WO2006077851A1 - Derive de quinolone et sel de ce dernier - Google Patents

Derive de quinolone et sel de ce dernier Download PDF

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Publication number
WO2006077851A1
WO2006077851A1 PCT/JP2006/300590 JP2006300590W WO2006077851A1 WO 2006077851 A1 WO2006077851 A1 WO 2006077851A1 JP 2006300590 W JP2006300590 W JP 2006300590W WO 2006077851 A1 WO2006077851 A1 WO 2006077851A1
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Prior art keywords
lower alkyl
lower alkylene
group
alkylene
substituted
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PCT/JP2006/300590
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English (en)
Japanese (ja)
Inventor
Yuji Koga
Takao Okuda
Ryoji Hirabayashi
Jiro Fujiyasu
Takehiro Miyazaki
Susumu Watanuki
Fukushi Hirayama
Yumiko Moritani
Jun Takasaki
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Astellas Pharma Inc.
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Publication of WO2006077851A1 publication Critical patent/WO2006077851A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a novel quinophone derivative or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly a platelet aggregation inhibitor, a P2Y12 inhibitor.
  • platelets Since its discovery in 1842 by Donne, platelets have long been treated as a component in blood necessary for hemostasis. Today, platelets not only play a leading role in the mechanism of hemostasis, but also become a clinically recognized arteriosclerosis, cardiovascular disease including thrombotic disease, cancer transition, inflammation, post-transplant rejection, and immune response. It has been clarified to show multifunctionality such as involvement of
  • PTCA therapy and stent placement have rapidly spread to treat diseases based on coronary stenosis such as angina pectoris and myocardial infarction and aortic stenosis, and have achieved certain results.
  • these therapies damage vascular tissues including endothelial cells, causing acute coronary occlusion and further restenosis that occurs in the chronic phase. Platelets play an important role in various thrombotic effects (such as reocclusion) after such revascularization therapy. Therefore, the effectiveness S of antiplatelet agents is expected to be effective S, and the effectiveness of conventional antiplatelet agents has not yet been proven.
  • Examples of the preventive or therapeutic agent for these cardiovascular diseases include aspirin, cilostazol, Rostaglandin I, prostaglandin E, ticlopidine, clopidogrel, dipyridamo
  • Inhibitors of platelet aggregation such as ru have been used.
  • GPIIb / IIIa antagonists that inhibit the final stage of platelet aggregation and have strong platelet aggregation inhibitory activity have been developed, but their use is limited to intravenous infusion in the acute phase of thrombosis (Non-Patent Documents) 2).
  • Patent Documents 6 and 7 are known as quinolone derivatives.
  • Patent Document 6 a compound represented by the formula (A) having an antibacterial action is known, but it is not known that these derivatives have a platelet aggregation inhibitory action.
  • Patent Document 7 filed by the present applicant and published after the priority date of the present application, it is reported that the compound represented by the formula (B) has a P2Y12 inhibitory action.
  • Non-Patent Document 1 “Journal of the American College of Cardiology”, 1988, No. 12, p.616-623
  • Patent Document 2 “Sogo Clinical", 2003, No. 52, p.1516-1521
  • Patent Document 1 International Publication WO 00/34283 Pamphlet
  • Patent Document 2 International Publication No. WO 02/098856 Pamphlet
  • Patent Document 3 International Publication No. WO 03/022214 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No. WO 05/000281
  • Patent Document 5 International Publication No. WO 05/035520 Pamphlet
  • Patent Document 6 International Publication No. WO 98/23592 Pamphlet
  • Patent Document 7 International Publication No. WO 05/009971 Pamphlet
  • an object of the present invention is to provide a novel compound useful as a platelet aggregation inhibitor and a P2Y 12 inhibitor, which has a good balance between pharmacological effects and safety with high pharmacological effects.
  • a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, P2Y12 It was found that the compound has a novel skeleton exhibiting an inhibitory action. Furthermore, as a result of intensive studies, it was found that a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, and the present invention was completed.
  • the present invention relates to a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof useful as a P2Y12 inhibitor.
  • R 6 _H, halogen, lower alkyl or halogeno lower alkyl.
  • R 2 lower alkyl, cycloalkyl, aryl or hetero ring each optionally substituted.
  • R 3 Neurogen.
  • R 4 cycloalkyl
  • R 5 -H, - ⁇ H or halogen.
  • R U -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.
  • R 12 lower alkyl which has at least one substituent selected from the P group and may further have a substituent.
  • R e -R xa , lower alkylene-0 (CO) R x , lower alkylene-0 (CO) OR x , lower alkylene-S (
  • R b the same or different from each other, ⁇ OR -NH, -NR -N (R a ), _0 (C0) R a or a cyclic amino group.
  • R d the same or different from each other, —0R e , —NH, —NHR a , —N (R a ), —0 (CO) R a or a cyclic amino group;
  • R b and R d are integrated, It is possible to form a group represented by L.
  • L _0_lower alkylene-0_, -0-lower alkylene-NH-, -0-lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, _NH_lower alkylene-N (lower alkyl) -, -N (lower alkyl) -lower alkylene- N (lower alkyl)-, -0-lower alkylene-0-CO
  • alkylene-0-, -0-lower alkylene-0-CO-, -0-aryl-CO- or -0-heterocyclic-CO- may be formed.
  • the lower alkylene moiety of each may be substituted with a group selected from group G 1.
  • the -0-aryl-C0- and -0-heterocyclic-CO- aryl and heterocycles are each G 2. Substituted with a group selected from the group.
  • R a the same or different from each other, _R X , lower alkylene-0 (C ⁇ ) R x , lower alkylene- ⁇ (C ⁇ ) 0R x , lower alkylene-S (C0) R x , lower alkylene-S (C0 ) 0R x or lower alkylene-SS-R x .
  • R x lower alkyl, cycloalkyl, aryl or heterocycle.
  • lower alkyl may be substituted with a group selected from group G 1
  • cycloalkyl, aryl and heterocycle may each be substituted with a group selected from group G 2 .
  • R xa lower alkyl substituted with a group selected from group G 3 (excluding lower alkyl substituted only with -C0 -lower alkyl), -CH ((-0 (C0) _lower alkyl) -Lower alkylene-C0 -lower alkyl, cycloalkyl, aryl or heterocycle.
  • cycloalkyl, aryl and heterocycles in R xa are each substituted with a group selected from Group G 2 .
  • G Group 1 Halogen, -0H, -0-lower alkyl, -NH, -NH-lower alkyl, -N (lower alkyl), -N (lower alkylene-0H), -N (lower alkyl) -C0- Lower alkylene-aryl, -CO H, -CO -lower alkyl, - ⁇ (C0) _lower alkyl, -C0NH, -C0NH-lower alkyl, -C0N (lower alkyl), aryl and heterocycle.
  • group G 1 is each substituted with a group selected from group G 2. May be.
  • G 2 group halogen, oxo, lower alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, -0-halogeno lower alkyl, -O (CO) -lower alkyl, -CO H, -CO -lower alkyl Kill, lower alkylene-0H, lower alkylene- ⁇ -lower alkyl, lower alkylene-NH
  • G 3 group -N (lower alkylene-OH), - ⁇ (C0) _lower alkyl, -CO -lower alkyl, aryl substituted with a group selected from group G 2 (however, aryl substituted only with halogen) heterocycle substituted with a group selected from the excluded) and G 2 groups.
  • R 2 and R 6 may be combined to form lower alkylene or lower alkenylene.
  • the present invention also provides a pharmaceutical composition comprising a quinolone derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in particular, a P2Y12 inhibitor, It also relates to a pharmaceutical composition that is a platelet aggregation inhibitor. That is, (1) a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
  • C6-15 cells in a 10 cm dish are seeded with DMEM medium to 1 ⁇ 10 6 cells and cultured for 1 day, then 8 ⁇ g of plasmid pEF- BOS-dhfr-human P2Y12 and 0.8 ⁇ g of pEF-BOS_neo (Nucleic Acid Res., 18,5322,1990) was gene-transferred using a transfection reagent (LipofectAMINE 2000; manufactured by GIBCO BRL).
  • the cells into which the gene has been transferred are collected, suspended in DMEM medium containing 0.6 mg / ml G418 (GIBCO BRL), and then diluted serially to a 10 cm petri dish. Sowed. Colonies that appeared after 2 weeks were individually obtained and used as P2Y12 protein-expressing C6-15 cells in the following experiments (WO 02/36631, Mol. Pharmacol., 60,432, 2001).
  • the P2Y12 protein-expressing C6-15 cell membrane fraction (100 ⁇ g / ml) produced above was prepared by adding 1.5 ⁇ 1 and 0.75 nM [ 3 H] _2_MeS_ADP (80 Ci / mmol, Amersham Pharm acia Biotech) (50 ⁇ l) was added and incubated in 50 mM Tris-HCl (pH 7.4) containing 100 mM NaCl and 50 mM MgCl for 1 hour at room temperature. Collected in a filter. A micro scintillator was added to the glass filter, and the radioactivity was measured with a liquid scintillation counter.
  • Platelet aggregation was measured using a platelet aggregometer (MCM Matreaser 212; Em 'Shiichi' Medical). After incubating 90 ⁇ 90 of PRP at 37 ° C for 1 min, adding 100 mg of ADP (50 ⁇ ) induced platelet aggregation, and the change in transmitted light was recorded for 5 min. The inhibition rate was calculated using the area under the platelet aggregation curve as an index.
  • Example 653 Was found to have a 50% inhibitory effect on oral administration to rats.
  • a male male quix (3-6 kg) was held on a holding table, and the compound of the present invention was orally administered using a catheter.
  • Blood is collected from the femoral vein using a syringe containing 1/10 volume of 3.8% sodium citrate solution before administration of the compound and 0.5, 1, 2, 4, 8, 12, 24, 48 hours after administration. It was. Centrifugation was performed to separate supernatant platelet-rich plasma (PRP).
  • PRP supernatant platelet-rich plasma
  • the number of platelets in PRP was measured with an automatic hemocytometer (MEK-6258, Nihon Kohden), and the platelet count in PRP was adjusted to 3 ⁇ 10 8 / ml using platelet poor plasma.
  • ADP which is a platelet aggregation inducer, used a product of M'C'Medical.
  • Platelet aggregation was measured using a platelet aggregometer (MCM Hematracer 212; Em 'Shiichi' Medical). After incubating 90 ⁇ 90 of PRP at 37 ° C for 1 minute, platelet aggregation was induced by adding 10 ⁇ 1 of ADP (50 ⁇ ), and the change in transmitted light was recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. As a result of evaluating the activity of the compound of the present invention after oral administration by this method, it was revealed that the compound has a strong and sustained platelet aggregation inhibitory effect in the oral administration of power quix monkeys.
  • the compound (I) of the present invention includes a compound that is metabolized in vivo and exhibits P2Y12 inhibitory activity, a so-called prodrug.
  • a compound selected from the group ⁇ is -P (0) (OH) (R d ) or -P (0) (R b ) (R d ), or selected from the group P
  • the compounds whose group is —CO 2 there are compounds that are converted to —PO 2 H and —CO 2 H in vivo and exhibit P2Y12 inhibitory activity.
  • the usefulness of such compounds can be confirmed by the above test method (3) or (4), or by combining the following test methods (5) and test methods (1) to (2).
  • the male compound of the present invention was orally administered to male SD rats (5-7 weeks old) using a sonde. Two hours after compound administration, blood was collected using a syringe containing 1/10 volume of a 3.8% sodium citrate solution. Centrifugation was performed to separate supernatant platelet-rich plasma (PRP). PRP was further centrifuged at high speed, and the supernatant from which platelets had been removed was separated as poor platelet plasma (PPP). In order to draw a standard curve, the PPP of SD rats not administered with the compound was also separated, and this PPP Prepare serial dilutions of the parent compound (final concentration 30 ⁇ to 0 ⁇ 0003 / ⁇ M: select as appropriate depending on the parent compound).
  • PRP supernatant platelet-rich plasma
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
  • lower alkyl means alkyl of C, specifically, for example, methyl
  • “Lower alkenyl” is a C alkyl having one or more double bonds at any position.
  • examples include ethyl, propenyl, butur, pentul, hexenyl, butagenyl, etc., preferably C alkenyl ethenyl, 1-
  • “Lower alkynyl” is an alkyl of C having one or more triple bonds at any position.
  • “Lower alkylene” means a divalent group formed by removing one hydrogen at any position of “lower alkyl”, and specifically includes methylene, methylmethylene, ethylene, trimethylene, propylene, butylene, etc. Preferably, they are methylene, ethylene and trimethylene.
  • “Lower alkenylene” means a divalent group formed by removing one hydrogen at any position of “lower alkenyl”, specifically vinylene, 1_propenylene, 2_propenylene. 1_butenylene, 2_butenylene, 3_butenylene and the like, preferably vinylene, 1-propenylene and 2_propenylene.
  • “Lower alkylidene” means a group in which a free valence formed by removing one hydrogen from a carbon atom having a “lower alkyl” bond becomes part of a double bond.
  • Cycloalkyl means a monovalent group of a non-aromatic hydrocarbon ring of C.
  • spiro ring It may form a spiro ring or may have a partially unsaturated bond.
  • Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctane genyl, adamantyl and norbornyl, and cyclopentyl or cyclohexenole is preferred.
  • Aryl means a monovalent group of a monocyclic to tricyclic C aromatic hydrocarbon ring.
  • phenyl and naphthyl examples thereof include phenyl and naphthyl, with phenyl being preferred.
  • Non-aromatic heterocycle means nitrogen, oxygen, sulfur which may be condensed with aryl or aromatic hetero ring which may have a saturated or partially unsaturated bond A monovalent group having 3 to 10 members, preferably 5 to 7 members, having 1 to 4 heteroatoms such as the above. However, the bond is on a saturated or partially unsaturated ring.
  • pyrrolidinyl piperidinyl, piperazil, azepinyl, monoreforinole, thiomorpholinyl, pyrazolidinyl, dihydropyrrolinole, tetrahydropyranyl, tetrahydrofuryl, dioxanyl, tetrahydrothiopyrael, tetrahydrothenyl and the like.
  • Preferred are pyrrolidinyl, piperidinyl, piperazil, azepinyl, monoreforinole, thiomorpholinyl, tetrahydroviranyl, dioxanyl and tetrahydrothiopyranyl.
  • Heterocycle is a general term in which “aromatic heterocycle” is added to “non-aromatic heterocycle”, and “aromatic heterocycle” is a group consisting of nitrogen, oxygen and sulfur. Containing 1 to 4 of the same or different selected heteroatoms, fused with a benzene ring, or may be aromatic or heteroaromatic.
  • a monovalent group of a ring specifically, for example, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furazanyl, pyridyl, biranyl, thiopyranyl, pyridazinyl, pyrimidinyl, virazil, indolyl, isoindolyl , Indolizinyl, benzofuryl, benzocenyl, benzimidazolyl, indazolyl, benzotriazolinole, benzoxazolinole, benzothiazolyl, benzoxazizonolinole, quinolinole, isoquinolyl, chromeninole, benzothiobilanyl, phthaladilyl, naphthyridinyl , Cinnolinole, benzodioxolyl, benzodioxur, be
  • Halogen means a halogen atom, and specific examples thereof include fluoro, black mouth, bromine and iodine, and preferred are fluoro and black mouth.
  • halogeno lower alkyl group means a group in which one or more arbitrary hydrogen atoms of the “lower alkyl group” are substituted with the “halogen”, specifically, for example, trifluoromethyl, trifluoroethyl and the like. Preferably, it is trifluoromethyl.
  • Cyclic amino is a monovalent heterocyclic group having at least one nitrogen atom and having a bond to the nitrogen atom, and may further contain oxygen or sulfur as a heteroatom.
  • Specific examples include pyrrolidino, piperidino, piperazino, homopiperazino, morpholino, thiomorpholine-containing 3,4-dihydroisoquinoline-2 (1H) _yl, etc., preferably pyrrolidone-containing piperidino, piperazino, 3,4 -Dihydroisoquinoline-2 (1H) _yl.
  • the "parent compound" of a prodrug refers to a compound that is released from a prodrug by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo.
  • Substituted means substituted with one or more substituents.
  • Substituents permitted in “substituted les, may be, cycloalkyl”, “substituted les, may be, aryl,” and “optionally substituted heterocycle” in R 2 Examples of these include groups represented by the following (a) to (h).
  • lower alkyl which may be substituted in R u , R lla , R ub and R Ue , “substituted ret , may les, lower alkyl” in R 12 , “substituted” in R 2
  • Substituents that are acceptable for “lower alkyl” and “lower alkenyl that may be substituted” include the groups shown in the following (a) to (g): .
  • substitutions allowed in “cyclic amino” which may have a substituent represented by R 11 and R 12 , R lla and R 12a , R ub and R 12b, and R Ue and R 12e together with the adjacent nitrogen atom
  • groups of the group include the P group, Pa group, Pb group, Pc group, and groups shown in the following (a) to (h).
  • the substituents allowed in the “lower alkyl” optionally having substituents in R 12 , R 12a , R 12b and R 12e include the P group, Pa group, Pb group, Pc group, and And the groups shown in the following (a) to (g).
  • i is -OH, -0-lower alkyl, amide-substituted -CO H, -CO R z , which may be substituted with one or two lower alkyls, or one or two lower alkyls. May be rubamoyl, aryl (this aryl may be substituted with halogen), aromatic heterocycle and lower alkyl optionally substituted with one or more groups selected from the group consisting of halogen Indicates.
  • aryl or cycloalkyl are substituted with _OH, -O_lower alkyl, one or two lower alkyls which may be substituted with amide -CO H, -CO R Z , one or two lower alkyls. And optionally substituted one or more groups selected from the group consisting of rubamoyl, aryl, aromatic heterocycle, halogen and Rz .
  • Amino optionally substituted with an optionally substituted lower alkyl group" in R ", R" a , Rllb and R “ e is the above R
  • Y is preferably CH or N, more preferably CH.
  • R 11 is preferably —H.
  • R 12 is preferably-(halogen or lower alkyl optionally substituted with -C0H.
  • a lower alkylene which may be substituted with a rogen (R d ).
  • the two R d isomers become-0-lower alkylene-0_,-0-lower alkylene-NH-, -0-lower alkylene-N (lower alkyl)-, _NH_lower alkylene-NH- , -NH-lower Alkylene-N (lower alkyl)-, -N (lower alkyl) -lower alkylene-N (lower alkyl)-, -0-lower alkylene-0-CO -lower alkylene-0-, -0-lower alkylene-0- CO-
  • -0-aryl-CO- or -0-heterocyclic-CO- may be formed.
  • -Les may be substituted with lower alkyl or aryl.
  • R qa is a group represented by Where -O_ lower alkylene-0 (C ⁇ ) -lower alkyl, -0-lower alkylene-o (co) -cycloalkyl, -0-lower alkylene-0 (C0) -lower alkylene- (one or NH optionally substituted with two lower alkyls), -0-lower alkylene-0 (C0) _lower alkylene-heterocycle,-
  • 0-lower alkylene-o (co) o-lower alkyl, -0-lower alkylene-o (co) o-cycloalkyl, -0-lower alkylene-0 (C0) 0-lower alkylene- (one or two Substituted with lower alkyl, NH), -0-lower alkylene-0 (C0) 0-lower alkylene-heterocycle, NH optionally substituted with one or two lower alkyls,- NH-lower alkylene-COH, -NH-lower alkylene-CO-lower alkyl, -0 (C0) -lower alkyl
  • R qa is lower alkylene-0 (C0) _lower alkyl, lower alkylene-o (co) -cycloalkyl, lower alkylene- ⁇ (co) -lower alkyl Xylene- (optionally substituted with one or two lower alkyls, NH), lower alkylene
  • H-heterocycle NH optionally substituted with one or two lower alkyls, -NH-C (Me) -CO lower alkyl, - ⁇ Ph, -0- (2-ethoxycarbonylsulfuric acid ), -OCH-(5-Methyl-2-oxo-1,3-dioxolan-4-yl)] (where two are combined to form - ⁇ -CH ( - ⁇ (C ⁇ ) _Lower alkyl) _ (CH) - ⁇ - or - ⁇ - (Orthophenylene)-
  • R is -CH 0 (C 0) _lower alkyl, -CH (Me) 0 (CO) _lower alkyl, -CH 0 (C 0) 0-lower alkyl, _CH (Me) 0 (CO) ⁇ -Lower alkyl, -CH ⁇ (C 0) _lower alkyl, -CH (Me) 0 (CO) ⁇ -Lower alkyl, -CH ⁇ (
  • -NR U R 12 is in the form of a cyclic amino group, preferably at least one -C 0 R c
  • R d -O-lower alkylene -O_, _0_lower alkylene -NH-, -0-lower alkylene -N (lower alkyl)-, -NH -lower alkylene.
  • 0-, -0-lower alkylene-0-CO-, -0-aryl-CO- or -0-heterocyclic-CO- may be formed.
  • R qa having at least one substituent selected from —CO R qa , _P (0) (0H) (R q ) and —P ( ⁇ ) (R q ), and further having a substituent Cyclic amino group (wherein R qa and R q are the above-mentioned groups), provided that two R q are in the form of _0 _ (-0 (C0) -lower alkyl and May be formed of lower alkylene) - ⁇ _ or - ⁇ -aryl -CO-. More particularly preferably has at least one substituent selected from —CO R ra , _P (0) (0H) (R F ) and —P (0) (), and further has a substituent.
  • the two isomers may form -0-CH (-0 (C0) -lower alkyl) _ (CH) -0- or-0- (orthophenylene) -CO-. Les. Particularly preferably, at least one substituent is -P (0) (0H) (0Ph), -P (0) (0H) [0CH
  • R 2 is preferably an optionally substituted lower alkyl, cycloalkyl or non-aromatic heterocycle.
  • R 3 is preferably halogen, more preferably fluoro.
  • R 4 is preferably cycloalkyl, more preferably cyclohexyleno.
  • R 5 is preferably —H, —OH or halogen, more preferably H, —OH or fluoro.
  • R 6 is preferably -H.
  • R Ua -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, and amino.
  • R 12a a lower alkyl having at least one substituent selected from the Pa group and further having a substituent.
  • Pa Group - CO R -P (0) ( ⁇ _H) (R d) and - P ( ⁇ ) (R b) (R d ).
  • R b and R d may be combined to form L in the case of Pa group -P ( ⁇ ) (R b ) (R d ).
  • NR Ua R 12a may integrally form a substituent selected from at least one Pa group and further form a cyclic amino group which may have a substituent.
  • R Ub -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, and amino.
  • R 12b a lower alkyl having a substituent selected from at least one Pb group and further having a substituent.
  • Pb group -CO R -P (0) (OH) (R d ) and -P (0) (R d ).
  • R d In (0) (R d ), two R d s may be combined to form a group represented by L. However, NRllb R 12b may integrally form a substituent selected from at least one Pb group, and may further form a cyclic amino group that may have a substituent. The same applies below.
  • R 12e a lower alkyl which has a substituent selected from at least one Pc group and may further have a substituent.
  • Pc group -CO R e , -P (0) (OH) (R e ) and -P (0) (R e ).
  • R e the same or different, - ⁇ -aryl, - ⁇ _lower alkylene- (_C ⁇ lower alkyl)
  • R ea the same or different from each other, aryl, lower alkylene-(-C0 lower alkyl and
  • R xb lower alkyl, cycloalkyl, aryl or heterocycle.
  • the lower alkyl may be substituted with a substituent of group G 4
  • the aryl may be substituted with -0 (CO) _lower alkyl.
  • G 4 group -NH, -NH (lower alkyl), -N (lower alkyl), _N (lower alkylene-OH),-
  • N (lower alkyl) -CO -lower alkylene -aryl, aryl, heterocycle N (lower alkyl) -CO -lower alkylene -aryl, aryl, heterocycle.
  • the aryl may be substituted with _o (co) -lower alkyl
  • the heterocycle may be substituted with lower alkyl.
  • NR "3 12e may be a isomer having a substituent selected from at least one Pb group, and may further form a cyclic amino group which may have a substituent. The same.] (4) The compound according to (3) represented by the formula (Id).
  • R 12d -(lower alkylene optionally substituted with halogen or -CO 2 H) _C ( ⁇ ) R f ,-(re substituted with halogen, or may be lower alkylene) -P ( ⁇ ) (OH) (R f ) or-(lower alkylene optionally substituted with halogen) -P (0) (R f ).
  • R f _0_lower alkylene-OC (0) _lower alkyl, -0-lower alkylene-OC ( ⁇ ) 0-lower alkyl, -0-lower alkylene _OC ( ⁇ ) 0-cycloalkyl or -0_lower alkylene -(5-methyl-2-oxo-1,3-dioxol-4-yl). The same applies below. ]
  • R 12e may be, lower alkylene) -P (0) (OH) (R f ) or-(lower alkylene optionally substituted by nodogen)- P ( ⁇ ) (R f ). The same applies below. ]
  • the quinolone derivative represented by the formula (I) may form a salt and is included in the compound of the present invention as long as the salt is a pharmaceutically acceptable salt.
  • inorganic salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and other acid addition salts with sodium, potassium, calcium,
  • inorganic bases containing metals such as gnesium, addition salts with organic bases such as methenoreamine, ethylamine, ethanolanolamine, lysine and onolenitine, and ammonium salts.
  • the compound of the present invention may contain an asymmetric carbon atom depending on the type of substituent, and optical isomers based on this may exist.
  • the present invention encompasses all of these optical isomer mixtures and isolated ones.
  • the compounds of the present invention may have tautomers, but the present invention includes a mixture of these isomers or a mixture thereof.
  • a label that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioisotope or a non-radioactive isotope is also encompassed in the present invention.
  • the present invention includes various hydrates and solvates of the compounds of the present invention and substances having crystal polymorphs. It should be understood that the compounds of the present invention include all of the quinolone derivatives represented by the formula (I) and pharmaceutically acceptable salts thereof, which are not limited to the compounds described in Examples below. To do.
  • the quinolone derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. can do.
  • the quinolone derivative represented by the formula (I) of the present invention can be easily synthesized from the quinolone derivative represented by the formula (I) by a known method.
  • typical production methods for the quinolone derivative represented by the formula (I) are exemplified.
  • the protecting group can be removed as necessary to obtain the desired compound.
  • functional groups include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of their protective groups include those described in “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. If you use these as appropriate, depending on the reaction conditions.
  • Y is the production method of the present invention compounds (I_ 1) which is a CR 6.
  • This step is a step for producing the compound (lc) by a condensation cyclization reaction between the compound (la) and the compound (lb).
  • the condensation 'cyclization reaction in this step can be performed without heating or in the presence of a high boiling point solvent (diphenyl ether or the like is preferably used) under heating to heating under reflux.
  • a high boiling point solvent diphenyl ether or the like is preferably used
  • This step is a step for producing the compound (le) by an alkylation reaction of the compound (lc) and the compound (Id).
  • the leaving group Lv in the compound (Id) in this step is commonly used in alkylation reactions. Any leaving group can be used.
  • Halogen such as bromo, iodine, black mouth, sulfonyloxy such as methanesulfonanoloxy, p-tonoleenesulfonyloxy, trifluoromethanesulfonyloxy and the like is preferably used.
  • the method described in J. Med. Chem., 23, 1358-1363, 1980. or a method analogous thereto can be employed.
  • This step is a step for producing the compound (lg) by substituting the leaving group of the compound (le) with the amino group of the compound (If).
  • the leaving group Lv in the compound (le) in this step can be any halogen that is commonly used in aromatic nucleophilic substitution reactions, such as halogens such as fluoro, black mouth, and bromo; methanesulfonyloxy, p-toluenesulfonyl Preferred examples include sulfonyloxy such as oxy, trifluoromethanesulfonyloxy, etc .; sulfonyl such as lower alkylsulfonyl, aryl sulfonyl, etc .; When sulfonyl is used as the leaving group Lv in Step C, the compound (la) having sulfonyl as Lv can be used as a starting material, and the compound (la) having a corresponding sulfanyl as Lv can be used as a starting material. Then, after an appropriate step, for example, step B, Lv can be converted to sulfonyl by an oxidation
  • the substitution reaction in this step is carried out in the absence of a solvent or aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane; dichloromethane, 1,2- Halogenated hydrocarbons such as dichloroethane and chloroform; N, N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); esters such as ethyl acetate (EtOAc); solvents inert to the reaction such as acetonitrile In a solvent such as methanol (MeO H), ethanol (EtOH), 2_propanol, etc., the compound (le) and the compound (If) are equimolar to one in an excess amount,
  • the reaction can be carried out at room temperature or under reflux with heating.
  • organic bases triethylamine, diisopropylethylamine, N-methylenomonoreforin, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used), or metal salt bases (carbonic acid) It may be advantageous to carry out in the presence of potassium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
  • This step is a step for producing compound (lh) by subjecting compound (lg) to a hydrolysis reaction.
  • the hydrolysis reaction in this step is based on aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, N, N_dimethylacetamide (DMA), N-methyl for compound (lg).
  • acids such as pyrrolidone, DMSO, pyridine, water, mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, organic acids such as formic acid, acetic acid; or lithium hydroxide, water oxidation
  • the reaction can be carried out under cooling to heating under reflux in the presence of a base such as sodium, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia.
  • the reaction temperature can be appropriately selected depending on the compound and the reaction reagent.
  • This step is a step for producing the compound (I 1) by amidation of the compound (lh) or a reactive derivative thereof and the compound (li).
  • amidation in this step those skilled in the art can employ a conventional amidation.
  • carbonyldiimidazole (CDI) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC 'HC1), dicyclohexylcarbodiimide, diphenylphosphoryl azide, jetylphosphoryl cyanide, etc.
  • WSC 'HC1 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • dicyclohexylcarbodiimide diphenylphosphoryl azide
  • jetylphosphoryl cyanide etc.
  • a method using a mixed acid anhydride using isotyl chloroformate, ethyl ethyl formate, and the like.
  • reaction usually in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, etc.
  • solvent inert such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, etc.
  • the reaction is carried out at room temperature or under reflux.
  • This step is a step of producing the compound (lj) by subjecting the compound (le) to a hydrolysis reaction, and can be carried out according to the step D.
  • This step is a step for producing compound (lh) by substituting the leaving group of compound (lj) with the amino group of compound (If), and can be carried out according to step C.
  • This step is a step of producing compound (lk) by amidation of compound (lj) or a reactive derivative thereof and compound (li), and can be performed according to step E.
  • This step is a step for producing compound (I-11) by substituting the leaving group of compound (lk) with the amino group of compound (If), and can be carried out according to step C.
  • This step is a step of producing the compound (11) from the alkyl group of the compound (la).
  • the alkylation in this step can be performed by a method according to Step B or by reductive alkylation.
  • reductive alkylation those skilled in the art can employ conventional reductive alkylation.
  • a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, and acetic acid. It is preferable to carry out at room temperature or under heating reflux.
  • an acid such as a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, or an organic acid such as formic acid or acetic acid.
  • This step is a step for producing compound (le) by a condensation and cyclization reaction between compound (lb) and compound (11), and can be carried out according to step A.
  • the production method via step A of this production method is a production method that can be adopted even when R 2 is difficult to introduce in the first production step B due to the bulkiness of R 2 such as tert-butyl group and adamantyl group.
  • the production method via Step B is a production method that can also be adopted when R 2 and R 6 are in the form of a ring to form a ring.
  • This step is a step of producing a compound (2c) in which is H by an addition / elimination reaction with the compound (2b) following a condensation reaction with the compound (2a) and orthoformate.
  • the condensation reaction with orthoformate in this step is carried out using a reagent that captures alcohol generated from orthoformate such as acetic anhydride as a solvent, or halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO. , In a solvent inert to the reaction such as esters such as ethyl acetate (EtOAc), acetonitrile, etc.
  • a reagent that captures alcohol generated from orthoformate such as acetic anhydride as a solvent, or halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO.
  • a solvent inert to the reaction such as esters such as ethyl acetate (EtOAc), acetonitrile, etc.
  • the addition / elimination reaction following the above condensation reaction is carried out in a solvent inert to the reaction such as alcohols, halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMSO, etc., under cooling, at room temperature to It can be carried out under heating to reflux.
  • reaction using an excess amount of compound (2b) Can also be done.
  • organic bases triethylamine, diisopropylethanolamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases potassium carbonate, cesium carbonate
  • This step is a step of producing compound (2c) by addition / elimination reaction of compound (2a) and compound (2d).
  • the addition / elimination reaction in this step involves equimolar compound (2a) and compound (2d) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. It is possible to carry out by using an excess amount of one side under cooling, at room temperature or under reflux with heating.
  • organic bases triethylamine, diisopropylethylamine, N-methylenomonophorin, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases carbonate It may be advantageous to carry out in the presence of potassium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
  • This step is a step of producing compound (le) by intramolecular cyclization reaction of the amino group of compound (2c).
  • the addition / elimination reaction in this step involves cooling compound (2c) from room temperature to heating under reflux in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. Can be done below.
  • organic bases triethylamine, disopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridin, etc. are preferably used
  • metal salts It may be advantageous to carry out in the presence of a base (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxy potassium etc. are preferably used).
  • the compound (1-1) can be produced by subjecting the compound (le) produced by this step to the same method as in the first production process. [Third manufacturing method]
  • This production method is a method for producing the compound (I 1 1) of the present invention that can be employed even when R 2 is formed into a ring to form a ring.
  • This step is a step of producing compound (2c) by a condensation reaction between compound (3a) and compound (3b).
  • halogen such as black mouth and bromo, alkoxy, vinyloloxy, sulfonyloxy such as p-toluenesulfonyl and the like are preferably used.
  • a compound (3b ′) in which the position of the double bond is isomerized can also be used.
  • the condensation reaction in this step is carried out by mixing equimolar amounts of compound (3a) and compound (3b) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO and the like.
  • a solvent inert such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO and the like.
  • One of them can be used in an excessive amount under cooling, at room temperature or under reflux with heating.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • metal salt bases potassium carbonate, Cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride ⁇ beam, tert- butoxy potassium or the like is when force s is advantageously carried out in the presence of a suitable are used).
  • This step is a step of producing compound (le) by cyclization reaction of compound (2c).
  • the intramolecular cyclization reaction in this step can be performed according to the second production step C.
  • (le) may be obtained from (3a) at once without isolating (2c).
  • the compound (1-1) can be produced by subjecting the compound (le) produced by this step to the same method as in the first production process.
  • This production method is a production method of the compound (I1) of the present invention in which a condensed ring is constructed after R 4 NH- is first introduced.
  • this step can also be performed by a substitution reaction using a rhodium catalyst (in this case, as Lv of the compound (la), halogens such as bromo and iodine, and trifluoromethanesulfonyloxy are preferably used).
  • a rhodium catalyst in this case, as Lv of the compound (la), halogens such as bromo and iodine, and trifluoromethanesulfonyloxy are preferably used.
  • This step is a step of producing compound (4b) by condensation / cyclization reaction of compound (4a) and compound (lb), and can be carried out according to the first production step A.
  • This step is a step for producing compound (4c) by an alkylation reaction of compound (4b) and compound (Id), and can be carried out according to the first production step B.
  • This step is a step of producing compound (lh) by subjecting compound (4c) to a hydrolysis reaction, and can be carried out according to the first production step D.
  • This step is a step of producing compound (I 1) by amidation of compound (lh) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E. .
  • This production method is a production method of the compound (I-12) of the present invention in which Y is N in the formula (I).
  • This step is a step for producing compound (5b) by diazotizing compound (5a) and subsequently adding cyanoethyl cyanoacetate.
  • the diazotization reaction which is the first step in this process, is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid, in a solvent inert to the reaction such as water or alcohol, and in the presence of an acid such as sodium nitrite or amylnitrite
  • the reaction can be carried out under cooling using an equimolar amount of compounding agent and compound (5a) in an excess amount.
  • the second stage addition reaction can be carried out by cooling the diazo compound prepared in the first stage and cyanoacetyl acetate in the presence of a base, using an equimolar amount or an excess of one, and cooling at room temperature or under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylolmonoreforin, pyridine, 4- ( ⁇ , ⁇ -dimethylamino) pyridine, etc. are preferably used), or metal salt bases ( Potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxy potassium, sodium acetate, etc. are preferably used).
  • This step is a step of producing compound (5c) by an alkylation reaction of compound (5b) and compound (Id), and can be carried out according to the first production method step B.
  • This step is a step for producing compound (5d) by subjecting compound (5c) to a hydrolysis reaction, and can be carried out according to the first production step D.
  • This step is a step for producing compound (5e) by acid halogenation and cyclization of compound (5d).
  • the first step of this process is carried out in the absence of solvent or in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as ethyl acetate, and acetonitrile.
  • the compound (5d) and a halogenating agent such as thionyl chloride and oxalyl chloride can be cooled using an equimolar amount to an excessive amount of a halogenating agent, and can be carried out at room temperature or under reflux.
  • the reaction may proceed advantageously by adding a catalytic amount of DMF or the like.
  • the acid halide obtained in the first stage is not used in the reaction without solvent, or in the reaction with aromatic hydrocarbons, halogenated hydrocarbons, acetyl acetate such as acetyl acetate, and acetonitrile.
  • the reaction can be carried out using an equimolar or excess amount of a Lewis acid such as aluminum chloride and cooled at room temperature or under reflux.
  • This step is a step for producing compound (5f) by substituting the leaving group of compound (5e) with the amino group of compound (If), and can be carried out according to the first production step C.
  • This step is a step for producing compound (5d) by subjecting compound (5f) to a hydrolysis reaction, and can be carried out according to the first production step D.
  • This step is a step for producing compound (I-12) by amidation of compound (5g) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E.
  • This production method is a production method of the compound (I2) of the present invention in which Y is N in the formula (I).
  • This step is a step of diazotizing compound (2a) to produce compound (6a).
  • the diazotization reaction in this step is carried out in a solvent inert to the reaction such as hydrocarbons such as pentane and hexane, aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, acetonitrile, and water.
  • a diazotization reagent such as toluenesulfonyl and compound (2a) can be used in an equimolar amount or in an excess amount and at room temperature or under reflux with heating.
  • organic bases triethylamine, diisopropylethylamine, N-methinomonomonoline, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used), or metal salt bases (potassium carbonate, It may be advantageous to carry out in the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
  • This step is a step of producing the compound (6b) by a reductive intramolecular cyclization reaction of the compound (6a).
  • This step uses trialkylphosphine or triarylphosphine as the reducing agent.
  • Can do As the leaving group Lv in the compound (6a), halogen such as fluoro, black mouth and bromo, sulfonyloxy such as P-toluenesulfonyl, nitro and the like are used. In particular, it is preferable to use fluoro.
  • halogen such as fluoro, black mouth and bromo
  • sulfonyloxy such as P-toluenesulfonyl, nitro and the like are used.
  • fluoro The method described in Chem. Pharm. Bull., 36, 1321-1327, 1988, or a method based thereon can be employed.
  • This step is a step of producing compound (6c) by an alkylation reaction of compound (6b) and compound (Id), and can be carried out according to the first production method step B.
  • This step is a step of producing compound (6d) by substituting the leaving group of compound (6c) with the amino group of compound (If), and can be carried out according to the first production method step C.
  • This step is a step for producing compound (6e) by subjecting compound (6d) to a hydrolysis reaction, and can be carried out according to the first production step D.
  • This step is a step of producing compound (I 2) by amidation of compound (6e) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E.
  • R 8 may be substituted with an unsaturated bond at the ⁇ -position such as allyl, propargyl, etc., lower alkenyl group or substituted ret, lower alkynyl group, R 9 and R 1Q represents H or a lower alkyl group, or R 9 and R 1Q together may represent a lower alkylidene, and m and n represent 0 to 3.
  • This production method is a production method of the compound (I-13) of the present invention in which R 2 forms a ring with R 2 in formula (I).
  • This step is a step of producing compound (7b) by an alkyl reaction between compound (1) and compound (7a).
  • the alkylation reaction in this step is not carried out in the absence of a solvent or in the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as DMF, DMSO, and ethyl acetate (EtOAc), and acetonitryl.
  • an active solvent or a solvent such as alcohols the compound (lc ′) and the compound (7a) can be used in an equimolar amount or in an excess amount and at room temperature or under reflux with heating.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used.
  • a metal salt base may be advantageous.
  • This step is a step of producing compound (7c) by intramolecular rearrangement reaction of compound (7b).
  • the cyclization reaction in this step can be performed without heating or in the presence of a high-boiling solvent (1,2-dichlorobenzene or the like is preferably used) under heating to heating under reflux. (Process.)
  • R 8 is a leaving group such as halogen (black mouth, bromo is preferably used), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy is preferably used) or a triple bond
  • halogen black mouth, bromo is preferably used
  • sulfonyloxy methanesulfonyloxy, p-toluenesulfonyloxy is preferably used
  • a triple bond Is a step of producing a compound (le ′) by an intramolecular cyclization reaction of the compound (7c).
  • the intramolecular cyclization reaction in this step involves cooling compound (7c) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, and DMSO without solvent.
  • the reaction can be carried out at room temperature or under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases potassium carbonate
  • (le ') may be obtained from (7b) at once without isolating (7c).
  • Compound (1-3) can be produced by subjecting compound (le ′) produced in this step to the same method as in the first production process.
  • R 13 represents an optionally substituted lower alkylene
  • -X-OH represents -CO H, -SO H, -P
  • the alkylation reaction in this step is not carried out in the absence of a solvent or in the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as DMF, DMSO, and ethyl acetate (EtOAc), and acetonitryl.
  • a base in an active solvent or a solvent such as an alcohol, equimolar amounts of compound (8a) and compound (8b) can be used in an excess amount, or from room temperature to heating under reflux.
  • Bases include organic bases (triethylamine, diisopropylethanolamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, 1,8-diazabicyclo [5.4.0] -7_undecene, etc.
  • a metal salt base carbonic acid lithium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, silver nitrate, silver carbonate, silver oxide, etc. are preferably used.
  • Is preferably used.
  • the compounds represented by the formula (I) are usually employed by those skilled in the art, such as known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. from the compounds obtained as described above. It can also be produced by arbitrarily combining the possible processes.
  • the compound of the present invention thus produced can be isolated or purified as it is as it is, or after being subjected to a salt formation treatment by a conventional method. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography. Various isomers can be isolated by conventional methods using differences in physicochemical properties between isomers . For example, a racemic mixture can be converted to an optically pure heteroisomer by a general racemic resolution method, such as a method of optical resolution by diastereomeric salt with a general optically active acid such as tartaric acid. The diastereo mixture can be separated by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.
  • a pharmaceutical composition containing the compound of the present invention or one or more of pharmaceutically acceptable salts thereof as an active ingredient includes a carrier, excipient, and other additives that are usually used in a formulation. It is prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc. and administered orally or parenterally.
  • the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which it is applied.
  • the daily dose is usually about 0.0001 per body weight. ⁇ 50 mg / kg, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, which is administered once or divided into 2 to 4 times.
  • the daily dose is about 0.0001 to 1 mg / kg per body weight, preferably about 0.0001 to 0.1 mg / kg, and is administered once to several times a day. Since the dosage varies depending on various conditions, a sufficient effect may be obtained with an amount smaller than the above dosage range.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substances are present in at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl senolate, microcrystalline cellulose, starch, polyvinylinole. Mixed with pyrrolidone, magnesium metasilicate aluminate, etc.
  • the composition contains additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrating agents such as calcium calcium glycolate, stabilizers, solubilizing agents and the like according to conventional methods. It may be.
  • the tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropenoresenololose, hydroxypropenoremethenoresenololose phthalate, or a gastric or enteric film.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and are generally used as inert dilutions.
  • Agent for example Contains water, ethanol (EtOH).
  • the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solutions and suspensions include distilled water for injection and physiological saline.
  • non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80, and the like.
  • Such a composition may further contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and solubilizing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. They can also be prepared by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.
  • R, R 5 , A Substituents in the general formula (Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, iBu: isobutyl, sBu: sec_butyl, tBu: tert-butyl, nP en: normal Pentyl, cPr: Cyclopropyl, cBu: Cyclobutyl, cPen: Cyclopentyl, cHex: Cyclohexyl, cH: Cycloheptyl, cOct: Cyclooctyl, Ph: Phenyl, Py: Pyridyl, fur: Furyl, the: Chenyl, Bn: Benzyl, btria: benzotriazolyl, bimi d: benzimidazolinole, pyrr: pyrrolidininore, pipe: piperidinole, pipa
  • 3-Bromo _4_Fluorobenzoic acid is dissolved in toluene, tert-butanol, triethylamine, diphenylphosphoryl azide are added in that order, and the mixture is stirred at 100 ° C for 20 hours.
  • -Fluorophylzinore obtained the strength rubamate.
  • the compound of Reference Example 3 was suspended in DMF, and potassium carbonate and iodinated chill were sequentially added under ice cooling, followed by stirring at room temperature for 24 hours, extraction with black mouth form, and concentration under reduced pressure.
  • the obtained residue was suspended in acetic acid, 6M HC1 aq was added at room temperature, and the mixture was stirred at 120 ° C for 4 hours, and then 6,7-difluoguchi-1-ethyl-4-oxo-1, 4-Dihydroquinoline-3-carboxylic acid was obtained.
  • the reference examples 31 to 39 shown in Table 5 are used as the corresponding raw materials. Manufactured using.
  • the compound of Reference Example 30 was suspended in DMSO, added with cyclohexylamine at room temperature, stirred at 80 ° C for 2 hours, and recrystallized with 80% aqueous acetic acid to give 7- (cyclohexylamino)- 1-Ethyl-6-fluoro-4_oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
  • Ethyl 3- (2-chloro-4,5-difluorophenyl) 3-oxopropanoate was dissolved in acetic anhydride, and ethyl orthoformate was added at room temperature, followed by stirring at 140 ° C for 12 hours And concentrated under reduced pressure.
  • the obtained residue was dissolved in EtOH, and triethylamine, tetrahydrofuran-3-amamine hydrochloride in EtOH was added under ice-cooling, and stirred for 30 minutes under ice-cooling and 1 hour at room temperature. did. Water was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.
  • Reference Examples 110 to 125 shown in Table 11 were produced using the corresponding raw materials.
  • Reference Examples 123 and 124 are the hydroxyl groups in the corresponding raw materials. Those protected with a dimethylsilyl group were used as raw materials).
  • Reference Example 128 was produced using the corresponding raw material.
  • Reference Example 130 was produced using the corresponding raw material.
  • Reference Example 133 In the same manner as in Reference Example 132, Reference Examples 133 to 134 were produced using the corresponding raw materials. [0101] Reference Example 133
  • the compound of Reference Example 129 was dissolved in methylene chloride, triethylamine and methanesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a mesyl form.
  • the mesyl form was dissolved in DMF, sodium azide was added, and the mixture was stirred at room temperature for 5 hours to obtain an azide form.
  • the azide was dissolved in THF, triphenylphosphine was added, stirred at 50 ° C for 1 hour, water was added, and the mixture was stirred at 80 ° C overnight.
  • pyridine and acetic anhydride were added, and the mixture was stirred at room temperature for 3 hours.
  • Reference Examples 138 to 140 were prepared using the corresponding raw materials. Made.
  • Reference Examples 142 to 143 were produced using the corresponding raw materials.
  • Triethylamine and methanesulfonyl chloride were added to a methylene chloride solution of the compound of Reference Example 130 at 0 ° C., and the mixture was stirred for 1 hour to obtain a mesinole. Dissolve the mesinole compound in THF, add potassium tert-butoxide, stir at room temperature for 3 hours, ethyl 7- (cyclohexylamino) -6_fluoroxy-1-isopropenyl _4_oxo-1,4 -Dihydroquinoline-3-carboxylate was obtained.
  • Reference Example 149 was produced using the corresponding raw material.
  • Reference Example 151 was produced using the corresponding raw material.
  • Reference Example 153 was produced using the corresponding raw material.
  • Ethyl 3-oxo-3- (2,4,5-trifluorophenyl) propanoate was dissolved in acetic anhydride, ethyl orthoformate was added at room temperature, stirred at 140 ° C for 3 hours, and concentrated under reduced pressure .
  • the obtained residue was dissolved in EtOH, and [2-fluoro-1- (fluoromethyl) ethylenol] amine hydrochloride and triethylamine were added under ice cooling, followed by stirring at room temperature for 30 minutes and reducing the pressure. The bottom was concentrated. Water was added to the obtained residue and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • Jetyl (ethoxymethylene) malonate was added to the compound of Reference Example 156, and the mixture was stirred at 130 ° C for 20 hours to obtain jetylethyl) (3,4,5-trifluorophenyl) amino] methylene ⁇ malonate. It was.
  • Reference Example 160 was produced using the corresponding raw material.
  • Methylamine aqueous solution was added to the toluene suspension of the compound of Reference Example 88, and the mixture was stirred at 70 ° C. for 20 hours. Ethyl 1-ethyl-6,7-difluo-5- (methylamino) -4-oxo-1,4 -Dihydroquinoline-3-carboxylate was obtained.
  • Reference Example 162 was produced using the corresponding raw material.
  • 3-Methylcyclopent-3-en-1-carboxylic acid was dissolved in tolylene, tert-butanol, triethylamine, diphenylphosphoryl azide were added in that order, and the mixture was stirred at 90 ° C for 3 days. (3-Methylcyclovent-3-en-1-inore) force rubamate was obtained.
  • Reference Example 164 Dissolve the compound of Reference Example 163 in salt methylene, add trifluoroacetic acid, stir at room temperature for 4 hours, and then add 3-methylcyclopent-3-ene-1-amamine trifluoroacetate salt.
  • Ethyl 3_ (2_black mouth -4,5-difluorophenyl) -3-oxopropanoate was dissolved in acetic anhydride, ethyl orthoformate was added, and the mixture was stirred at 150 ° C for 2 hours. And concentrated under reduced pressure.
  • Ethyl 7- (cyclohexylamino) -1- (2,2-jetyl-1,3-dioxane-5_ _6_fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
  • the compound of Reference Example 223 was suspended in toluene, and after addition of sodium chloride, the mixture was stirred at 90 ° C. for 1.5 hours and concentrated under reduced pressure. Azeotropically with toluene, hexane was added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was dissolved in dichloroethane, and after the salt and aluminum were prepared, the mixture was stirred at 55 ° C. for 24 hours, and further refluxed for 23 hours. 1-Ethyl-6,7-difluoro-4-oxo-1 , 4-Dihydrocinnoline-3_carbonitryl was obtained.
  • the compound of Reference Example 225 was dissolved in acetic acid, and after HC1 aq was prepared, the mixture was stirred at 120 ° C. for 2 days, and 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1, 4-Dihydrocinnoline-3-carboxylic acid was obtained.
  • N-chlorosuccinimide is added to the compound of Reference Example 40, and the mixture is stirred at 100 ° C for 14 hours, and then 8-chloro-_7- (cyclohexylamino) -1-ethyl _6_fluoro-4 _Oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
  • Cyclohexylamine was added to a DMSO solution of the compound of Reference Example 153, and the mixture was stirred at 80 ° C for 14 hours. After cooling the reaction solution to room temperature, water and a saturated aqueous ammonium chloride solution were added and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol, 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours.
  • Reference Example 230 was produced using the corresponding raw material.
  • Reference Example 232 The compound of Reference Example 40 was suspended in DMF, 1,1′-carbonylbis-1H-imidazole was added at room temperature, and the mixture was stirred at 100 ° C. for 24 hours. 7- (Cyclohexylamino) -1-ethyl-6-fluoro-3- (1 ⁇ -imidazol-1-ylcarbonyl) quinolin-4 (1H) _one was obtained
  • Reference Example 234 was produced using the corresponding raw material.
  • Reference Example 236 was produced using the corresponding raw material.
  • the compound of Reference Example 237 was dissolved in DMF, and after diisopropylethylamine was prepared, the mixture was stirred at room temperature for 2 days to obtain dibenzyl (2-aminoethyl) phosphonate. Further, dibenzinole (2-aminoethyl) phosphonate oxalate was obtained by adding oxalic acid to the obtained phosphonate.
  • Jetyl [2- (1,3-Dioxo-1,3-dihydro-2H-isoindole-2-yl) -1,1-difluoroethyl] phosphonate at room temperature. The mixture was stirred for 1 hour to obtain Jetyl (2-amino-1,1-difluoroethyl) phosphonate.
  • Reference Example 241 was produced using the corresponding raw material.
  • Example 6 300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, and 0.8 ml of 1M NaOH aq was added under ice cooling, followed by stirring at room temperature for 25 hours. Water was added to the reaction solution and neutralized with 1M HC1 aq. The precipitated solid was collected by filtration and washed with EtOH to give ( ⁇ [7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4_oxo-1,4-dihydroquinolin-3-yl] Carbon ⁇ amino) acetic acid (263 mg) was obtained.
  • TMSBr trimethylsilane bromide
  • N_ (4-amino_4_oxobutyl) _7- (cyclohexylamino) -1_ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline- 214 mg of 3_carboxamide was obtained.
  • Example 10 210 mg of the compound of Example 161 was suspended in 5.0 ml of DMF, and 0.1 ml of ethoxycarborubiperazine, 130 mg of WSC-HC1 and 100 mg of 1_hydroxybenzotriazole were added in this order under ice-cooling, followed by 17 at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with black mouth form. The obtained organic layer was washed successively with saturated NaHCO aq and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 196 530 mg of the compound of Example 196 was suspended in a mixed solvent of acetone 10 ml-7X3.0 ml, and N-methylmorpholine-N-oxide 0.30 g OsO (2.5 wt% in tBuOH) 2.0 ml was sequentially added at room temperature. After galling, the mixture was stirred at room temperature for 1 week. Water was added to the reaction mixture, and 2.0 g of sodium thiosulfate was collected at room temperature, followed by stirring overnight at room temperature. Insoluble matters in the reaction solution were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the compound of Reference Example 233 (0.20 g) was dissolved in DMSO (5.0 ml), and cyclohexylmethylamine (0.2 ml) was prepared at room temperature, followed by stirring at 80 ° C. for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 16 0.45 g of the compound of Example 412 was dissolved in 10 ml of methylene chloride, and 1.0 ml of trimethylsilane bromide was added under ice cooling, followed by stirring at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and MeOH was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the solid precipitated by filtering EtOH was collected by filtration to give [2-( ⁇ [7_ (cyclohexylamino) -1-cyclopentyl-6-fluoro. -4_oxo-1,4-dihydroquinoline-3-yl] carbonyl ⁇ amino) ethyl] phosphonic acid hydrobromide 344 mg was obtained. [0181] Example 16
  • Example 200 0.51 g of the compound of Example 200 was dissolved in 5.0 ml of sodium chloride and 0.5 ml of triethylenamine and 0.2 ml of methanesulfonyl chloride were sequentially added under ice cooling, followed by stirring for 30 minutes under ice cooling. Water was added to the reaction solution and extracted with black mouth form. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a mesyl form. The obtained mesinole body was dissolved in 10 ml of DMF, and 0.10 g of sodium azide was added under ice cooling, followed by stirring at room temperature for 20 hours. Water was added to the reaction solution and extracted with black mouth form.
  • the obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an azide.
  • the obtained azide was dissolved in 10 ml of THF, 0.40 g of triphenylphosphine was added at room temperature, and the mixture was stirred at 50 ° C. for 1 hour.
  • To the reaction solution 2.0 ml of water was added and stirred at 80 ° C. for 3.5 hours.
  • the reaction solution was allowed to cool, 0.30 g of di-tert-butyl dicarbonate was added under ice cooling, and the mixture was stirred at room temperature for 27 hours. Water was added to the reaction solution and extracted with black mouth form. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 31 148 mg of the compound of Example 31 was suspended in 5 ml of acetonitrile, 67 mg of potassium carbonate, 46 ⁇ l of benzyl bromide, and 5 ml of DMF were added and stirred overnight. Water was added, extracted with black mouth form, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 220 183 mg of the compound of Example 220 was suspended in 20 ml of black mouth form, and 1.35 ml of trimethylsilane bromide was added under ice cooling, followed by stirring at room temperature for 24 hours. After adding 1.35 ml of trimethylsilane bromide and stirring for 3 days, EtOH was added. After evaporating the solvent under reduced pressure, water, saturated NaHCO aq
  • Example 29 148 mg of the compound of Example 31 was suspended in 5 ml of black mouth form, 75 ⁇ of triethylamine was added, the mixture was cooled to ⁇ 45 ° C., and 32 ⁇ 1 of methanesulfonyl chloride was added. After gradually warming up and stirring at room temperature overnight, water was added, extracted with black mouth form and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • 300 mg of the compound of Example 644 was dissolved in 1.2 ml of 1M NaOH aq, and a solution of 21.7 mg of silver nitrate in 3 ml of water was prepared at room temperature, followed by stirring at room temperature for 15 minutes. Insoluble material was collected by filtration and washed with water to obtain 393 mg of silver salt. Of this, 300 mg was suspended in 8 ml of toluene, 140 ⁇ L of chloromethyl bivalate was added at room temperature, and the mixture was stirred at 80 ° C. for 7 hours. The reaction mixture was filtered through celite, and concentrated under reduced pressure.
  • Tables 16 to 47 below show the structures and physical data of the example compounds.
  • Tables 52 to 80 show other structures of the compound represented by the formula (I). These can be easily produced by using the production methods described above, the methods described in the examples, methods obvious to those skilled in the art, or variations thereof.
  • the quinolonic acid derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, it is a pharmaceutical, particularly a platelet aggregation inhibitor, P2Y12 inhibitor. Useful as an agent.
  • the compound of the present invention is a cardiovascular disease closely related to blood clot formation due to platelet aggregation, such as unstable angina pectoris, acute myocardial infarction and its secondary prevention, hepatic artery bypass surgery, PTCA surgery or stent Ischemic diseases such as reocclusion and restenosis after implantation, promotion of hepatic artery thrombolysis and prevention of reocclusion; transient cerebral ischemic attack (TIA) cerebral infarction, subarachnoid hemorrhage (vascular spasm), etc. It is useful as a preventive and Z or therapeutic agent for disorders, peripheral arterial diseases such as chronic arterial occlusion, and the like, and as an adjunct in cardiac surgery or vascular surgery.
  • TIA transient cerebral ischemic attack
  • vascular spasm subarachnoid hemorrhage

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Abstract

La présente invention concerne un composé ayant une excellente activité inhibitrice de l'agrégation plaquettaire. La présente invention décrit plus spécifiquement un dérivé de la quinolone caractérisé par un groupe amide en position 3 substitué par un substituant ayant un ester de carboxylate, un ester de phosphate, un ester de sulfate ou analogue, et un groupe amino en position 7, substitué par un substituant avec une structure cyclique. L'invention décrit aussi un sel acceptable sur le plan pharmaceutique dudit dérivé de quinolone. Le dérivé de quinolone et un sel acceptable sur le plan pharmaceutique dudit dérivé présentent une excellente activité inhibitrice vis-à-vis de P2Y12 et une activité inhibitrice par rapport à l'agrégation plaquettaire. Par conséquent, le dérivé de quinolone et un sel de ce dernier acceptable sur le plan pharmaceutique sont utiles en tant qu’inhibiteur de l'agrégation plaquettaire.
PCT/JP2006/300590 2005-01-20 2006-01-18 Derive de quinolone et sel de ce dernier WO2006077851A1 (fr)

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Cited By (11)

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WO2007105751A1 (fr) 2006-03-16 2007-09-20 Astellas Pharma Inc. Derive de quinolone ou sel pharmaceutiquement acceptable de celui-ci
WO2008131134A1 (fr) * 2007-04-17 2008-10-30 Cylene Pharmaceuticals, Inc. Composés hydrazides et leurs utilisations
WO2008133155A1 (fr) 2007-04-19 2008-11-06 Astellas Pharma Inc. Composé hétérocyclique bicyclique
US7910576B2 (en) 2007-06-18 2011-03-22 Sanofi-Aventis Pyrrole derivatives as P2Y12 antagonists
US8389545B2 (en) 2005-12-05 2013-03-05 Merck, Sharp & Dohme, Corp. Quinolone M1 receptor positive allosteric modulators
US8609717B2 (en) 2010-08-18 2013-12-17 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/β-catenin signaling pathway activators
US8669266B2 (en) 2007-04-23 2014-03-11 Sanofi Quinoline-carboxamide derivatives as P2Y12 antagonists
US9382208B1 (en) 2015-01-26 2016-07-05 Vanderbilt University Negative allosteric modulators of metabotropic glutamate receptor 2
US9533976B2 (en) 2013-02-22 2017-01-03 Samumed, Llc γ-diketones as WNT/β-catenin signaling pathway activators
US9795550B2 (en) 2014-08-20 2017-10-24 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
CN113461612A (zh) * 2021-07-20 2021-10-01 上海应用技术大学 一种喹诺酮类端锚聚合酶2抑制剂及其制备方法和应用

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WO2005009971A1 (fr) * 2003-07-24 2005-02-03 Astellas Pharma Inc. Derive de quinolone ou sel de ce dernier

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WO2004019932A1 (fr) * 2002-08-30 2004-03-11 Pharmacia & Upjohn Company Methode de prevention ou de traitement d'atherosclerose ou de restenose
WO2005009971A1 (fr) * 2003-07-24 2005-02-03 Astellas Pharma Inc. Derive de quinolone ou sel de ce dernier

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8389545B2 (en) 2005-12-05 2013-03-05 Merck, Sharp & Dohme, Corp. Quinolone M1 receptor positive allosteric modulators
JPWO2007105751A1 (ja) * 2006-03-16 2009-07-30 アステラス製薬株式会社 キノロン誘導体又はその製薬学的に許容される塩
US8133882B2 (en) 2006-03-16 2012-03-13 Astellas Pharma Inc Quinolone derivative or pharmaceutically acceptable salt thereof
JP5169821B2 (ja) * 2006-03-16 2013-03-27 アステラス製薬株式会社 キノロン誘導体又はその製薬学的に許容される塩
WO2007105751A1 (fr) 2006-03-16 2007-09-20 Astellas Pharma Inc. Derive de quinolone ou sel pharmaceutiquement acceptable de celui-ci
US8629126B2 (en) 2006-03-16 2014-01-14 Astellas Pharma Inc. Quinolone derivative or pharmaceutically acceptable salt thereof
WO2008131134A1 (fr) * 2007-04-17 2008-10-30 Cylene Pharmaceuticals, Inc. Composés hydrazides et leurs utilisations
WO2008133155A1 (fr) 2007-04-19 2008-11-06 Astellas Pharma Inc. Composé hétérocyclique bicyclique
US8669266B2 (en) 2007-04-23 2014-03-11 Sanofi Quinoline-carboxamide derivatives as P2Y12 antagonists
US7910576B2 (en) 2007-06-18 2011-03-22 Sanofi-Aventis Pyrrole derivatives as P2Y12 antagonists
US8629176B1 (en) 2010-08-18 2014-01-14 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/ β-catenin signaling pathway activators
US8921413B2 (en) 2010-08-18 2014-12-30 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/ β-catenin signaling pathway activators
US9303010B2 (en) 2010-08-18 2016-04-05 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
US9493437B2 (en) 2010-08-18 2016-11-15 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/ β-catenin signaling pathway activators
US9884053B2 (en) 2010-08-18 2018-02-06 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/β-catenin signaling pathway activators
US10314832B2 (en) 2010-08-18 2019-06-11 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as Wnt/β-catenin signaling pathway activators
US8609717B2 (en) 2010-08-18 2013-12-17 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/β-catenin signaling pathway activators
US10457672B2 (en) 2013-02-22 2019-10-29 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
US11673885B2 (en) 2013-02-22 2023-06-13 Biosplice Therapeutics, Inc. γ-diketones as Wnt/β-catenin signaling pathway activators
US9533976B2 (en) 2013-02-22 2017-01-03 Samumed, Llc γ-diketones as WNT/β-catenin signaling pathway activators
US11034682B2 (en) 2013-02-22 2021-06-15 Samumed, Llc Gamma-diketones as wnt/β-catenin signaling pathway activators
US9951053B2 (en) 2013-02-22 2018-04-24 Samumed, Llc γ-diketones as Wnt/β-catenin signaling pathway activators
US10434052B2 (en) 2014-08-20 2019-10-08 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
US9795550B2 (en) 2014-08-20 2017-10-24 Samumed, Llc Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11077046B2 (en) 2014-08-20 2021-08-03 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles
US11839679B2 (en) 2014-08-20 2023-12-12 Biosplice Therapeutics, Inc. Gamma-diketones for treatment and prevention of aging skin and wrinkles
US9382208B1 (en) 2015-01-26 2016-07-05 Vanderbilt University Negative allosteric modulators of metabotropic glutamate receptor 2
CN113461612A (zh) * 2021-07-20 2021-10-01 上海应用技术大学 一种喹诺酮类端锚聚合酶2抑制剂及其制备方法和应用

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