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WO2002022614A1 - Derives de quinolizine - Google Patents

Derives de quinolizine Download PDF

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Publication number
WO2002022614A1
WO2002022614A1 PCT/JP2001/007842 JP0107842W WO0222614A1 WO 2002022614 A1 WO2002022614 A1 WO 2002022614A1 JP 0107842 W JP0107842 W JP 0107842W WO 0222614 A1 WO0222614 A1 WO 0222614A1
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tht
ring
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English (en)
Japanese (ja)
Inventor
Satoshi Ohya
Nobuhisa Masuda
Yoshiaki Kuroki
Teruhiko Inoue
Makoto Okudo
Toshihide Iwata
Koji Kokubo
Gen Mizuno
Masahiko Hagihara
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Sankyo Co Ltd
Ube Corp
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Sankyo Co Ltd
Ube Industries Ltd
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Priority to AU2001286191A priority Critical patent/AU2001286191A1/en
Publication of WO2002022614A1 publication Critical patent/WO2002022614A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

Definitions

  • the present invention relates to novel quinolidine derivatives having excellent antibacterial activity.
  • Examples of the quinolizine compound having an antibacterial effect include EP 380 19, WO 9 yarn.
  • Quinolone-based synthetic antibacterial agents are widely used clinically as therapeutic agents for infectious diseases.
  • the emergence of quinobacteria-resistant bacteria has become a major problem, and the development of new synthetic antibacterial agents effective against these resistant bacteria has been desired.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 represents a hydrogen atom, a C—C 6 alkyl group, a C i-C 6 alkyl group substituted with one or more halogen atoms, a C 3 —C 7 cycloalkyl group, ( ⁇ — ( ⁇ In Arkir Or more substituted C 3 - C 7 cycloalkyl group, one or more halogen atoms replacement has been C 3 - C 7 cycloalkyl group, Ariru group, Heteroariru group, or a halo gen atom, and ⁇ Mi Bruno Represents an aryl group or a heteroaryl group substituted with one or more same or different substituents selected from
  • R 2 is a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C] —C 6 alkyl group, or a C!
  • R 3 is a hydrogen atom (however, when the group formed by the phenyl ring and the cyclic group G in the group represented by the general formula (b) in R 5 below is an isodolin ring, R 3 is limited to a halogen atom) or Represents a halogen atom,
  • R 4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group or a C 6 alkyl group,
  • R 5 is a general formula (a)
  • cyclic group A represents a heteroaryl ring
  • the cyclic group G represents a cycloalkene ring having 5 to 8 carbon atoms, or a cycloalkane ring having 5 to 8 carbon atoms, wherein a carbon atom may be optionally substituted with a nitrogen atom, an oxygen atom or a sulfur atom; "to 1?" are the same or different, a hydrogen atom, a halogen atom, hydroxycarboxylic group, a nitro group, Amino group.
  • Shiano groups C ⁇ one C 4 alkyl groups, C i-C 4 an alkoxy group, Represents a C i -C 4 alkyl group substituted with 1 or 2 or more halogen atoms, or a ⁇ 4 alkoxy group substituted with 1 or 2 or more halogen atoms,
  • R 7a to R 7d are the same or different, a hydrogen atom, a halogen atom, arsenic Dorokishi group, nitro group, Shiano group, arsenate Dorokishiimino groups, C -! C ⁇ alkyl groups, C One C 4 an alkoxy group, C 1 -C 4 alkyl group substituted by 1 or 2 or more halogen atoms, C 1 -C 4 alkoxy group substituted by 1 or 2 or more halogen atoms, hydroxy C 1 -C 4 alkyl group, C i -C alkyl group Xyimino group, amino group, 1 to 4 alkyl and 3 to 7 Amino groups substituted by one or more same or different substituents selected from cycloalkyl, C 1 -C 4 alkyl groups substituted by amino, C—C 4 alkyl and C 3 —C 7 cycloalkyl A C i -C 4 alkyl group, an oxo group
  • cyclic group G represents a ring as defined above, except that a condensed ring formed by a phenyl ring and cyclic group G is tetrahydroisoquinoline
  • R 6a to R 6c and R 7a to R 7d are as defined above.
  • R 1 is a C i -C 4 alkyl group, a C i -C 3 alkyl group substituted with one or more fluorine or chlorine atoms, a C 3 -C 4 cycloalkyl group, a C i -C 2 C substituted with an alkyl 3 - C 4 cycloalkyl group, one or more substituted C 3 fluorine atom or a chlorine atom - C 4 cycloalkyl group, 2, 4-difluorophenyl group, a 2-thiazolyl group, 2-fluorophenyl group, 4-monofluorophenyl group, 3-amino-4,6-difluorophenyl group, 5-fluoro-2-pyridyl group, 2,6-difluoro-3-pyridyl group or 6-amino-3,5-difluoro- A compound which is a 2-pyridyl group, an ester thereof or a pharmacologically acceptable salt thereof,
  • R 1 is a C 1 -C 4 alkyl group, a C-substituted or substituted C 1 -C 3 alkyl group, which is substituted with one or more fluorine or chlorine atoms, a C 3 -C 4 cycloalkyl group, a C i -Cs alkyl C 3 -C 4 cycloalkyl group substituted with 1 or 2 or more of C 3 -C 4 cycloalkyl groups substituted with 1 or more fluorine or chlorine atoms, 2,4-difluorophenyl group, 2-thiazolyl group, 2 A compound which is a 6,6-difluoro-3-pyridyl group or a 6-amino-1,3,5-difluoro-2-pyridyl group, an ester thereof or a pharmaceutically acceptable salt thereof, (3) R 1 is ethyl, propyl, isopropyl, 2-fluoroethyl, 2-chloroethyl,
  • R 1 is an ethyl group, a 2-fluoroethyl group, a cyclopropyl group or a 2-fluoropropyl group, an ester thereof or a pharmacologically acceptable salt thereof,
  • R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a 2-fluoroethyl group, a methoxy group, an ethoxy group, A compound which is a fluoromethyoxy group, a difluoromethyoxy group or a trifluoromethyoxy group, an ester thereof or a pharmacologically acceptable salt thereof,
  • R 2 is a fluorine atom, a chlorine atom, a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group or a difluoromethoxy group, an ester thereof, or a pharmaceutically acceptable salt thereof.
  • R 3 is a hydrogen atom, a fluorine atom or a chlorine atom, an ester thereof or a pharmaceutically acceptable salt thereof
  • R 4 is a hydrogen atom, an amino group, a fluorine atom, a chlorine atom or a methyl group, an ester thereof or a pharmaceutically acceptable salt thereof
  • R 4 is a hydrogen atom, an amino group or a methyl group, an ester thereof, or a pharmaceutically acceptable salt thereof;
  • the condensed ring formed by the cyclic group A and the cyclic group G in the general formula (a) in R 5 is a tetrahydrodrochenoviridine ring, a dihydrodrochenovirol ring, or a dihydrocyclobenthathiophene ring , Tetrahydrodrobenzothiophene ring, tetrahidrothiazolopyridine ring, tetrahidropyropyridin pyridine ring, tetrahydrodroindole ring, dihydropyrolopyrrole ring, dihydrocyclopentapyrrole ring, dihydrochenothiopyran ring, dihydric Dorocheno pyran ring, Te Jerusalemi Dorochi 'Enoazepin ring, Te Jewishi Dorobe emission zone furan ring or dihydric Doropiro port pyridine ring, or where: formula in R 5 (b) phenyl ring in
  • the fused ring group formed by the cyclic group A and the cyclic group G in the general formula (a) in R 5 is 4, 5, 6, 7-tetrahydrocheno [3, 2-c] Pyridin-1-yl group, 4,5,6,7-Tetrahidrocheno [2,3-c] Pyridine-1-yl group, 5,6-dihydro-4H-thieno [2,3 -c] Pyroyl-2-yl group, 5,6-dihydro-4H-cyclopenta [b] thiophene-12-yl group, 4,5,6,7-tetra PC leak 42
  • One C 2 alkyl ⁇ Pi identical or different substituents 1 or 2 substituted C i-C 2 alkyl group substituted by an amino group with a group selected from cyclopropyl, Okiso group, or cyclopropane together with the carbon atom bonded A compound which forms a ring, an ester thereof or a pharmacologically acceptable salt thereof,
  • the fused ring group formed by the cyclic group A and the cyclic group G in the general formula (a) in R 5 is 4, 5, 6, 7-tetrahydrodrocheno [3, 2-c ] Pyridine-1-yl group, 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-12-yl group, 5,6-dihydro 4 H-thieno [2,3-c] 1-pyrrol-2-yl group, 5,6-dihydro-4H-cyclopenta [b] thiof; 1-2-yl group, 4,5,6,7-tetrahydro 1H-pyro [3,2-c] pyridine-1-yl group, 4,5,6,7- whatsoeverC
  • the “C] -C 6 alkyl group for R 1 includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, a t-butyl group.
  • Examples include a straight-chain or branched alkyl group such as a group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group or a t-butyl group.
  • the “halogen atom” in the “Ci-C 6 alkyl group substituted by one or more halogen atoms” for R 1 is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine An atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.
  • a C 6 alkyl group substituted with one or more halogen atoms refers to a group in which the above-mentioned “re-c 6 alkyl group” has been substituted with a “halogen atom”.
  • examples of the “C 3 -C 7 cycloalkyl group” for R 1 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group It is preferably a cyclopropyl group or a cyclobutyl group, and particularly preferably a cyclopropyl group.
  • the “C 3 —C 7 cycloalkyl group substituted with 1 or more than 1 C 6 alkyl” of R 1 means that the above “C 1 -C 6 alkyl group” is “C 3 —C 7 cycloalkyl group” refers to a group substituted by one or more than two groups. Examples of such a group include a monomethylcyclopropyl group, a 1-ethylcyclopropyl group, and a 2-methylcyclyl group.
  • the “C 3 —C 7 cycloalkyl group substituted with one or more halogen atoms” for R 1 means that the “halogen atom” is the “C 3 —C 7 cycloalkyl group” To It refers to a group substituted by 1 or 2 or more. Examples of such a group include 1-fluorocyclopropyl group, 2-fluorocyclopropyl group, 2,2-difluorocyclopropyl group, and 2,3.
  • —Difluorocyclopropyl group 1—Fluorocyclobutyl group, 2 monofluorocyclobutyl group, 3-Fluorocyclobutyl group, 1—Fluorocyclopentyl group, 2-Fluorocyclopentyl group, 2— C 3 -C 7 cycloalkyl group substituted with 1 or 2 or more fluorine atoms such as fluorocyclohexyl group and 2-fluorocycloheptyl group, or 2-chlorocyclopropyl group, 2,3-dichlorocyclo Examples thereof include a C 3 -C 7 cycloalkyl group in which one or more chlorine atoms are substituted, such as a propyl group, and a 2-fluorocyclopropyl group and a 2,2-difluorocyclopropyl group are preferred.
  • a C 3 — ⁇ 4 cycloalkyl group in which one or more fluorine atoms are substituted such as a 1,2-difluorocyclopropyl group, a 2-fluorocyclobutyl group, a 3-fluorocyclobutyl group, or A C 3 -C 4 cycloalkyl group in which one or more chlorine atoms have been substituted, such as 1,2-chlorocyclopropyl group and 2,3-dichlorocyclopropyl group; It is a fluorocyclopropyl group, a 2,2-difluorocyclopropyl group or a 2,3-difluorocyclopropyl group, and particularly preferably a 2-fluorocyclopropyl group.
  • the “aryl group” of R 1 includes, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group or an anthracenyl group. And preferably a phenyl group.
  • the “heteroaryl group” for R 1 is a 5- to 10-membered heteroaromatic group containing 1 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • heteroaromatic ring group examples include, for example, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a birazinyl group, a thiazolyl group, a phenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, an oxazolyl group and a quinolyl group.
  • the group include a pyridyl group, a pyrimidinyl group and a thiazolyl group, and particularly preferred are a pyridyl group and a thiazolyl group.
  • examples of the specific group of “aryl group substituted by one or more same or different substituents selected from halogen atom and amino” of R 1 include, for example, 2-aminophenyl 2-, 3-aminophenyl, 4-aminophenyl, 2-fluoro Phenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl Group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,4-dibromophenyl group, 2-fluoro-1-naphthyl group, 1-fluoro-2-naphthyl group or 3-amino-4,6-difluoro Preferred are 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 41
  • a dichloromouth phenyl group or a 3-amino-14,6-difluorophenyl group more preferably a 2-fluorophenyl group, a 4-fluorophenyl group, or a 2,4-difluoro group; Phenyl group or a 3-amino 4, a 6-difluorophenyl group, particularly preferably, 2, 4-difluoro-off We group.
  • heteroaryl group and “heteroaryl group substituted by one or more same or different substituents selected from halogen atom and amino” for R 1
  • the group include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-pyrimidyl group, a 4-pyrimidyl group, a 5-pyrimidyl group, a 3-pyridazinyl group, a 4-pyridazinyl group, —Pyrazinyl group, 2-thiazolyl group, 4-monothiazolyl group,
  • 6-dichloro-3-pyridyl 3-chloro-2-phenyl, 4-chloro-2-phenyl, 5-chloro-2-phenyl, 2-chloro-3-phenyl, 5-chloro-1-phenyl Group, 3-chloro-2-furyl group, 4-chloro-1-2-furyl group, 5-chloro-2-furyl, 2-chloro-3-furyl, 5-chloro-3-furyl, 3-chloro-1-pyrrolyl, 4-chloro-1-pyrrolyl, 4-chloro-2-thiazolyl, 4-Mono-2-imidazolyl, 6-amino-1-pyridyl, 6-amino-3,5-dichloro-2-pyridyl or 6-amino-3,5-difluoro-2-pyridyl
  • the “halogen atom” of R 2 has the same meaning as described above, and is preferably a fluorine atom, a chlorine atom, or a bromine atom, and particularly preferably a fluorine atom or a chlorine atom. .
  • C i one C 6 alkyl group” and “Flip substituted on one or two or more halogen atoms ⁇ one C 6 alkyl group” of R 2 represents the same meanings as defined above, re
  • the “C 6 alkyl group” is preferably a C 3 alkyl group, more preferably a methyl group or an ethyl group, particularly preferably a methyl group, and “1 halogen atom”.
  • C ⁇ one C 6 alkyl group is preferably a Furuoro or black port C i one c 3 alkyl group, more preferably a Furuoromechiru group, Jifuruoromechiru group, tri Furuoromechiru group
  • i is a fluoroethyl group or a 2-fluoroethyl group, particularly preferably a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.
  • examples of the “C 6 alkoxy group of R 2 ” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, an s-butoxy group and a t-butoxy group.
  • Ru cited Penchiruokishi group or to Kishiruokishi group preferably a C j- C 3 alkoxy group, more preferably a main butoxy group Or an ethoxy group, and particularly preferably a methoxy group.
  • ⁇ C 6 alkoxy group substituted one or more chlorine atoms such as chloromethane butoxy group, preferably, Furuorome butoxy group, Jifuruorome butoxy group D-Cs alkoxy groups substituted by one or more fluorine atoms such as trifluoromethoxy, 1-fluoroethoxy, 2,2,2-trifluoroethoxy or 3-fluoropropoxy More preferably, it is a fluoromethyoxy group, a difluoromethyoxy group or a trifluoromethyoxy group, and particularly preferably a difluoromethyoxy group.
  • the “halogen atom” of R 3 has the same meaning as described above, and is preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.
  • the “halogen atom” of R 4 has the same meaning as described above, and is preferably a fluorine atom or a chlorine atom.
  • the “C i -C 4 alkyl group” for R 4 has the same meaning as described above, and is preferably a methyl group.
  • the "heteroaryl ring" of A in the group represented by the general formula (a) for R 5 represents a 5- to 10-membered heteroaromatic ring having the same meaning as described above, and is preferably pyridine.
  • R 5 represents a cyclic group G in the group represented by the general formula (a): “A carbon atom having 5 to 8 carbon atoms which may be Examples of the cycloalkene ring or cycloalkane ring having 5 to 8 carbon atoms include cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, cyclopentene ring, cyclohexene ring, and cycloheptene ring.
  • the cyclic group A and the general group G in the group represented by the general formula (a) for R 5 in R 5 are, for example, a condensed ring represented by a tetrahydrodrochenoviridine ring, a dihydrodrochenopyrroyl ring , Tetrahydrodrothiazolopyridin ring, dihydropyropyrothiazole ring, tetrahydropyridopyrididine ring, tetrahydrodropyridopyrimidine ring, dihydropyropyridin pyridine ring, dihydropyropyropyridimidine ring, dihydrocyclopentathiophene Ring, tetrahydrobenzobenzophene ring, dihydrocyclobenzotapyridine ring, tetrahydroquinazolidin ring, tetrahydroquinoxalin ring, dihydrocyclopentathiazole ring,
  • Drocheno virole ring dihydrocyclopentathiophene ring, Tet Lahydrobenzothiophene ring, tetrahydrothiazolopyridine ring, tetrahydropropylopyridine ring, tetrahydrodolone ring, dihydropyropyro-pyrroyl ring, dihydrocyclopentapyrrole ring, dihydroclopentapyrrole ring It is a notopyran ring, a dihydrodrochenovirane ring, a dihydrodrochenoazepine ring, a tetrahydrodrobenzofuran ring, or a pyridyl ring having a dihydropyropyro mouth.
  • specific examples of the condensed ring group represented by the cyclic group A and the cyclic group G in the group represented by the general formula (a) in R 5 are preferably 4, 5 , 6,7-Tetrahydrocheno [3,2-c] pyridine-1-yl group, 4,5,6,7-Tetrahydrocheno [3,2-c] pyridin-13-yl group, 4,5,6,7—Tetrahidrotheno [2,3-c] pyridin-1-yl group, 4,5,6,7—Tetrahidrothieno [2,3—c] pyridin One 3-yl group, 4,5,6,7-Tetrahydrodrocheno [3,4-c] pyridin-1-yl group, 4,5,6,7-Tetrahidrothieno [3,4- c] pyridine-1-3-yl group, 5,6-dihydro-4H-thieno [2,3-c] pyrroyl-2-yl group
  • examples of the condensed ring formed by the phenyl ring and the cyclic group G in the group represented by the general formula (b) in R 5 include an indane ring, a tetrahydronaphthalene ring, and an Ring, isoindolin ring, 2,3-dihydrobenzimidazole ring or 2,3-dihydroindazole ring; preferred are an indane ring, a tetrahydronaphthalene ring, and an And more preferably a tetrahydronaphthalene ring or an isoindolin ring.
  • specific examples of the condensed ring group formed by the phenyl ring and the cyclic group G in the group represented by the general formula (b) for R 5 are preferably —Yl group, indone-1-5-yl group, 5,6,7,8—tetrahydrodronaphthalene-1—yl group, 5,6,7,8—tetrahydrodronaphthalene-1- Group, indolin-4-yl group, indolin-5-yl group, indolin-16-yl group, indolin-17-yl group, isoindolin-14-yl group or isoindolin A 5-yl group; more preferably, an indane-4-yl group, an indane-5-yl group, 5, 6, 7, 8—tetrahydronaphthalene-12-yl group; an indolin A 5-yl group, an isoindrin-14-yl group or an isindolin-5-yl group, particularly preferably an indane-5-yl group;
  • the “hydroxy-C 4 alkyl group” of R 7a to R 7d in the general formula (a) group or general formula (b) group in R 5 means that the hydroxy group is A group substituted with "C 4 alkyl group", such as, for example, a hydroxymethyl group, a 1-hydroxyl group, a 2-hydroxyl group, a 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 1-hydroxypropyl group, 2-hydroxybutyl group, 3-hydroxybutyl group or 4-hydroxybutyl group Hydroxymethyl ⁇ , 1-hydroxyxethyl group, 2-hydroxyxyl group, 1-hydroxypropyl group, 2-hydroxypropyl group or 1-hydroxy-1-methyl group are preferred.
  • a human Dorokishi one C 3 alkyl group such as Echiru group, more preferably a human Dorokishimechiru group, 1 over human Dorokishechiru group, 2-arsenide Dorokishechiru group or 1 - a human Dorokishipuropi group, a particularly preferred, It is a hydroxymethyl group or a 1-hydroxyxethyl group.
  • the “ci-c 4 alkyloxyimino group” of R 7a to R 7d in the group of the general formula (a) or the group of the general formula (b) in R 5 is the rc—C
  • 4 alkoxy group refers to a group substituted by an amino group. Examples of such a group include a methoxyimino group, an ethoxyimino group, a propoxyimino group, an isopropoxyimino group, a butoxyimino group, and an isobutoxy group.
  • imino group s- Butokishii amino group or t - Butokishiimino group can be mentioned, preferably, main Tokishii Mi amino group, Etokishiimino groups, C Interview one C 3 Arukiruokishi such Purobokishii amino group or Isopuropokishii amino group It is an imino group, more preferably a methoxyimino group or an ethoxyimino group, and particularly preferably a methoxyimino group.
  • R 7a to R 7d in the general formula (a) group or the general formula (b) group in R 5 are selected from “C” mono-C 4 alkyl and C 3 —C 7 cycloalkyl identical or 1 or 2 or more substituted amino group "in the different substituents, wherein" Ji 1-4 Arukiru group " ⁇ Pi the” C 3 - C 7 identical or different substituents selected from cycloalkyl group " In one Refers to an amino group substituted by 2 or more, such as a methylamino group, a dimethylamino group, an ethylamino group, a acetylamino group, an N-ethyl-1-N-methylamino group, a propylamino group, and an isopropyl group.
  • C 1 -C 4 alkyl group refers to such groups as, for example, aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-amino Aminopropyl group, .1-amino-l-methylethyl group, l-aminobutyl group, 2-aminobutyl group, 3-aminobutyl group or 4-aminobutyl group are preferred.
  • a C a -C 3 alkyl group substituted with an amino group such as a monoaminoethyl group, a 2-aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group or a 1-amino-11-methylethyl group; is aminomethyl group, 1 - amino ethyl group or a 2-C one C 2 alkyl group substituted by a amino group as aminoethyl groups, Ri preferably by further amino A switch group or 1 primary amino ethyl group, particularly preferably a aminomethyl group.
  • R 7a to R 7d in the general formula (a) group or the general formula (b) group in R 5 are selected from “C! —C 4 alkyl and C 3 —C 7 cycloalkyl. that is the same or different substituted C i-C 4 alkyl group substituted by one or more amino group substituted with groups " The - the "Ci one C 4 Al substituted by" C one C 4 alkyl and C 3!
  • Formula ⁇ 1) the general formula in R 5 (a) group or the general formula (b) of R 7a to R w in the group "C 3 with bonded carbon atoms - group forming a C 5 cycloalkane ring"
  • a C 3 —C 5 cycloalkane ring is bonded by sharing a carbon atom on the cyclic group A to form a spiro ring.
  • a C 3 —C 4 cycloalkane ring is It is a group that forms, and more preferably a group that forms a cyclopropane ring.
  • a specific group of R 5 is preferably a 4,5,6,7-tetrahydrothieno [3,4-c] pyridin-1-yl group, 3 — Trifluoromethyl-4,5,6,7—tetrahidrothieno [3,4-c] pyridin-4-yl group, 3-chloro 4,5,6,7—tetrahidrocheno [3,4— c] pyridin-4-yl group, 3-cyano 4,5,6,7-tetrahydrocheno [3,4-c] pyridine-14-yl group, 3-fluoro-1-5-methyl-14 , 5, 6, 7—Tetrahi Dorocheno [3,
  • Thiophene 4-yl group 4-amino 3-methyl-4,5,6,7-tetrahydrobenzo [b] Thiophene 4-yl group, 4-amino-3 difluoromethoxy 4,5,6,7-Tetrahydrobenzo [b] thiophene 1 4-yl group, 4-amino-3-methoxyl 4,5,6,7-Tetrahydrobenzone [b] Thiophen-1 4-yl group, 4-amino-6-hydroxymethyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-1-yl group, 4-amino-6-methyl-4,5,6,7 —Tetrahidrobenzo [b] thiophene 4-yl group, 4-amino-1-6-methoxy-1,4,5,6,7—tetrahydrobenzo [b] thiophene-1-yl group, 4 Amino 7-fluoromethyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-4-yl group
  • the ester means the ester of the compound of the present invention because it can be converted into an ester, and such esters include "ester of a hydroxy group” and "ester of a carboxy group.
  • Ester means an ester in which each ester residue is a "general protecting group” or a "protecting group which can be cleaved in vivo by chemical or enzymatic hydrolysis".
  • General protecting group refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.
  • the protective group include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, bivaloyl, norrelyl, isonoleryl, octanoyl, nonanoyl, decanol, 3-methylnonanoyl, 8-methylnonanoyl, and 3-methylnonanoyl.
  • the “general protecting group” for the “ester of a carboxy group” preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, Isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, "Lower alkyl groups” such as 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl; ethenyl, 1-propenyl, 2-probutyl Benzyl, 1-methyl-1-propenyl,
  • alkenyl groups such as, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-1-2-propynyl, 2-methyl-
  • Alkyl group such as a lower alkyl group, or trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropyl pyrsilyl, methyldiphenylsilyl
  • sil groups such as pyridine diphenylsilyl, butyldiphenylsilyl and phenyldiisopropylpropylsilyl.
  • Protective group that can be cleaved in vivo by chemical or enzymatic hydrolysis means a protective group that is cleaved in the human body by hydrolysis or other biological methods to generate free acids or salts thereof.
  • whether or not such a derivative is used can be determined by administering to a test animal such as a rat or a mouse by intravenous injection and then examining the body fluid of the animal to determine the original compound or its pharmacologically acceptable salt. It can be determined by detecting it.
  • Examples of the “protecting group that can be cleaved in vivo by chemical or enzymatic hydrolysis” as the “ester of a hydroxy group” include, for example, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionylo Xymethyl, ptyryloxymethyl, pivaloyloxymethyl, norrelyloxymethyl, isonoleryloxymethyl, hexanoyloxymethyl, 1-formyloxyxetil, 1-acetoxyl, 1-propionyloxyl , 1 Petyriloxyxetil, 1-Pinyloloxyxetil, 1-Norelyloxyxetil, 1—Isonorelyloxyl, 1-Hexanoyloxyxetil, 1-Formyl 1-Acetoxypropyl, 1-propionyloxypropyl, 1-butyryl 1-Bivaloyloxypropyl, 1-Valeryloxypropyl, 1-Isovaleryloxy
  • propoxymethyl isopropoxymethyl, butoxymethyl, t-butoxymethyl
  • Lower alkoxy lower alkyl such as 2-methoxyethoxymethyl, lower alkoxy lower alkyl such as 2-methoxyethoxymethyl
  • aryl group such as phenoxymethyl, oxy "lower alkyl", 2,2,2-trichloro mouth
  • Alkoxy lower alkyl groups such as halogenated lower alkoxy lower alkyl groups such as ethoxymethyl and bis (2-chloroethoxy) methyl: “lower alkoxy” carbonyl “lower alkyl groups” such as methoxycarbonylmethyl
  • a "lower alkyl group” such as cyanomethyl or 2-cyano
  • the compound (I) of the present invention has an optical isomer (including diastereomer) based on an asymmetric carbon atom in the molecule and a geometric isomer based on a ring structure in some cases. Each isomer is also included in the present invention.
  • the “pharmacologically acceptable salt” means the compound (I) of the present invention can be converted into a salt, and thus refers to a salt thereof.
  • a salt is preferably sodium Alkali metal salts such as salts, lithium salts, lithium salts, alkaline earth metal salts such as calcium salts, magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.
  • Metal salts; inorganic salts such as ammonium salts, t-octylamine salts, PC orchid 42
  • the compound (I) of the present invention can also exist as a hydrate.
  • suitable compounds in the general formula (I) include the compounds shown in Tables 1 and 2 below. However, the compound of the present invention is not limited to these.
  • F-cPr 2-Fluorocyclopropyl group
  • 6-NH 2 -THBT-2-yl 6-amino-4,5,6,7-tetrahidrobenzo [b] thiophen-2-yl group
  • 4-NHMe-THBF-2-y 4-methylamino-4,5,6,7-Tetrahydrobenzo [b] is a furan-2-yl group.

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Abstract

Composés représentés par la formule (I), ses esters ou ses sels acceptables sur le plan pharmacologique, utiles en tant qu'agents antimicrobiens de synthèse, formule (I) dans laquelle R1 représente hydrogène, alkyle, R2 représente hydrogène, alkyle, alcoxy C¿1?-C6, R?3¿ représente hydrogène ou halogéno, R4 représente hydrogène, halogéno, R5 représente un groupe de formule (a), dans laquelle A représente un noyau hétéroaryle, G représente un noyau cycloalkène et R?6a à R7d ¿représentent chacun hydrogène, halogéno.
PCT/JP2001/007842 2000-09-12 2001-09-10 Derives de quinolizine Ceased WO2002022614A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227096A4 (fr) * 1999-10-19 2003-04-02 Sato Pharma Antimicrobiens 4-oxoquinolizine presentant des squelettes 2-pyridone en tant que structure partielle
WO2003029253A1 (fr) * 2001-09-28 2003-04-10 Sato Pharmaceutical Co.,Ltd. Antimicrobiens 4-oxoquinolizine comportant un squelette 2-pyridone comme structure partielle
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016894A1 (fr) * 1990-05-02 1991-11-14 Abbott Laboratories Composes de type quinolizinone
WO1999007696A1 (fr) * 1997-08-09 1999-02-18 Korea Research Institute Of Chemical Technology Derives d'acide quinolizine-carboxylique
WO2001029035A1 (fr) * 1999-10-19 2001-04-26 Sato Pharmaceutical Co., Ltd. Antimicrobiens 4-oxoquinolizine presentant des squelettes 2-pyridone en tant que structure partielle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016894A1 (fr) * 1990-05-02 1991-11-14 Abbott Laboratories Composes de type quinolizinone
WO1999007696A1 (fr) * 1997-08-09 1999-02-18 Korea Research Institute Of Chemical Technology Derives d'acide quinolizine-carboxylique
WO2001029035A1 (fr) * 1999-10-19 2001-04-26 Sato Pharmaceutical Co., Ltd. Antimicrobiens 4-oxoquinolizine presentant des squelettes 2-pyridone en tant que structure partielle

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227096A4 (fr) * 1999-10-19 2003-04-02 Sato Pharma Antimicrobiens 4-oxoquinolizine presentant des squelettes 2-pyridone en tant que structure partielle
WO2003029253A1 (fr) * 2001-09-28 2003-04-10 Sato Pharmaceutical Co.,Ltd. Antimicrobiens 4-oxoquinolizine comportant un squelette 2-pyridone comme structure partielle
WO2011031745A1 (fr) 2009-09-09 2011-03-17 Achaogen, Inc. Analogues de fluoroquinolone antibactériens
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11987591B2 (en) 2018-02-16 2024-05-21 Sumitomo Pharma America, Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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