the 1,3-dipole addition reaction of acetylene derivatives with acetylene derivatives (J. Med. Chem. 10, 411-418 (1967)). Ital. 92, 1084-1092 (1962)) The compound can be produced by a reaction of an imidate derivative, a 2-hydroxyketone derivative and ammonia (J. Med. Chem. 43, 1071-1084 (2000)) or the like.

Further, the compound of the present invention wherein one of R ^2a or R ^2b is lower alkyl is produced by subjecting the above intermediate (IV), (VI) or (VIII) or the compound of the present invention (Γ) to an alkylidation reaction. it can. As the reaction conditions, the same conditions as in the above-described alkyl can be applied.

In addition, the compound of the present invention has a substantially similar manner to the above-mentioned production method even when the ring is other than A ′, It can be produced by a method obvious to those skilled in the art.

 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 physical differences between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. The optical isomer can also be produced from a suitable optically active raw material mixture. Industrial applicability

 The compounds of the present invention are useful as active ingredients in pharmaceutical preparations. In particular, it has PARP inhibitory activity, and therefore, PARP-related inflammatory diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.), autoimmune diseases (eg, type I diabetes) Etc.), Prevention of diseases associated with ischemia reperfusion disorder (eg, stroke, myocardial infarction, organ transplantation, etc.) · It is useful as a therapeutic drug.

 The effects of the compound of the present invention were confirmed by the following pharmacological tests.

 1. Cell-free PARP inhibitory activity assay (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- The reaction was carried out at 25 ° C for 3 hours in a reaction solution containing NAD and 0.06 unit human recombinant PARP.

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

3) The reaction solution was reacted with 0.5 mg of anti- mouse IgG antibody-bound SPA beads, and the enzyme activity was measured by Top count (trade name, Packard).

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

The compounds described in Examples 1, 62, 72, 77 and 88 are 16, 23, 17, IC50s of 16 and 8.3 nM were shown.

 2. Live cell line PARP inhibitory activity assay (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 The cells were cultured under the conditions for 24 hours.

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 Thus, a reaction solution was obtained.

3) The DMEM medium was replaced with the above reaction solution, and the cells were cultured at 37 ° C. and 5% CO ₂ for 15 minutes.

4) After washing the cells with cold 5% trichloroacetic acid, the cells were lysed with 2% SDS and 0.1 M NaOH and the radioactivity was measured.

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

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. Zymosan-induced peritonitis (in vivo)

 1) Male and female Balb / c mice (Nippon-charlsriver) were used for the experiment.

 2) The mice were fasted and had free access to water from the evening before the test.

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

 4) Each test compound suspension was orally administered to the above-mentioned Balb mouse at 5 ml / kg to a desired dose. To the negative and positive control groups, a solvent, 0.5% methyl senorellose, was administered at 5 ml / kg.

 5) Zymosan (Sigma) was suspended in physiological saline to a concentration of 0.5 mg / ml, and the compound was orally administered and intraperitoneally at 1 ml / mouse. To the negative control group, physiological saline was intraperitoneally administered at 1 ml / mouse.

 6) Four hours after the administration of Zymozan, the peritoneal cavity of each mouse was washed with 5 ml of saline containing 0.1% heparin to collect cells in the peritoneal cavity.

 7) The number of collected cells was measured with Celltak (trade name, Nihon Kohden).

8) ED30 is a test compound that inhibits the number of cells infiltrated into the abdominal cavity by 30% by Zymosan The dose was calculated for each compound.

 4. Collagen-induced arthritis (in vivo)

 1) 3 mg / ml / type II collagen (collagen workshop) Fully mix the same amount of FCA (Freund complete adjuvant H37 Ra, DIFCO Laboratories) as 8 ml and mix with male DBA / 1J mouse (Nippon Chillers River). 1) Immunization was carried out 100 to the ridge skin.

 2) After 21 days, a booster immunization was performed as described above.

 3) The booster day was set as day 0, and the body weight and arthritis score of each body were measured twice a week. The arthritis score was set as follows. 0 is normal, 1 is redness and mild swelling, 2 is moderate swelling, 3 is severe swelling or joint stiffness.

 4) Test compounds were suspended at concentrations of 1, 3, 10, and 30 mg / 5 ml in 0.5% methylcellulose as a solvent, and were orally administered once daily at a dose of 5 ml / kg until day 21. . To the negative control group, 0.5% methylcellulose as a solvent was administered at 5 ml / kg. '

 5) The measurement results were expressed as changes over time and as area under the curve (AUC). A steel test was used for arthritis score, and a Dunnett test was used for weight change, and a case where the p value was 0.05 or less was considered significant.

 From the above experiments, it was confirmed that the compound of the present invention has a PARP inhibitory activity and is useful as a prophylactic / therapeutic agent for diseases involving PARP.

 Pharmaceutical compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a pharmaceutical carrier, excipient and a carrier commonly used in the art. The compound can be prepared by a commonly used method using an agent. For oral administration in tablets, pills, capsules, granules, powders, liquids, etc., or for injections in joints, intravenous, intramuscular, etc., suppositories, transdermal solutions, ointments, transdermal Any form of parenteral administration such as a patch, a transmucosal solution, a transmucosal patch, an inhalant, or the like may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active ingredients may be combined with at least one inert excipient such as lactose, mannitol, pudose, hydroxy It is mixed with cypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain an inactive additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. Tablets or pills may be coated with sugar coating or a gastric or enteric coating, if necessary.

 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. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysonolate 80 (trade name). Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent. 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 drugs are administered using ordinary spraying equipment, nasal drops, tubes, nasal implants and the like.

Usually, for oral administration, the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg per body weight, which is divided into single doses or 2 to 4 doses. 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. In the case of intra-articular administration, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight. The dose is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 1100 / 1¾ per body weight is administered once a day or divided into multiple doses. The dose is determined as appropriate for each individual case, taking into account symptoms, age, gender, etc. BEST MODE FOR CARRYING OUT THE _c invention as

 Hereinafter, the present invention will be described in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following examples. The production methods of the starting compounds are shown in Reference Examples. Reference example 1

 To a solution of 2,3-diaminoethyl benzoate (29.3 g) in DMF (500 ml) was added 1-tert-butoxycarbodilpiridine-4-carboxylic acid (40.0 g), WSC-HC1 (40.0 g) and HOBt ( 1.5 g) was added, and the mixture was stirred overnight at room temperature. After concentrating the reaction solution, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off to obtain crude ethyl 2-ethyl-3-[(l-tert-butoxycarbubiperidine-4-carbonyl) amino] benzoate (56.9 g). The crude product was dissolved in acetic acid (600 ml) and heated and stirred at 120 ° C. for 1 hour. After the reaction solution was concentrated, toluene was added to the residue, and the mixture was concentrated under reduced pressure. The residue was diluted with chloroform, washed with 1M aqueous sodium hydroxide solution, further extracted from the aqueous layer with chloroform, and the combined organic layers were concentrated. Purification was performed in a single step to obtain ethyl 2- (1-tert-butoxycarbolpiperidin-4-yl) -1H-benzoimidazole-4-carboxylate (27.5 g).

Reference example 2

 Ethinole 2- (l-tert-butoxycarbylbiperidin-4-yl) -1H-benzoimidazole _4-carboxylate (27.5 g) in ethanol (400 ml) solution 1M sodium hydroxide aqueous solution (250 ml) And stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water, and then treated with 2- (l-tert-butoxycarbonylbiperidine-4-yl) -1H-benzoimidazolone-4. -A carboxylic acid (23.3 g) was obtained.

Reference example 3

CDI (16.2 g) was added to a suspension of 2- (l-tert-butoxycarbonylpyridine-4-inole) -1H-benzoimidazole-4-carbonic acid (23.2 g) in THF (300 ml). Was added and stirred at room temperature for 3 hours. Ammonia saturated THF (200 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried, and the solvent was distilled off to obtain tert-butyl 4- (4-carbyl-1H-benzimidazole-2- (Inole) piperidine-1-carboxylate (18.9 g) was obtained.

Reference example 4

 Trifluoroacetic acid (50 ml) was added to 2- (l-tert-butoxycarbonylpyridine-4-inole) -1H-benzoimidazole-4-carpoxamide (14.1 g) under ice cooling, and the mixture was allowed to stand at room temperature overnight. Stirred. The reaction mixture was concentrated under reduced pressure, and the residue was added with ethyl acetate and diisopropyl ether. The resulting solid was collected by filtration, washed with ethyl acetate and isopropyl ether, and washed with 2-piperidine-4-yl- 1H-Benzimidazole-4-carboxamide · 2 trifluoroacetate (15.1 g) was obtained.

 In the same manner as in Reference Example 1, the compounds of Reference Examples 5 to 8 shown in Table 1 below were referenced, and in the same manner as in Reference Example 2, the compounds of Reference Examples 9 to 12 were referenced in the same manner as in Reference Example 3. The compounds of Examples 13 to 16 were synthesized from the compounds of Reference Examples 17 to 20 in the same manner as in Reference Example 4. Table 1 shows the structures of the compounds of Reference Examples 1 to 20. In the table, compounds with blank physicochemical data indicate that they were used for the next reaction without purification.

Example 1

 2-piperidine-4-yl -1H-benzoimidazole-4-hexylboxamide · 2 trifluoroacetate (710 mg), 4- (4-fluorophenoxy) butyl bromide (310 mg), carbonic acid A mixture of potassium hydroxide (1.4 g), potassium iodide (129 mg) and DMF (10 ml) was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue obtained was purified by silica gel column chromatography (form-form-methanol) to give 2- {1- [4- (4-fluoro Lofenoxy) butyl] piridin-4-inole) -1H-benzoimidazole-4-carboxamide (519 mg) was obtained. The obtained compound (519 mg) was dissolved in ethanol, and a 4 M hydrogen chloride / ethyl acetate solution (4 ml) was added. The solvent was concentrated under reduced pressure, and the resulting crystals were recrystallized (ethanol / water) to give 2- {1- [4- (4-fluorophenoxy) butyl] piperidin-4-yl} -1Η-benzoimidazole Nore-4-carboxamide 'dihydrochloride (200 mg) was obtained (colorless powder).

Example 2

2-piperidine-4-yl-1H-benzoimidazole-4-carboxamide · 2 trifluoroacetate (860 mg), thiophene-2-aldehyde (1.1 g), acetic acid (5 ml) and 1,1 2-Dichloroethane (5 ク ロ ロ η1) To the mixture was added sodium triacetoxyborohydride (1.10 g), and 2 days While stirring. A saturated aqueous sodium hydrogen carbonate solution and a 1 M aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was extracted with a port form. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 2- [1- (thiophen-2-ylmethyl) pi [Pyridine-4-yl] -1H-benzoimidazole-4-carboxamide (95 mg) was obtained. The obtained compound was dissolved in methanol, and fumaric acid (30 mg) was added. The resulting crystals were recrystallized (2-propanol) to give 2- [1- (thiophen-2-ylmethyl) piperidin-4-yl] -1H-benzoimidazole-4-carboxamide. The acid salt (10 ⁸ mg) was obtained (colorless powder).

Example 3

 2- {1- [4- (2-benzyloxyphenoxy) butyl] piperidine-4-yl} -1Η-benzoimidazonole-4-carboxamide (344 mg), methanol (15 ml) and 10% palladium A mixture of monocarbon (90 mg) was stirred under a hydrogen atmosphere at room temperature overnight. After filtering the reaction mixture, the solvent was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 2- {1- [4- (2-hydroxyphenoxy) butyl] piperidine-4-ynole} -1} -benzoyl Midazole-4-carboxamide (254 mg) was obtained. The obtained compound was dissolved in methanol, and a 4M hydrogen chloride Z-ethyl acetate solution (4 ml) was added. The solvent was concentrated under reduced pressure, and the resulting crystals were recrystallized (ethanol / water) to give 2- {1- [4- (2-hydroxyphenyloxy) butyl] pyridin-4-yl} -1} -benzimidazole -4-Holepoxamide dihydrochloride (244 mg) was obtained (colorless powder). ·

 The compounds of Examples 4 to 106 shown in Tables 2 to 6 described below in the same manner as in Example 1 were replaced with the compounds of Examples 107 and 108 shown in Table 6 below in the same manner as in Example 2. Was synthesized. Tables 2 to 6 show the structures and physicochemical data of the example compounds.

 Tables 7 to 9 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, and methods obvious to those skilled in the art, or modified methods thereof.

In the table, the following abbreviations are used. Rex: reference example number, Ex: example number, Cmpd: compound number, Me: methyl, Et: ethyl, Pr: 1-propyl, iPr: 2-propyl, tBu: tert-butynole, Boc: tBu-0- CO-, Ac: acetinole, Ph: phenol, Bn: benzyl, cHex: hexinole, Ad: rare adamantyl, INaph: 1-naphthyl, 2Naph: 2-naphthyl, 2Thi: 2-Chenyl, 3Thi: 3-Chyl, 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 Body: HC1: hydrochloride; Fu: fumarate; numbers indicate ratios of acid components, for example, 2HC1 means dihydrochloride. Further, the numeral before the substituent indicates the substitution position, and a numeral having a plurality of numbers indicates a plurality of substitutions. For example, 2-OMe-Ph indicates 2-methoxyphene, and 2,4-F ₂ -Ph indicates 2,4-difluorophenyl.

 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 3 1 (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)

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S 挲 sculpture oar / ェ :) d 890/0 OAV οε

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I LlO / ZOdT / lDd 890/0 OAV

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CO

Claims

The scope of the claims

1. A benzimidazole derivative represented by the general formula (I) or a salt thereof.

(I)

 (The symbols in the formula have the following meanings.

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

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

A: nitrogen-containing saturated heterocycle,

 X: lower alkylene or a bond optionally substituted with an oxo group,

Y ¹ and Y ³ : the same or different, lower alkylene optionally substituted with an oxo group, lower alkenylene optionally substituted with an oxo group, lower alkynylene optionally substituted with an oxo group or a bond ,

^{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),

Ζ: cycloalkyl which may be substituted, aryl which may be substituted or heterocyclic group which may be substituted (provided that the heterocyclic group is bonded via a carbon atom which is a ring atom. ³ ),

When the group represented by-, -Υ Υ ² -Υ ³ -is -CO-0-, C _1-8 alkylene or -CO-0-C _M alkylene which may be substituted with an oxo group, Represents a heterocyclic group which may be substituted, and when Y ¹ and Y ² are both a bond, Y ³ represents a group other than a bond. )

2.2. 2- [1- (6-Phenoxyhexynole) piperidine-4-inole] -1H-benzoimidazo-mono--4-butaneboxamide, 2- {1- [2- (4-fluorophenoxy) Ethyl] piperidine-4-inole} -111-benzoimidazole-4-carboxamide, 2- {1- [4- (4-fluorophenoxy) butyl] piperidin-4-yl} -1Η-benzimidazonole-4-carboxamide, 2- {1- [3- (3-pheninole-1,2.4-oxaziazonole-5-inole) propyl] piperidin-4-yl}- 1Η-Benzimida Zonore-4-carboxamide and 2- {1- [2- (2-phenyloxazol-4-yl) ethyl] piperidin-4-yl} -1Η-benzimidazono-4 2. The benzoimidazole derivative or a salt thereof according to claim 1, which is selected from the group consisting of -hexylboxamide.

 A pharmaceutical composition comprising the benzoimidazonole derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

 4. The pharmaceutical composition according to claim 3, which is PARP P and a harmful agent.

 The pharmaceutical composition according to claim 4, which is an agent for preventing or treating an inflammatory disease.

 6. The medicament or composition according to claim 5, which is an agent for preventing or treating rheumatoid arthritis.