WO2003062234A1 - Composes de quinoxaline - Google Patents

Composes de quinoxaline Download PDF

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Publication number
WO2003062234A1
WO2003062234A1 PCT/JP2003/000545 JP0300545W WO03062234A1 WO 2003062234 A1 WO2003062234 A1 WO 2003062234A1 JP 0300545 W JP0300545 W JP 0300545W WO 03062234 A1 WO03062234 A1 WO 03062234A1
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Prior art keywords
alkyl
optionally substituted
group
halogen
substituted
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PCT/JP2003/000545
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English (en)
Japanese (ja)
Inventor
Kazuhisa Takayama
Naoyuki Masuda
Takeshi Hondo
Ryoji Hirabayashi
Norio Seki
Yuji Koga
Ryo Naito
Yoshinori Okamoto
Hiroyuki Kaizawa
Takao Okuda
Youhei Okada
Makoto Takeuchi
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to JP2003562112A priority Critical patent/JPWO2003062234A1/ja
Publication of WO2003062234A1 publication Critical patent/WO2003062234A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to quinoxaline derivatives useful as medicaments, especially PARP inhibitors.
  • RA Rheumatoid arthritis
  • 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.
  • PARP Poly (ADP-ribose) polymerase
  • PARP Poly (ADP-ribose) polymerase
  • 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)).
  • nitric oxide NO
  • active oxygen and their reaction product, peroxristol
  • PARP nitric oxide
  • activation strongly suppresses cell invasion during inflammation (J. Exp. Med., 186, 1041-1049 (1997), Immunology, 93, 96). -101 (1998)).
  • 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.
  • 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.
  • Patent Document 1
  • 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.
  • 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
  • a medicine particularly a PARP inhibitor, containing one or more species as active ingredients.
  • R 1 H, C 1-6 alkyl, halogen, C Les 6 alkyl substituted with halogen or 0-C 1-6 ⁇ Rukinore,
  • the C 1-10 alkyl is halogen, OH, 0-C 1-6 alkyl, ⁇ 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, CON3 ⁇ 4, 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),
  • 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.
  • 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,
  • 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, ⁇ 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.
  • R 5 , R 6 , or R 8 When two or more groups R 5 , R 6 , or R 8 are present, they may be the same or different.
  • R 3 represents OH or a group other than halogen. Also excludes 2,3-dimethylquinoxaline-5-carboxamide. The same applies hereinafter. )
  • a medicine particularly a PARP inhibitor, comprising a quinoxaline derivative or a salt thereof.
  • a medicine particularly a PARP inhibitor, comprising a quinoxaline derivative or a salt thereof.
  • alkyl means 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.
  • 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).
  • cyclopentyl, cyclohexyl, Chloroheptyl, phenyl, naphthyl, indanyl and tetrahydronaphthyl groups 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).
  • a spiro ring including an acetal such as a 1,3-dioxolan ring derived from an oxo group.
  • 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 ⁇ Pi cycloalkyl of 1-5 C 1-6 ⁇ alkyl, halogen, 0H
  • 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 ( ⁇ ). 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 ⁇ , 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.
  • Y ⁇ YR May be a pyrrolidinyl, piperidinyl, homopiberidinyl, piperazur, homopiperazinole, feninole, pyridinole, piperazinole feninole, homopiperazininolefenir, pirazinyl pyridyl or homopiperagel pyridyl group
  • 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-flu
  • R 1 and R 3 are H
  • 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
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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. .
  • 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.
  • 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.
  • 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.
  • R represents d_4 alkyl such as methinole and ethyl or H.
  • 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., ⁇ , ⁇ -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.
  • 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.
  • 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.
  • 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.
  • mixed acid anhydrides examples 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.
  • 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.
  • condensing agent examples include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
  • WSC 1,1′-carbonylbis-1H-imidazole
  • CDI 1,1′-carbonylbis-1H-imidazole
  • further additives for example, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole ( HOBt) etc.
  • the solvent examples 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.
  • 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
  • pyridine dimethylsulfoxide
  • solvents can be used alone or as a mixture of two or more.
  • 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.
  • 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.
  • 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.
  • 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.
  • a conventional method of reductive alkylation reductive amination from the viewpoint of a carbonyl compound
  • 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).
  • 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).
  • DPPA diphenylphosphoryl azide
  • 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.
  • the quinoxaline compound (VIII) is a diaminobenzoate compound (V) and a diketo compound ( VI) or a haloketone or the like (VII).
  • the diketo compound (VI) 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.
  • 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.
  • 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
  • Compound (V) can be produced by the method described in US5380719 and the like. Ring closure 2
  • 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.
  • 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.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • 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.).
  • inflammatory diseases eg, rheumatoid arthritis, ulcerative colitis, Crohn's disease, peritonitis, pleurisy, nephritis, etc.
  • autoimmune diseases eg, type I diabetes
  • ischemia-reperfusion injury eg, stroke, myocardial infarction, organ transplantation, etc.
  • 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.
  • 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.
  • 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.
  • the compound of the present invention is useful as a therapeutic agent for various diseases involving PARP.
  • mice 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.
  • Each test compound suspension or solution was orally administered to the above-mentioned Balb mass at a desired dose of 5 ml / kg.
  • 0.5% methylcellulose as a solvent was administered at 5 ml / kg.
  • 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.
  • 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.
  • 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. .
  • 0.5% methylcellulose as a solvent was administered at 5 ml / kg.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the numeral before the substituent indicates the substitution position, and a numeral having a plurality of numbers indicates a plurality of substitutions.
  • 2-MeO-Ph represents 2-methoxyphenyl
  • 2,4- (MeO) 2-Ph represents 2,4-dimethoxyphenyl.

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Abstract

La présente invention concerne des composés cliniquement efficaces qu'on peut utiliser comme remèdes contre diverses maladies dans lesquelles la poly(ADP-ribose) polymérase intervient (PARP), en particulier, des maladies inflammatoires telles que l'arthrite rhumatoïde. Cette invention concerne aussi des dérivés de quinoxaline possédant un groupe carbamoyle en position 5 et un ou des substituants en positions 2 et/ou 3, en particulier, des composés possédant un groupe hydrocarbure cyclique ou un groupe hétérocyclique substitué par Y1 Y2 R4 en position 3, ou des sels de ceux-ci répondant aux normes pharmaceutiques.
PCT/JP2003/000545 2002-01-23 2003-01-22 Composes de quinoxaline WO2003062234A1 (fr)

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EP1683523A1 (fr) * 2005-01-25 2006-07-26 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. 2-phenylquinoxalines comme inhibiteurs de mpp1
JP2006519806A (ja) * 2003-03-07 2006-08-31 グラクソ　グループ　リミテッド 尿素誘導体および疼痛治療におけるバニロイド受容体拮抗剤としてのそれらの使用。
JPWO2005028438A1 (ja) * 2003-09-22 2007-11-15 萬有製薬株式会社 新規ピペリジン誘導体
WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
WO2008015429A2 (fr) * 2006-08-01 2008-02-07 Sentinel Oncology Limited Composés pharmaceutiques
JP2009530287A (ja) * 2006-03-13 2009-08-27 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 高血圧、炎症および他の疾患の治療のための可溶性エポキシドヒドロラーゼの阻害剤としてのピペリジニル、インドリル、ピリニジル、モルホリニルおよびベンズイミダゾリル尿素誘導体
JP2009197010A (ja) * 2005-08-26 2009-09-03 Iyaku Bunshi Sekkei Kenkyusho:Kk Ｐｐａｒアゴニスト活性を有する誘導体
KR100916716B1 (ko) * 2007-09-27 2009-09-10 한국화학연구원 3-클로로-5-치환-퀴녹살린-2-아민 유도체 및 약제학적으로허용 가능한 그의 염, 그의 제조방법 및 그를 유효성분으로함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련 질환치료제
US7592347B2 (en) 2003-04-23 2009-09-22 Glaxo Group Limited Piperazine derivates and their use for the treatment of neurological and psychiatric diseases
US7709496B2 (en) 2006-04-06 2010-05-04 Glaxo Group Limited Antibacterial agents
US7812025B2 (en) 2005-08-12 2010-10-12 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent and therapeutic agent for sleep disorder
JP2010537969A (ja) * 2007-08-31 2010-12-09 パーデュー、ファーマ、リミテッド、パートナーシップ 置換キノキサリンタイプピペリジン化合物とその使用
US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
WO2012085648A1 (fr) 2010-12-22 2012-06-28 Purdue Pharma L.P. Composés de pipéridine de type quinoxaline substitués par du phosphore et leurs utilisations
JP2012517448A (ja) * 2009-02-11 2012-08-02 リアクション バイオロジー コープ． 選択的キナーゼ阻害剤
EP2537844A1 (fr) 2008-07-21 2012-12-26 Purdue Pharma L.P. Composés pipéridine à liaison et substitués par une quinoxaline, et leurs utilisations
US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
WO2013080036A1 (fr) 2011-12-01 2013-06-06 Purdue Pharma L.P. Composés de pipéridine de type quinoxaline substituée par une azétidine et leurs utilisations
WO2014020405A1 (fr) 2012-07-30 2014-02-06 Purdue Pharma L.P. Composés de pipéridine cycliques de type quinoxaline substitués par un groupe dérivé d'urée ou un groupe dérivé de lactame et leurs utilisations
WO2014102592A2 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine de type quinoxaline substituée par oxime et leurs utilisations
WO2014102589A1 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine du type quinazolin-4(3h)-one et utilisations de ceux-ci
WO2014102588A2 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine de type indole et indoline et leurs utilisations
WO2014102594A2 (fr) 2012-12-27 2014-07-03 Purdue Pharma L.P. Composés de pipéridine de type benzimidazole substitué et leurs utilisations
WO2015163435A1 (fr) * 2014-04-24 2015-10-29 田辺三菱製薬株式会社 Nouveaux dérivés de 2-amino-pyridine et 2-amino-pyrimidine et leur utilisation médicinale
JP2016536302A (ja) * 2013-10-23 2016-11-24 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 有害生物防除剤としての置換されているキノキサリン誘導体
WO2017079641A1 (fr) * 2015-11-06 2017-05-11 Neurocrine Biosciences, Inc. Dérivés de n-[2-(1-benzylpipéridin-4-yl)éthyl]-4-(pyrazin-2-yl)-pipérazine-1-carboxamide et composés apparentés en tant qu'antagonistes du récepteur muscarinique 4 (m4) pour le traitement de maladies neurologiques
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WO2004014873A1 (fr) * 2002-08-09 2004-02-19 Kyorin Pharmaceutical Co., Ltd. Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci
JP2006519806A (ja) * 2003-03-07 2006-08-31 グラクソ　グループ　リミテッド 尿素誘導体および疼痛治療におけるバニロイド受容体拮抗剤としてのそれらの使用。
US7592347B2 (en) 2003-04-23 2009-09-22 Glaxo Group Limited Piperazine derivates and their use for the treatment of neurological and psychiatric diseases
JPWO2005028438A1 (ja) * 2003-09-22 2007-11-15 萬有製薬株式会社 新規ピペリジン誘導体
JP4765627B2 (ja) * 2003-09-22 2011-09-07 Ｍｓｄ株式会社 新規ピペリジン誘導体
WO2006040192A1 (fr) * 2004-10-15 2006-04-20 Glaxo Group Limited Ligands de recepteurs histaminiques a base de derives pyrrolidiniques
EP1683523A1 (fr) * 2005-01-25 2006-07-26 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. 2-phenylquinoxalines comme inhibiteurs de mpp1
WO2006079478A1 (fr) * 2005-01-25 2006-08-03 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. 2-phenylquinoxalines comme inhibiteurs de mpp1
US7812025B2 (en) 2005-08-12 2010-10-12 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent and therapeutic agent for sleep disorder
JP2009197010A (ja) * 2005-08-26 2009-09-03 Iyaku Bunshi Sekkei Kenkyusho:Kk Ｐｐａｒアゴニスト活性を有する誘導体
US7750012B2 (en) 2005-12-21 2010-07-06 Decode Genetics Ehf Biaryl nitrogen-heterocycle inhibitors of LTA4H for treating inflammation
WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
US9029550B2 (en) 2006-03-13 2015-05-12 The Regents Of The University Of California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
US8501783B2 (en) 2006-03-13 2013-08-06 The Regents Of The University Of California Conformationally restricted urea inhibitors of soluble epoxide hydrolase
JP2009530287A (ja) * 2006-03-13 2009-08-27 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 高血圧、炎症および他の疾患の治療のための可溶性エポキシドヒドロラーゼの阻害剤としてのピペリジニル、インドリル、ピリニジル、モルホリニルおよびベンズイミダゾリル尿素誘導体
US7709496B2 (en) 2006-04-06 2010-05-04 Glaxo Group Limited Antibacterial agents
WO2008015429A3 (fr) * 2006-08-01 2008-10-02 Sentinel Oncology Ltd Composés pharmaceutiques
WO2008015429A2 (fr) * 2006-08-01 2008-02-07 Sentinel Oncology Limited Composés pharmaceutiques
US8071623B2 (en) 2007-01-10 2011-12-06 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
EP2433936A1 (fr) 2007-08-31 2012-03-28 Purdue Pharma LP Composés de pipéridine de type quinoxaline substituée et leurs utilisations
JP2010537969A (ja) * 2007-08-31 2010-12-09 パーデュー、ファーマ、リミテッド、パートナーシップ 置換キノキサリンタイプピペリジン化合物とその使用
EP2433935A1 (fr) 2007-08-31 2012-03-28 Purdue Pharma LP Composés de pipéridine de type quinoxaline substituée et leurs utilisations
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US9527840B2 (en) 2007-08-31 2016-12-27 Purdue Pharma L.P. Substituted-quinoxaline-type piperidine compounds and the uses thereof
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US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
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US10519156B2 (en) 2008-07-21 2019-12-31 Purdue Pharma L.P. 9′-Aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-one and preparation thereof
US8476271B2 (en) 2008-07-21 2013-07-02 Purdue Pharma, L.P. Substituted-quinoxaline-type bridged-piperidine compounds as ORL-1 modulators
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US9145408B2 (en) 2008-07-21 2015-09-29 Purdue Pharma L.P. Substituted-quinoxaline-type bridged-piperidine compounds as ORL-1 modulators
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US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators
US9951038B2 (en) 2012-12-27 2018-04-24 Purdue Pharma L.P. Quinazolin-4(3H)-one-type piperidine compounds and uses thereof
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