WO2003062234A1 - Quinoxaline compounds - Google Patents

Abstract

Clinically efficacious compounds which are usable as remedies for various diseases in which poly(ADP-ribose) polymerase (PARP) participates, in particular, inflammatory diseases such as rheumatoid arthritis. Quinoxaline derivatives having a carbamoyl group at the 5-position and specific substituent(s) at the 2- and/or 3-positions, in particular, compounds having a cyclic hydrocarbon group or a heterocyclic group substituted by, for example, Y1-Y2R4 at the 3-position or pharmaceutically acceptable salts thereof.

Description

 Description Quinoxaline compound Technical field

 The present invention relates to quinoxaline derivatives useful as medicaments, especially PARP inhibitors. Background art

 Rheumatoid arthritis (RA) is a polyarthritis that recurs and remits repeatedly, causing joint destruction, with extra-articular manifestations, and sometimes a life-threatening disease. RA features include (1) mononuclear cell infiltration, (2) proliferation of synovial cells, and (3) consequent tissue destruction. 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 finger motifs at the N-terminus of PARP recognize DNA strand damage, and nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) appears on various nuclear proteins, including histones and DNA topoisomerases I and II. : NAD) is known to control the polymerization of the ADP-reports. Therefore, excessive activation of PARP is thought to deplete intracellular NAD and ATP contents and lead to cell death (J. Clin. Invest., 77, 1312-1330 (1986)).

 It is widely known that nitric oxide (NO), active oxygen, and their reaction product, peroxristol, are potent mediators that cause tissue damage in various inflammatory diseases. This tissue damage is thought to be the result of PARP recognizing and activating DNA strand damage caused by NO, active oxygen, and peroxitrite, resulting in energy depletion (Proc. Natl. Acad. Sci. USA 93 1753-1758 (1996)). It has also been clarified that inhibition of PARP activation strongly suppresses cell invasion during inflammation (J. Exp. Med., 186, 1041-1049 (1997), Immunology, 93, 96). -101 (1998)).

In RA patients, synovial fluid cells have an increased ability to produce active oxygen (Z. Rheumatol., 46, 227-232 (1987)), and the amount of Nion in synovial fluid and serum is markedly increased. (Ann. Rheum. Dis., 51, 1219-1222 (1992)). Increased damage (Ann. Rheum. Dis., 51, 8-12 (1992)) and decreased NAD content (Int. J. Clin. Pharm. Res., 14, 57-63). (1994)), etc., suggest that PARP is activated, which is thought to result in cell invasion and tissue destruction.

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

 As a quinoxaline derivative having a carpamoyl group at the 5-position, 6,7-dichloro-2,3-dimethoxyquinoxaline-5-carboxamide is used as an intermediate for producing an NMDA receptor antagonist (for example, Patent Document 1), 6-amino -Production examples of 2,3-diphenylquinoxaline-5-carboxamide (for example, Non-Patent Document 1) and production examples of 2,3-dimethylquinoxaline-5-carboxamide (for example, Non-Patent Document 2) are reported. Have been. However, the effects of these compounds on PARP are not disclosed or suggested.

 Patent Document 1

 International Publication No. 9 7/3 2 8 7 3 Pan fret

 Non-patent document 1

 Chemical and Pharmaceutical Bulletin, 1970 Volume 18 ρ22-25 Non-Patent Document 2-Journal of Heterocyclic Chemistry, (USA) 1987 Volume 24 p.949-953 Disclosure of the Invention

 The present inventors have conducted intensive studies on compounds that inhibit PARP.As a result, the quinoxaline derivative having a carbamoyl group at the 5-position of quinoxaline and a specific group at the 2-, Z- or 3-position has a good PARP inhibitory activity. And found that it is useful as a preventive, therapeutic or diagnostic agent for diseases involving PARP, and completed the present invention.

That is, according to the present invention, a quinoxaline 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, and There is provided a medicine, particularly a PARP inhibitor, containing one or more species as active ingredients.

 (The symbols in the formula have the following meanings.

R ^1:. H, C _1-6 alkyl, halogen, C Les ₆ alkyl substituted with halogen or 0-C _1-6 § Rukinore,

(1) Lower formula (II)

(2) -X ³ -C _1-10 alkyl (The C _1-10 alkyl is halogen, OH, 0-C _1-6 alkyl, 丽₂ , NH-C _1-6 alkyl, N (C _{1- 6} alkyl) 2, NHCO-C _1-6 alkyl, N (C _I-6 alkyl) -CO-C _1-6 alkyl, CON¾, CONH (C _1-6 alkyl), CON (C _1-6 alkyl) ₂ , C0 ₂ H, C0 ₂ (C _1-6 alkynole) and may be substituted with 1 to 5 groups selected from oxo),

 (3) halogen or

 (4) The following formula (III) (III)

 A group selected from

X ¹ and X ³ : 0, S, N (R ⁶ ) or a bond,

R ^6: H, C _1-6 Arukinore, halogen, C _1-6 alkyl substituted with Nono androgenic, C _1-6 § alkylene - OH, C _1-6 alkylene - 0-C _1-6 alkyl, C0 ₂ -C _1-6 alkyl or C0 ₂ - C _1-6 alkylene - phenyl,

X ^2: 1-5 may be substituted with R ⁷ C _1-6 alkylene, 1-5 optionally substituted with R ⁷ C _1-6 Anorekiren - N (R ^6), 1 to 5 R ⁷ optionally substituted with C _1-6 alkylene-S 0 ₂ or a bond,

R ⁷ : same or different, halogen, OH, 0-C _1-6 alkyl, NH ₂ , NH-d.

6 alkyl, N (C _1-6 alkyl) 2, NHCO-Cj- ₆ alkyl, N (C _1-6 alkynole) -CO- C _1-6 alkyl, CONH _2, CONH (C _1-6 alkyl), CON (C _{1-6 alkyl) 2, C0 2 H, C0} 2 (C 1-6 alkyl), phenyl or Okiso,

 A: hydrocarbon ring or hetero ring,

B: a divalent group comprising a hydrocarbon ring which may be substituted by 1 to 5, a divalent group comprising a heterocyclic ring which may be substituted by 1 to 5 R ⁸ , or a bond ,

Y ^1: Okiso may be substituted with a group C _1-10 alkylene, optionally C _2-10 7 Luque two Ren be substituted with Okiso group, optionally substituted with Okiso group C ₂ - ₁₀ Arukini Len or bond,

^{Y 2: 0, S, SO} , S0 2, N (R 6), N (R 6) CO, N (R 6) -CO-N (R 6), 0-CON (R 6), NH-C _2-10 alkylene-NHCO, C (= N-OH), C (= N-OC¾) or bond,

R ⁴ : H, an optionally substituted hydrocarbon ring, an optionally substituted hetero ring or an optionally substituted C _1-10 alkyl,

 D and E are the same or different and each may be an optionally substituted hydrocarbon ring or an optionally substituted hetero ring,

Y ^3: Okiso Good C _1-10 alkylene optionally substituted with a group, CONH, NHCO, S0 ₂ or a bond, provided that, E is is optionally Hue substituted - if a le or cycloalkyl, except bond Represents a group of

 n: 0, 1, 2, 3, 4 or 5,

R ⁵ and R ^8: the same or different from each other, C _1-6 alkyl, halogen, 0H, 0-C _1-6 al Kill,丽_2, NH (C _1-6 alkyl), N (C _1-6 alkyl ) ₂ , CONH ₂ , CONH (C _1-6 alkyl), CON (C _1-6 alkyl) ₂ , C 0 ₂ H, C 0 ₂ (C _1-6 alkyl), CN or oxo,

R ³ : H, OH, halogen, an optionally substituted hydrocarbon ring, an optionally substituted heterocyclic ring or an optionally substituted C _1-10 alkyl.

When two or more groups R ⁵ , R ⁶ , or R ⁸ are present, they may be the same or different.

However, when X ¹ or X ³ is 0, S or N (R ⁶ ), or when R ² is halogen, R ³ represents OH or a group other than halogen. Also excludes 2,3-dimethylquinoxaline-5-carboxamide. The same applies hereinafter. )

Further, according to the present invention, there is provided a medicine, particularly a PARP inhibitor, comprising a quinoxaline derivative or a salt thereof. 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 as “alkyl”, preferably C _{1 -1 ()} , more preferably a C _1-7 alkyl group, still more preferably a C _1-6 alkyl group, even more preferably a methyl or hexyl group. The “alkylene” is preferably a Cwo alkylene group, more preferably a C _2-6 alkylene group. "Aruke two Ren" means having a double bond on one or more at an arbitrary position of the C ₂ or more alkylene chain, "alkynylene" 1 at any position of C ₂ or more alkylene chain It means having three or more triple bonds.

“Halogen” refers to F, Cl, Br and I, preferably F, C1 and Br. "I have been C _1-6 alkyl substituted with Nono port Gen" means a d-6 alkyl substituted with one or more halogen, preferably been _d-6 alkyl substituted with one or more F Yes, and more preferably, fluorometinole, difluoromethyl, trifluoromesinole and trifluoromesyl.

 Various ring groups such as "cycloalkyl", "cycloalkenyl", "aryl", "hydrocarbon ring", and "heterocycle" may be present as two or more polyvalent groups in the compound of the present invention. However, in the following, it may be expressed by a monovalent group name for convenience.

 “Cycloalkyl” is preferably a cycloalkyl group having 3 to 14 carbon atoms, which may be crosslinked. More preferred are cycloalkyl groups having 3 to 10 carbon atoms, and still more preferred are cyclopentyl, cyclohexyl and cycloheptyl groups. “Cycloalkenyl” is a group having one or two double bonds in the above “cycloalkyl” ring.

 “Aryl” is preferably a monocyclic to tricyclic aryl 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 with the phenyl group to form, for example, an indanyl or tetrahydronaphthyl group.

“Hydrocarbon ring” refers to “cycloalkyl”, “cycloalkenyl” or “aryl”, or those in which they form a condensed ring with each other. The hydrocarbon ring may be cross-linked or form a spiro ring (including an acetal such as a 1,3-dioxolane ring derived from an oxo group). Preferably cyclopentyl, cyclohexyl, Chloroheptyl, phenyl, naphthyl, indanyl and tetrahydronaphthyl groups.

“Heterocycle” refers to a 5- to 6-membered monocyclic aromatic heterocyclic ring or a 4- to 8-membered monocyclic ring containing 1 to 4 heteroatoms selected from 0, S and N as ring atoms. Shows a non-aromatic heterocyclic ring. They may form a condensed ring with each other or with a cycloalkyl or benzene ring having 5 to 8 carbon atoms to form a bi- or tricyclic group. The ring atom S or N may be acidified to form an oxoxide-dioxide. The hetero ring may be cross-linked or form a spiro ring (including an acetal such as a 1,3-dioxolan ring derived from an oxo group). Preferably, pyridyl, pyridazinyl, pyrimidinyl, pyrajunore, furyl, chenyl, pyrrolyl, oxazolinole, isoxazolinole, oxaxazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolinylol, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl, benzofurazolyl , Quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinole, pyrazolidinole, imidazolidini, homopyrazinole, tetrahydrofuranilola, tetrahydrofuranilanoyl, tetrahydrofuranilone 1] Octane-3-yl, 9-azabisik mouth [3.3.1] Nonan-3-yl, 3-alpha Bicyclo [3.2.1] octane-6-yl, 7-azabicyclo [2.2. Heptane-2-yl, 2-azatricyclo [3.3.1.13,7] 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-azaspiro [5.5] Pindecan-9-yl And 2-azaspiro [4.5] decane-8-yl, 2-azaspiro [4.4] nonane-7-yl and 8-azaspiro [4.5] decan- _2- yl groups. More preferably, pyridyl, pyrimidyl, furyl, thienyl, oxazolyl, isoxazolyl, oxdiazolyl, thiazolyl, benzofuranyl, benzochel, benzimidazolyl, pyrrolidinyl, piperidyl, homopiridinyl, morphipinyl, and the like. .

 The term "optionally substituted" means unsubstituted or has 1 to 5, preferably 1 to 3, substituents. It may be different.

The substituent in the “optionally substituted hydrocarbon ring” and the “optionally substituted hetero ring” is preferably a group selected from the following group. P group: C _1-6 alkyl, halogen, halogen-substituted C _1-6 alkyl, OH, Okiso, N0 _2, CN, 0-C _1-6 alkyl, 0-C _3-7 cycloalkyl, phenyl, cycloalkyl alkyl, 0-Hue - le, NH _2, NH (C _1-6 alkyl), N (C _1-6 alkyl) _2, NH-C _1-6 alkylene - C0 ₂ -C _1-6 alkyl, C0 ₂ - C _1-6 alkyl, C _1-6 alkylene - 0-C _1-6 alkyl and C _1-6 § alkylene - 0- phenyl group (said, phenyl及Pi cycloalkyl of 1-5 C _1-6 § alkyl, halogen, 0H, 0-C _1-6 alkyl or 0 but it may also be substituted with Fueeru.).

The substituent in the “optionally substituted C _1-10 alkyl” is preferably a group selected from the following Q group. '

Group Q: halogen, OH, oxo, CN, phenol, cycloalkyl, heterocycle, NH ₂ , NH (C _1-6 alkynole), N (C _1-6 alkyl) ₂ , N (C _1-6 alkynole) ) -Phenyl, 0-C _1-6 alkyl, 0-C _3-7 cycloalkyl and 0-phenyl group (the above-mentioned phenyl and cycloalkyl are 1 to 5 Q- ₆ alkyl, halogen, 0H, 0H --It may be substituted by ₆ alkyl or 0-phenyl.

A preferred compound in the present invention is a compound in which R ¹ and R ³ are H and R ² is a group represented by the formula (Π). More preferably, X ¹ and X ² are a bond, A force be substituted by Ariru or 1-5 R ⁵ may be substituted in the number of R ^5! Terrorist ring toヽ, B is heterocyclic group or a bond to a substituted with 1-5 of, Y ¹ is alkylene, C ₂ - ₁₀ Aruke - Len or bond, Y ² is 0, N ( R ⁶ ) or a bond, R ⁴ is H, optionally substituted C _1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted hetero. It is a compound of a ring group. More preferably, may be substituted by A force Sl~3 amino R ^5, pyrrolidine - substituted Le, Ho Mopiperajiniru, phenyl or pyridyl group, B force ^ 1-3 for at - le, piperidinyl, homopiperidinyl, piperazine which may be the pyrrolidine - Honoré, piperidines Rijininore, Homopi Bae Rijenore, Piperajininore, Homopiperajini Honoré, Pirijinore, Choi - Honoré, Okisazorinore, O hexa di § sled Honoré, Benzofura two Honoré, Ben Zoimidazoriru or bond, R ⁴ is H or optionally substituted C _1-6 alkyl, cycloalkyl, phenyl, pyrrolidyl, piperidinyl, homopiperidinyl, piperazil-, homopiperazinyl, pyridyl, chenyl, oxazolyl, oxaziazolyl, benzofuranyl or benzo Zoimidazolyl compound Even more preferably, the AB moiety is unsubstituted or substituted with one or two halogens or C _1-6 alkyl. May be a pyrrolidinyl, piperidinyl, homopiberidinyl, piperazur, homopiperazinole, feninole, pyridinole, piperazinole feninole, homopiperazininolefenir, pirazinyl pyridyl or homopiperagel pyridyl group And ⁴ parts of Y ^ YR are compounds of a group selected from Group G.

Group G: hydrogen atom, cyclohexyl methyl, 4-hexoxymethyl hexyl, 4- (2-phenoxethyl) cyclohexylmethyl, benzyl, 3- (phenylamino) propyl, 3- (N-phenyl-N- Methylamino) propyl, phenetinoleamino, (phenetinole) (methyl) amino, phenylpropylamino, 2-phenoxethylamino, 2- (4-methoxyphenyl) ethyl, 3- (4-methyl) amino Toxylphenyl) propyl, 3- (4-methylphenyl) propyl, 3- (4-chlorophenyl) propyl, 3- (2-phenyl) propyl, 3- (2-benzofuranoyl) propyl 3-phenyl Nolepropaninole, 2-phenoxysheth_ ;; 3-phenoxypropyl, 4-phenoxybutyl, 2- (2-fluorophenoxy) ethyl, 3- (2-fluorophenoxy) propyl, 4- (2-fluorophenoxy) Cis) butyl, 2- (3-fluorophenoxy) (S) ethyl, 3- (3-fluorophenoxy) propyl, 4- (3-fluorophenoxy) butyl, 2- (4-fluorophenoxy) ethyl, 3- (4-fluorophenoxy) Propyl, 4- (4-Funoleolophenoxy) butyl, 5- (4-Fluorophenoxy) pentyl, 2- (2-Chlorophenoxy) ethyl, 3- (2-Chlorophenoxy) propyl, 4 -(2-chlorophenoxy) butyl, 3- (3-chlorophenoxy) propyl, 3- (4-chlorophenoxy) propyl, 2- (2,4-difluorophenoxy) ethyl, 3- ( 2,4-difluorophenoxy) propyl, 4- (2,4-difluorophenoxy) butyl, 2- (2,4-dichlorophenoxy) ethyl, 3- (2,4-dichlorophenyl) Enoxy) propyl, 4- (2,4-dichlorophenoxy) butynole, 2- (3-phenyl-1,2,4-oxaziazol-5-yl) ethyl, 3- (3-phenyl) -1,2,4-oxaziazol-5-inole) propyl, 4- (3-phenyl-1,2,4-oxaziazol-5-yl) butyl, 2- (5-phenyl-1,2,4-oxaziazol-3-yl) ethyl, 3- (5-phenyl-1,2,4-oxaziazol-1-yl) propyl, 4- (5-phenyl-1,2,4-oxaziazol-3-yl) butyl, 3- [3- (2 -C-mouth phenyl) -1,2,4-oxadiazole-5-yl] propyl, 3- [3- (3-fluorophenylinole) -1,2,4-oxaziazol-1-yl ] Propyl, 2- (2-phenyloxazonole-4-yl) ethyl, 3- (2-phenyloxazol-4-yl) propyl, 4- (2-phenyloxazonole-4-yl) -4- 2- (4-full mouth feninole) ethyl, 2- (4-black phenoxy) ethyl, 2- (2- (2-chloro-2-phenoxy) ethyl) 4-chlorophenyl) -1,3-oxazole-4-ynole] ethyl, 2- [2- (4-fluorophenyl) Heninole) -1,3-oxazole-4-inole] ethyl, 3- (3,4-dichlorophenoxy) propyl, 2- (4-ditrophenyl) ethyl and 2- (4-bromophenyl) ethyl groups.

Particularly preferably, R ¹ and R ³ are H, and R ² is 1- (4-phenoxybutyl) piperidin-4-yl, 4-[(4-phenoxycyclohexyl) methyl] -1,4-diazepan-1 -Yl, 4- [2- (4-fluorophenyl) ethyl] piperazine-1-yl, 4- [2- (4-chlorophenyl) ethyl] piperazine-reyl, 1- [2- (4-chlorophenyl) S) Ethyl] piperidin-4-yl, 1- [3- (4-chlorophenoxy) propyl] piperidine-4-inole, 1- {2- [2- (4-c Nore) -1,3-oxazole-4-ynole] ethyl} piperidine-4-yl, 1- {2- [2- (4-fluorophenyl) -1,3-oxazole-4-yl ] Ethyl} piperidin-4-yl, 1- [3- (3,4-dichlorophenoxy) pyropen] pyrazine-4-yl, 4- [2- (4-ditrophenyl) [Echinole] piperazin-1-yl, 4- [2- (4-bromophenyl) ethynole] piperazin-1-yl or 4- [2- (4-bromophenylinole) ethyl] -1 , 4-Diazepan-1-yl. The compound (I) of the present invention may have a geometric isomer or a tautomer depending on the type of the substituent, but the present invention also includes a separated form of these isomers or a mixture thereof. I do. In particular, or when R ³ is bonded to the quinoxaline ring with a hetero atom (for example, a compound in which R ² or R ³ is OH or a compound in which X ¹ is NH), in the present application, only one of the tautomers is used. , But also includes those isomers. Further, 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 optical isomers and an isolated one. The present invention also includes a compound obtained by labeling the present compound (I) with a radioisotope.

 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 the compound (I) is included in the present invention as long as the strong salt is a pharmaceutically acceptable salt. Included. 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 maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; methylamine And salts with organic bases such as ethylamine, ethanolamine, lysine, orditin, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound (I) of the present invention and a pharmaceutically acceptable salt thereof.

The compounds of the present invention also include pharmacologically acceptable prodrugs. Pharmacology Pharmaceutically acceptable prodrugs are those compounds of the present invention that are obtained by solvolysis or under physiological conditions.

It is a compound having a group that can be converted into NH ₂ , OH, CO ₂ H and the like. Prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Hirokawa Shoten, 1990), Volume 7, Molecular Design 163-198. .

 (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. . 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 the raw material or intermediate, or to replace the functional group with a group that can be easily transferred to the functional group in terms of manufacturing technology. May be effective. Such functional groups are, for example, amino group, hydroxyl group, hydroxyl group and the like, and their protecting groups are, for example, “Protective Groups in Organic Synthesis (third edition)” by TW Greene and PGM Wuts. Edition, 1999) "), and these may be appropriately selected and used according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group as necessary or converting the protective group to a desired group. Further, the prodrug of the compound of the present invention (I) is produced by introducing a specific group at the stage of a raw material or an intermediate, or by carrying out a reaction using the obtained compound of the present invention (I), similarly to the above protective group. it can. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, rubbamate diversion, dehydration and the like.

 (IV) (I)

 (In the formula, R represents d_4 alkyl such as methinole and ethyl or H.)

First production method (R = C _1-4 alkyl group)

This production method is a method for producing the present compound (I) by an amidation reaction from the carboxylic acid compound (IVa). The reaction is carried out in a solvent inert to the reaction of water, alcohols such as methanol, ethanol, etc., Ν, Ν-dimethylformamide (DMF), tetrahydrofuran (THF), etc., or in a solvent-free condition from room temperature to under heating. . In some cases, it is recommended that It may be advantageous in some cases.

 Second manufacturing method (R = H)

 This production method is a method for producing the present compound (I) by treating a carboxylic acid compound (IVb) or a reactive derivative thereof with ammonia. In particular, in the present invention, a mixed acid anhydride method, an acid halide method, and a method of reacting in the presence of an active esterifying agent and a condensing agent are advantageous. When the carboxylic acid compound (IVb) has a functional group active in a reaction such as a hydroxy group or an amino group, these functional groups are protected with a protecting group in advance, and this reaction is carried out. The compound (I) of the present invention can be obtained by removing the protecting group. Examples of mixed acid anhydrides include organic acid-based mixed acid anhydrides obtained by reacting with alkyl carbonate halides and pivaloyl halides, and phosphoric acid-based mixed acids obtained by reacting with salted diphenylphosphoryl and the like. Anhydrides and the like.

 When the reactive derivative is an acid halide, examples of the halogenating agent used for the production thereof include thiol chloride, shirokishikorin, shiroizanirin, pentasaniline, hydrochloric acid, and hydrobromic acid. No.

 Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.

(WSC), 1,1′-carbonylbis-1H-imidazole (CDI) and the like, and in some cases, further additives (for example, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole ( HOBt) etc.) in some cases.

 Examples of the solvent include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as getyl ether, THF, and 1,4-dioxane. , DMF, dimethylsulfoxide (DMSO), pyridine, and other inert solvents can be used. These solvents can be used alone or as a mixture of two or more.

Third production method (conversion of group R ² or R ³ )

Various compounds of the present invention can be produced by subjecting the compound of the present invention to a group R ² or R ³ and subjecting it to a reaction.

 (1) Alkylation by nucleophilic substitution

It can be produced by reacting an arginyl nitride or an organic sulfonic acid ester with a nucleophile. Alternatively, it can also be produced by subjecting it to the Mitsunobu reaction. The reaction is halogenated The reaction is carried out in a solvent inert to the reaction of hydrocarbons, aromatic hydrocarbons, ethers, DMF, N-methylpyrrolidone, etc., or without a solvent, under cooling to heating. Sodium hydride-Potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, potassium tert-ptoxide, sodium hydroxide, hydroxylating power, sodium carbonate, potassium carbonate, cesium carbonate, etc. The reaction in the presence of a base is sometimes advantageous for the smooth progress of the reaction.

 Alkyl halides are obtained by the reaction of a compound having an OH group with thionyl chloride, oxychlorine, trichlorine, pentachlorine, hydrochloric acid, hydrobromic acid and the like. Organic sulfonates can be obtained by reaction with methanesulfonyl chloride, tansulfonyl chloride, benzenesulfonyl chloride, P-toluenesulfonyl chloride, and the like.

 This substitution reaction can also be applied to a halogenated or organic sulfonic acid esterified quinoxaline ring by ipso substitution reaction.

 (2) Reductive alkyli-dani

 Alkylic reaction can be carried out by reacting a compound having a primary or secondary amine with a compound having a ketone or an aldehyde. For the reaction, a conventional method of reductive alkylation (reductive amination from the viewpoint of a carbonyl compound) can be used. For example, “Experimental Chemistry Course (4th edition)” edited by The Chemical Society of Japan, Volume 20 (1992) (1992) ( Maruzen) and the like.

 (3) Amidation, sulfonamide and esterification

The carboxylic or sulfonic acid compounds can be prepared in the presence of condensing agents or by using their reactive derivatives. The reactive derivative of the carboxylic acid or sulfonic acid conjugate includes an acid halide, an acid anhydride, and an active ester. The reaction can be carried out, for example, according to the method described in “Experimental Dagger Study Course (4th edition)”, edited by The Chemical Society of Japan, Vol. ²² ( ¹⁹⁹² ) (Maruzen).

 (4) Conversion to Lebamart and rare

It can be produced by reacting an isocyanate compound obtained by Curtius rearrangement of acid azide or Hofinam rearrangement of primary amide with a compound having an OH group or an amine compound. The acid azide is obtained by reacting a reactive derivative of a carboxylic acid with an azide salt such as sodium azide, or by reacting a carboxylic acid with diphenylphosphoryl azide (DPPA). The reaction is carried out in an organic solvent inert to the reaction of a halogenated hydrocarbon, an aromatic hydrocarbon, an ether, DMF, or the like, or without a solvent, under cooling to heating. In the reaction, an equivalent amount or one of them can be used in excess.

 The starting compound can be produced by the following method.

Ring closure 1

(In the formula, ^Ra represents C _1-4 alkyl such as methyl and ethyl, and L represents a leaving group. The same applies hereinafter.) The quinoxaline compound (VIII) is a diaminobenzoate compound (V) and a diketo compound ( VI) or a haloketone or the like (VII).

When the diketo compound (VI) is used, its equivalent (for example, acetal or hydrate) can be used. In particular, when R ³ is H, it is advantageous to use the equivalent. The reaction is carried out in an inert solvent such as water, alcohols, acetonitrile, aromatic hydrocarbons, ethers, DMF, etc., in an equimolar amount or one of the diaminobenzoic acid ester compound and the diketo compound in excess. It can be performed at room temperature or under heating. In some cases, the reaction in the presence of an acid is advantageous in that the reaction proceeds smoothly. Examples of the acid used include acetic acid, sulfuric acid, phosphoric acid, and tosylic acid.

 When the haloketone (VII) is used, the same solvent as in the case of the diketo compound can be used, and the reaction can be performed at room temperature or under heating. As the leaving group L, a halogen or various sulfonyloxy groups is preferable. It is sometimes advantageous to carry out the reaction in the presence of a base in order to make the reaction proceed smoothly. Examples of the base used include potassium carbonate, cesium carbonate, sodium hydroxide, triethylamine, pyridine and the like. Pyridines can also be used as solvents. The reaction proceeds with air oxidation, but it may be advantageous to carry out the reaction in the presence of various oxidizing agents. Copper compound as oxidizing agent

(Eg, copper acetate), manganese compounds (eg, manganese dioxide), benzofuroxane, and quinone compounds (eg, chloranil).

Compound (V) can be produced by the method described in US5380719 and the like. Ring closure 2

(In the formula, R ^b and R ^e represent C _1-4 alkyl such as methyl and ethyl. The same applies hereinafter.)

 The quinoxaline compound (X) having an OH group at the 3-position can be produced using a hemiacetal aldehyde compound (IX). The reaction can be carried out under substantially the same conditions as in the case where the ring-closing 1 diketo compound is used.

 The corresponding carboxylic acid compounds can be obtained by subjecting the quinoxaline compounds (VIII) and (X) to a general carboxylic acid ester hydrolysis reaction. The reaction can be performed, for example, under the conditions ^; i described in ij gGI Protective Groups in Organic Synthesis].

 The reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate. The salt can be produced by subjecting the salt to a usual salt formation treatment.

 Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

 Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or close chromatography. The optical isomer can also be produced from a suitable optically active starting compound. Industrial applicability

 The compounds of the present invention are useful as active ingredients in pharmaceutical preparations. In particular, it has PARP inhibitory action, so it is involved in inflammatory diseases (eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.), autoimmune diseases (eg, type I diabetes) Etc.), and is useful as a prophylactic / therapeutic agent for diseases associated with ischemia-reperfusion injury (eg, stroke, myocardial infarction, organ transplantation, etc.).

 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 Kariu arm, 10 mM magnesium chloride, 5 mM dithiothreitol I torr, lOO ^ g / ml histone, 26 nM ³ H- The reaction was performed 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 compound (I) of the present invention shows good inhibitory activity.For example, the compounds described in Examples 6, 28, 47, 74, 102, 105, 108, 110, 120, 169, 200 and 215 have 3.8 An IC ₅₀ of 7272 nM was shown.

 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 magnetic Shiumu, adjusted to a desired concentration in 56 mM HEPES (pH 7.5) solution containing 0.01% digitonin and 26 nM ³ H-NAD The reaction solution was used.

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 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%.

The compound of the present invention also showed good inhibitory activity I ¹ in the above test.

 Therefore, it is clear that the compound of the present invention is useful as a therapeutic agent for various diseases involving PARP.

 Further, the usefulness of the compound of the present invention can be confirmed by the following test.

 . Zymozan-induced peritonitis test (in vivo)

1) Male Balb / c mice (Nippon-charlsriver), 6-8 weeks old, were subjected to 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 or solution was orally administered to the above-mentioned Balb mass at a desired dose of 5 ml / kg. To the negative and positive control groups, 0.5% methylcellulose as a solvent 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 0.1% heparin-containing saline to collect cells in the peritoneal cavity.

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

 8) ED30 was calculated for each compound as the amount of test compound that inhibited the number of cells infiltrated into the peritoneal cavity by 30% by Zymozan.

4. Collagen-induced arthritis test (in vivo)

 1) 3 mg / ml ゥ type II collagen (collagen workshop) Fully mix the same amount of FCA (Freund co mplete adjuvant H37 Ra, DIFCO Laboratories) as 8 ml with male DBA / 1J mouse

(Nippon Chariser Slipper) 100 1 was immunized inside the ridge skin.

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

 3) With the booster day as day 0, body weight and arthritis score of each 胺 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) The test compound was suspended in 0.5% methylcellulose as a solvent at 1, 3, 10, and 30 mg / 5 ml concentrations, and orally administered once daily at a dose of 5 ml / kg until day 21. . To the negative and positive control groups, 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 performed for arthritis scores, and a Duimett test was performed for weight fluctuations. A p value of 0.05 or less was considered significant.

Pharmaceutical compositions containing one or more of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient include pharmaceutical carriers, excipients, and the like commonly used in the art. Can be prepared by a commonly used method. Dosing tablets Or pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular, etc. injections, suppositories, transdermal solutions, ointments, transdermal patches It may be in the form of parenteral administration by transmucosal solution, transmucosal patch, inhalant, or the like.

 As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances include at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybutyl. It is mixed with pyrrolidone, metasilicate and magnesium aluminate. The composition may contain an inert additive such as a lubricating agent such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, and a solubilizing agent according to a conventional method. The tablets or pills may be coated with a bran coat or a gastric or enteric coating, if necessary.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert solvents such as purified water, ethanol 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 polysorbate 80 (trade name). Such compositions may further comprise 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 Pacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by producing a sterile solid composition, dissolving and suspending in sterile water or a sterile solvent for injection before use.

 Thickening agents such as nasal agents are used in solid, liquid or semi-solid form, and can be produced according to known methods. For example, known pH adjusters, preservatives, thickeners, and excipients are appropriately added to form a solid, liquid, or semi-solid. Nasal preparations are administered using ordinary spray equipment, nasal drops, tubes, intranasal inserts, and the like.

In the case of normal 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 administered once or divided into 2 to 4 times. I do. When administered intravenously, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is to be administered once or more than once a day. In the case of intra-articular administration, the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and it is administered once or more than once a day. As a transmucosal agent, about 0.001 to 100 mg / kg of body weight is to be administered once or more than once a day. The dose is determined as appropriate for each individual case, taking into account symptoms, age, gender, and the like. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail based on practical 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 20.0 g of N- (tert-butoxycarbyl) isonipecotic acid in 200 ml of THF was added 17.0 g of CDI, and the mixture was stirred at room temperature for 3 hours. 12.7 g of Ν, Ο-dimethylhydroxylamine hydrochloride and 18.7 ml of triethylamine were added to this solution, and the mixture was further stirred at room temperature for 14 hours. After evaporating the solvent under reduced pressure, the residue was extracted with ethyl acetate, washed successively with hydrochloric acid and aqueous sodium bicarbonate, and the solvent was distilled off to give 4- (N-methoxy-N-methylcarbamoyl) piperidine-1-butyric acid tert-butyl ester. 23.7 g of -butyl was obtained as a colorless syrup. .

Reference example 2

 To a solution of 23.7 g of the compound obtained in Reference Example 1 in 200 ml of THF were added 9.6 ml of chloroiodomethane and 9.12 g of lithium bromide, and the mixture was cooled to -78 ° C. 115 ml of a 1.14 mol / 1 methyl lithium dimethyl ether solution was added dropwise to the reaction solution, and the mixture was stirred for 1 hour. After terminating the reaction with a saturated aqueous solution of sodium chloride, the mixture was extracted with ethyl acetate. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1; 4) to give 4- (2-chloroacetyl). 12.5 g of tert-butyl piperidine-1-carboxylate was obtained as a pale yellow syrup.

Reference Example 3 6.82 g of the compound obtained in Reference Example 2, 4.50 g of carbonated potassium and 3.60 g of potassium iodide were sequentially added to a solution of 3.60 g of methyl 2,3'-diaminobenzoate in 100 ml of DMF, and the mixture was cooled to room temperature. For 12 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2) to give 3- (l-tert-butoxycarbonylbiperidine-4-yl) quinoxaline-5-carboxylate 3.73 g Was obtained as an orange syrup.

Reference example 4

To a solution of 9.06 g of methyl 2,3-diaminobenzoate in 100 ml of methanol was added 7.86 g of methyl 2-hydroxy-2-methoxyacetate, and the mixture was stirred at 60 ° C. for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2) to obtain 3.08 g of methyl 3-hydroxyquinoxaline-5-carboxylate as yellow crystals. (FAB-MS [(M + H) ⁺ ]: 205)

Reference example 5

 38 ml of a 1 M aqueous sodium hydroxide solution was added to a solution of the compound 3.08 obtained in Reference Example 4 in 50 ml of ethanol, and the mixture was stirred at 60 ° C for 2 hours. After evaporating the solvent under reduced pressure, the residue was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 2.66 g of 3-hydroxyquinoxaline-5-carboxylic acid as brown crystals. (FAB-MS [(M-H) —]: 189)

Reference example 6

 3- (4-Bromopheninole) -quinoxaline-5-methyl methyl sulfonate In a solution of 1.00 g of toluene in 20 ml of toluene, tert-butyl piperazine-1-carboxylate 652 mg, palladium acetate 65 mg, BIAP 271 mg 1.43 g of cesium carbonate was added to the mixture (j) and the mixture was stirred at 100 ° C for 24 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 2) to give 3- [4- (4-tert-butoxycarbonylbiperazine-1). 1.12 g of [(yl) phenyl] quinoxaline-5-methyl methyl sulfonate were obtained.

Reference Example 7

 To 3.33 g of 2-nicotine isonicotinic acid was added 30 ml of Shiridani Thionyl, and the mixture was refluxed for 12 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of acetonitrile was added. To this solution, 50 ml of a 2.0 M trimethylsilyldiazomethane / hexane solution was added dropwise, and the mixture was stirred for 2 hours. 25 ml of 33% hydrogen bromide acetic acid solution was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with acetonitrile to give 6.32 g of 2-bromosmall (2-chloropyridine-4-yl) ethanone hydrobromide.

Reference Example 8 (1) An aqueous solution of 11.8 g of laurel hydrate, 14.8 g of hydroxy / reamine hydrochloride and 85.2 g of anhydrous sodium sulfate in a 400 ml aqueous solution was heated to 55 ° C, and 4-methoxy-2-ditroaniline 10.0 was heated. g of 2M hydrochloric acid (40 ml) was gradually added thereto, and the mixture was stirred at 55 ° C for 12 hours. The solution was cooled to room temperature, and the precipitated reddish-brown solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 13.0 g of 4-methoxy-2-nitroisonitose soucetanilide. (FAB = MS [(M + H) +]: 240)

 (2) 50 ml of concentrated sulfuric acid was heated to 90 ° C., and 13.0 g of the above-obtained compound was gradually added at 105 ° C. or lower. The solution was stirred at 90 ° C for 30 minutes, cooled to 60 ° C, poured into 100 g of ice water, and stirred at room temperature for 3 hours. The precipitated brown solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 7.10 g of 5-methoxy-7-nitroisatin. (FAB = MS [(M + H) +]: 223)

 (3) 7.10 g of the isatin compound obtained above and 25 ml of a 2M aqueous sodium hydroxide solution were cooled to 5 ° C, and 7.5 ml of 30% hydrogen peroxide solution was added dropwise at 5 to 10 ° C. The solution was stirred for 15 hours in a room, cooled on ice, acetic acid (5 ml) was added slowly, and the mixture was further stirred at room temperature for 2 hours. The precipitated brown solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 4.51 g of 2-amino-5-methoxy-3-nitrobenzoic acid. (FAB = MS [(M-H)-]: 211)

(4) 50 ml of methanol was cooled to -15 ° C, and 5 ml of concentrated sulfuric acid was gradually added dropwise at -15 to -20 ° C. After 4.51 g of the carboxylic acid compound obtained above was gradually added to this solution at −15 to −20 ° C., the mixture was stirred for 15 hours under reflux with heating. The solution is poured into 200 g of ice water, adjusted to about pH 9 with sodium carbonate, extracted with chloroform, and the solvent is distilled off under reduced pressure.2.53 g of methyl 2-amino-5-methoxy-3-nitrobenzoate is brownish brown. Obtained as a solid. (FAB = MS [(M + H) ⁺ ]: 227)

 (5) A mixture of 2.40 g of the ester compound obtained above, 500 mg of 10% palladium on carbon and 50 ml of methanol was stirred at room temperature under a hydrogen atmosphere at normal pressure for 5 hours to give 2,3-diamino-5-methoxyanhydride. 1.90 g of methyl benzoate was obtained as a black oil. (FAB = MS [(M-H; r]: 195)

 (6) Using 1.90 g of the diamino compound obtained above, 1.93 g of α-bromoacetophenone, 1.47 g of potassium carbonate and 1.77 g of potassium iodide, a reaction was carried out in the same manner as in Reference Example 3, 0.51 g of methyl 7-methoxy-3-phenyl-quinoxaline-5-carboxylate was obtained as a brown solid. (FAB = MS [(M + H) +]: 295)

Reference Examples 9 to 4 6

In the same manner as in Reference Example 1, the compounds of Reference Examples 9 to 13 shown in Table 1 below were used, and in the same manner as in Reference Example 2, the compounds of Reference Examples 14 to 18 shown in Table 1 below were used. In the same manner as in Reference Example 3, the compounds of Reference Examples 25 to 42 shown in Table 2 below are shown in Table 2 below in the same manner as in Reference Example 6. The compounds of Reference Examples 43 to 46 were synthesized in the same manner as in Reference Example 7, and the compounds of Reference Examples 19 to 24 shown in Table 1 below. Table 1 shows the structures of the compounds of Reference Examples 1, 2, 7, 9 to 24, and Table 2 shows the structures of the compounds of Reference Examples 3, 6, 25 to 46. In addition, in the table, the compound in which the physic data is blank indicates that the compound was used for the next reaction without purification. Example 1

 To a solution of 3.73 g of methyl 3- (l-tert-butoxycarbonylpiperidin-4-yl) quinoxaline-5-carboxylate in 40 ml of ethanol, add 20 ml of 1 M aqueous sodium hydroxide solution, and add For 5 hours. After the solvent was distilled off under reduced pressure, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude carboxylic acid. This carboxylic acid was dissolved in 100 ml of THF, 3.24 g of CDI was added, and the mixture was stirred at room temperature for 5 hours. To this solution was added 200 ml of an ammonia-saturated THF solution under ice-cooling, followed by stirring at room temperature for 12 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1: G) to give 3- (l-tert-butoxy 1.94 g of carboxypyridin-4-yl) quinoxaline-5-carboxamide was obtained as yellow crystals.

Example 2

Dissolve 1.94 _g of 3- (l-tert-butoxycarbonylpiperidin-4-yl) quinoxaline-5-carboxamide in 20 ml of chloroform and add 4 M solution of dihydrogen dioxane in dioxane. The mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was recrystallized from water-ethanol-ethyl ether to obtain 1.34 g of 3-piperidine-4-ylquinoxaline-5-carboxamide hydrochloride as pale yellow crystals. Was.

Example 3

To a solution of 3-piperidine-4-ylquinoxaline-5-carboxamide hydrochloride (446 mg) in DMF (30 ml) was added 4-phenoxybutyl chloride (396 mg), potassium carbonate (298 mg) and potassium iodide. 23 mg were sequentially added, and the mixture was stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (methanol / ethyl acetate 1: 9). To the obtained crude product was added a 4 M solution of hydrogen chloride / g / ethyl acetate, and the solvent was distilled off.The obtained crude crystals were recrystallized from water-ethanol-ethyl ether to give 3- [1- 433 mg of (4-phenoxybutyl) piperidine-4-yl] quinoxaline-5-carboxamide hydrochloride in colorless form Obtained as crystals.

Example 4

 2.66 g of 3-hydroxyquinoxaline-5-carboxylic acid was suspended in 30 ml of 1,2-dichloroethane, and under ice-cooling, 5.15 ml of oxysulfine salt was added. This suspension was heated to 80 ° C and stirred for 5 hours. 'The reaction solution was added dropwise to saturated aqueous ammonia under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, water was added and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 2.29 g of 3-cloguchiquinoxaline-5-carboxamide as brown crystals.

Example 5

 To a solution of 2.00 g of 3-chloroquinoxaline-5-carboxamide in 50 ml of N-methylpyrrolidone, 3.59 g of N-Boc-pyrazine and 4.71 g of cesium carbonate were successively added and stirred at 120 ° C for 12 hours. Was. Water was added to the reaction solution, and the mixture was extracted with a lip mouth form. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was recrystallized from ethyl acetate-hexane to give 3- (1-tert-butoxycarbonylbiperazine-4-yl). 2.44 g of quinoxaline-5-carboxamide was obtained as pale yellow crystals.

Example 6

 425 mg of piperidine was added to a solution of 284 mg of 3- (2-chloropyridine-4-inole) quinoxaline-5-carboxamide in 10 ml of N-methylvirolidone, and the mixture was stirred at 120 ° C for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 3- (2-piperidyl-4-yl) Lu) Quinoxaline-5-carboxamide (76 mg) was obtained as yellow crystals.

 The compounds of Examples 7 to 557 shown in Tables 3 to 17 below were synthesized in the same manner as in Examples 1 to 6. Tables 3 to 17 show the structures and physicochemical data of the example compounds.

 Tables 18 to 19 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-mentioned production methods, the methods described in the examples, methods obvious to those skilled in the art, or modifications thereof.

In the table, the following abbreviations are used. REx: Reference example number, Ex: Example number, Cmpd: Compound number, Str: Molding method, Syn: Production method (showing the number of the example produced similarly), Me: Methyl, Et: Ethyl, Pr: 1-propyl, iPr: 2-propyl, tBu: tert-butyl, Boc: tBu-O-CO-, Ac: acetyl, Ph: phenyl, Bn: benzyl, nHex: n-hexyl, cHex: shik Mouth hexyl, Dat: physicochemical data (F: FAB-MS [(M + H) ⁺ ]; FN: FAB-MS [(M-H) —]; EI: EI-MS (M +); ES: ESI- MS [(M + H) +]; NMR1: δ at iHNMR in _{DMSO-d 6 (ppm);} NMR2: CDC1 δ at HNMR in ₃ (ppm)); Sal: salt (blank: pretend integrally; HC1: hydrochloride; Fu: fumarate; OX: oxalate; the numbers indicate the ratio of acid components, for example, 2HC1 means dihydrochloride). Also, 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-MeO-Ph represents 2-methoxyphenyl, and 2,4- (MeO) 2-Ph represents 2,4-dimethoxyphenyl.

1 (continued)

Two

Three

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Table 4

Table 5

5 (continued)

Table 5 (continued)

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Table 8

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Table 11

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Table 17

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Claims

The scope of the claims

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

 (The symbols in the formula have the following meanings.

R ^1: H, C _1-6 alkyl, halogen, C _1-6 alkyl or 0-C _1-6 § Norekinore substituted by halogen,

R ² : h) Lower type (Π) (e)

Alkyl (C _1-10 alkyl is halogen, OH, 0-C _1-6 alkyl, NH ₂ , NH-C _1-6 alkyl, N (C _1-6 alkyl)

2, NHCO-C _1-6 alkyl, N (C _1-6 alkyl) -CO-C ^ alkyl, CONH ₂ , CONH (C _1-6 alkyl), CON (C _1-6 alkyl) ₂ , C0 ₂ H , C0 ₂ (C _1-6 alkyl) and optionally substituted with 1 to 5 groups selected from oxo),

 (3) halogen or

(4) Lower formula (III)

 A group selected from

X ¹ and X ³ : 0, S, N (R ⁶ ) or a bond,

R ^6: H, C _1-6 alkyl, halogen, C _1-6 alkyl substituted with halogen, C _1-6 § alkylene - 0H, C _1-6 alkylene - 0-C _1-6 alkyl, C de alkyl Or C0 _2-

C _1-6 Anolekiren-Feninole,

X ^2: 1-5 may be substituted with R ⁷ C _1-6 alkylene, it is substituted with 1-5 R ⁷ Optionally C _1-6 alkylene-N (R ⁶ ), C _1-6 alkylene-S 0 ₂ or a bond which may be substituted with 1 to 5 R ⁷ ,

R ⁷ : same or different, halogen, OH, 0-C _1-6 alkyl, NH ₂ , NH-Ci.

6 alkyl, N (C _1-6 alkyl) ₂ , NHCO-C _1-6 alkyl, N (C _I-6 alkyl) -CO-C _6- alkyl, CON¾, CONH (C _1-6 alkyl), CON ( C _1-6 alkyl) ₂ , C 0 ₂ H, C 0 ₂ (C _1-6 alkyl), phenyl or oxo,

A: hydrocarbon ring or hetero ring,

B: 1-5 divalent radical consisting may hydrocarbon ring optionally substituted by R ^8, divalent radicals consisting of 1-5 terrorist ring to Yo Le, optionally substituted by R ⁸ Or binding,

Y ^1: Okiso good Cwo alkylene optionally substituted with a group, may be substituted with Okiso group ₂ - ₁₀ Aruke two Ren, which may be substituted with Okiso group C ₂ - ₁₀ alkylene or a bond,

^{Y 2: 0, S, SO} , S0 2, N (R 6), N (R 6) CO, N (R 6) -CO-N (R 6), 0-CON (R 6), NH-C _2-10 alkylene - NHCO, C (= N- OH), C (= N-OCH 3) or a bond,

R ⁴ : H, an optionally substituted hydrocarbon ring, an optionally substituted hetero ring, or an optionally substituted C _1-10 alkyl,

D and E: the same or different, optionally substituted hydrocarbon ring or optionally substituted hetero ring,

Y ^3: Okiso group Yo optionally substituted by Les, if C _1-10 alkylene, CONH, NHCO, S0 ₂ or a bond, provided that, E is a good phenyl or cycloalkyl which may be substituted, except bond Represents a group of

n: 0, 1, 2, 3, 4, or 5,

R ⁵ and R ⁸ : the same or different, C _1-6 alkyl, halogen, OH, 0-C _1-6 alkyl, NH ₂ , NH (C _1-6 alkynole), N (C _{1-6 Arukinore) 2, CONH 2, CONH (} C 1-6 alkyl Le), CON (C _{1-6 alkyl) 2, C0 2 H, C0} 2 (C 1-6 alkyl), CN or Okiso,: H, OH, Halogen, an optionally substituted hydrocarbon ring, an optionally substituted heterocyclic ring or an optionally substituted Cwo alkyl.

When two or more groups R ⁵ , R ⁶ , R ⁷ and R ⁸ are present, they may be the same or different from each other.

However, when X ¹ or X ³ is 0, S or N (R ⁶ ), or when R ² is halogen, R ³ is Shows a group other than OH or halogen. Also excludes 2,3-dimethylquinoxaline-5-carboxamide. )

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

 3. The pharmaceutical composition according to claim 2, which is a poly (ADP-ribose) polymerase inhibitor.

 4. The pharmaceutical composition according to claim 3, which is an agent for preventing or treating rheumatoid arthritis.