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WO2006066950A2 - Aminoalcools tricycliques, procedes de realisation associes et utilisation comme anti-inflammatoires - Google Patents

Aminoalcools tricycliques, procedes de realisation associes et utilisation comme anti-inflammatoires Download PDF

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Publication number
WO2006066950A2
WO2006066950A2 PCT/EP2005/013943 EP2005013943W WO2006066950A2 WO 2006066950 A2 WO2006066950 A2 WO 2006066950A2 EP 2005013943 W EP2005013943 W EP 2005013943W WO 2006066950 A2 WO2006066950 A2 WO 2006066950A2
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group
groups
alkyl
general formula
optionally
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PCT/EP2005/013943
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German (de)
English (en)
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WO2006066950A3 (fr
Inventor
Markus Berger
Norbert Schmees
Heike Schäcke
Stefan BÄURLE
Hartmut Rehwinkel
Anne Mengel
Konrad Krolikiewicz
Danja Grossbach
David VOIGTLÄNDER
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Bayer Schering Pharma Aktiengesellschaft
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Priority to JP2007547379A priority Critical patent/JP2008524300A/ja
Priority to AU2005318354A priority patent/AU2005318354A1/en
Priority to BRPI0519710-4A priority patent/BRPI0519710A2/pt
Priority to CA002586973A priority patent/CA2586973A1/fr
Priority to MX2007007420A priority patent/MX2007007420A/es
Publication of WO2006066950A2 publication Critical patent/WO2006066950A2/fr
Publication of WO2006066950A3 publication Critical patent/WO2006066950A3/fr
Priority to IL183060A priority patent/IL183060A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Tricyclic amino alcohols process for their preparation and their use as anti-inflammatory agents
  • the invention relates to tricyclic amino alcohols, processes for their preparation and their use as anti-inflammatory agents. From the prior art WO 02/10143 and WO 03/082827 open-chain non-steroidal anti-inflammatory agents are known. These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.
  • the present invention relates to compounds of the general formula (I),
  • R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted
  • R 3 is a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 10) -alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 5 ) - Perfluoroalkyl group, a cyano group,
  • R 4 is a C r Cio-alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (CrC 5) - alkoxy substituted C r Cio-alkyl group, an optionally substituted (C 3 -C 7) Cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally one or more groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR 10 groups, wherein R 3 10 C r C 6 alkyl or benzyl), (CrCs) alkoxy groups, hydroxy groups, halogen atoms, (CrC 3 ) - Exoalkylidenement substituted, optionally 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and or mono- or bicyclic heteroaryl group containing one to two keto groups
  • R 5 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group, a (C 3 -C 7 ) -cycloalkyl group, a (C 3 -C 7 ) -cycloalkyl (C 1 -C 8 ) -alkyl group, (C 3 -C 7) cycloalkyl (C 2 -C 8) alkenyl (8 -C) alkyl group, a heterocyclyl group, a heterocyclyl, heterocyclyl (C 2 - Ce) alkenyl group, an aryl group, an aryl (-C 8) alkyl group,
  • R 6 and R 7 independently represent a hydrogen atom, a halogen atom, a (Ci-C 5 ) alkyl group which may be substituted with OR 8 , SR 8 , NR 8 R 9 , p 1-3 and
  • X represents an oxygen, a sulfur atom, a CH 2 - or an NR 9 group.
  • R 4 is a C 1 -C 18 -alkyl group, represented by one or more groups selected from the group consisting of 1-3 hydroxy groups, halogen atoms, C 1 -C 15 -alkoxy substituted CiC-io-alkyl group, an optionally substituted
  • Phenyl group an optionally substituted by 1-2 keto groups, 1-2 (C 1 -C 5 ) - alkyl groups, 1-2 (C 1 -C 5 -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C 3 ) -Exoalkyliden law, substituted 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic
  • R 5 is a (Ci-C 5) alkyl group or an optionally partially or completely fluorinated (Ci-C 5) alkyl group, an aryl group, an aryl (-C 8) alkyl, aryl (C 2 -C 8) alkenyl group, a ( C 3 -C 7 ) cycloalkyl group, a (C 3 -C 7 ) cycloalkyl (C 1 -C 8 ) alkyl group, (C 3 C 7 ) cycloalkyl (C 2 -C 8 ) alkenyl group
  • R 6 and R 7 independently of one another represent a hydrogen atom, a halogen atom , a methyl or ethyl group which may be substituted with OR 8 , SR 8 , N (R 9 ) 2 , p 1-3 and
  • X represents an oxygen, a sulfur atom, a CH 2 - or an NR 9 group.
  • An object of the present invention are stereoisomers of the general formula (I) wherein
  • Bodies can be hydrogenated
  • R 5 is a (Ci-C 5 ) alkyl group or an optionally partially or completely fluorinated (d-CsJ-alkyl group
  • R 6 and R 7 are independently a hydrogen atom, a halogen atom, a methyl or ethyl group, with OR 8 , SR 8 , N (R 9 ) 2 may be substituted, wherein R 8 and R 9 are independently hydrogen, C- ⁇ -C 5 alkyl or
  • a preferred subject of the present invention are stereoisomers of the general formula (I) according to claim 1, wherein R 1 , R 2 and R 3 are each independently a hydrogen atom, a
  • R 4 is optionally selected from one or more groups
  • Heteroaryl group which group can be linked via any position with the amine of the ring system and optionally at one or more
  • Bodies can be hydrogenated
  • R 5 is a (dC 5 ) -alkyl group or an optionally partially or completely fluorinated (CrCsJ-alkyl group
  • R 7 and R 8 are independently a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2
  • X represents an oxygen or a sulfur atom.
  • Another object of the present invention are stereoisomers of the general formula (I) wherein
  • R 1 , R 2 and R 3 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 10) -alkoxy group, a cyano group
  • R 4 is optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 (Ci-C 5 ) alkyl groups, 1-2 (C- ⁇ -C 5 ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (dC 3) -Exoalkyliden law substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl-, Dihydroisochinolinyl-, thiophthalidyl, Benzoxazinonyl-, Phthalazinonyl-,
  • Quinolinyl isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, which groups may be linked via any position with the amine of the ring system and may optionally be hydrogenated at one or more sites,
  • R 5 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group
  • R 6 and R 7 are independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2 and
  • X represents an oxygen or a sulfur atom.
  • a particularly preferred subject of the invention are stereoisomers according to claims 1-5, wherein
  • R 1 , R 2 and R 3 independently represent a hydrogen atom or a
  • R 4 is optionally selected from one or more groups
  • R 5 is a fluorinated (CrC 3 ) alkyl group
  • R 6 and R 7 independently represent a hydrogen atom, or a (CrC 2 ) alkyl group, p 2 and X represents an oxygen or a sulfur atom.
  • a very particularly preferred subject of the invention are stereoisomers of general formula I, wherein
  • R 1 , R 2 and R 3 independently of one another represent a hydrogen atom or a halogen atom
  • R 4 is optionally selected from one or more groups
  • Halogen atoms substituted phthalazinonyl, quinolinyl, isoquinolinyl,
  • Ringsystems can be linked and optionally at one or more
  • Bodies can be hydrogenated
  • R 5 is a fluorinated (CrC 3 ) alkyl group
  • R 6 and R 7 independently of one another represent a hydrogen atom, or a (C 1 -C 2 ) -alkyl group, p 2 and
  • X represents an oxygen or a sulfur atom.
  • a very particularly preferred subject of the invention are stereoisomers of general formula I, wherein
  • R 1 , R 2 and R 3 independently represent a hydrogen atom or a
  • R 4 is optionally selected from one or more groups
  • keto groups 1-2 (d-CsJ-alkyl groups, 1-3 hydroxy groups, 1-3 halogen atoms, substituted phthalazinonyl, quinolinyl, quinolonyl,
  • Amine of the ring system can be linked and optionally at one or can be hydrogenated several sites, R 5 is a fluorinated (Ci-C 3 ) alkyl group
  • R 6 and R 7 independently of one another represent a hydrogen atom, or a (C 1 -C 2 ) -alkyl group, p 2 and
  • X represents an oxygen or a sulfur atom.
  • X may represent an oxygen atom, a sulfur atom, an NR 9 or a Chfe group.
  • the oxygen atom and the sulfur atom are preferred, and the oxygen atom is particularly preferred.
  • halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.
  • the alkyl groups R 1 , R 2 , R 3 , R 5 , R 8 and R 9 may be straight-chain or branched and may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso Butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group.
  • a CrC 3 alkyl group is preferred. They may optionally be substituted by a group selected from 1-3 hydroxy, 1-3 halogen, 1-3 (CrC 3 ) alkoxy, and / or 1-3 COOR 10 groups. Preference is given to hydroxy groups.
  • the alkyl group R 4 has the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group hydroxy, halogen, (Ci-C 5 ) alkoxy.
  • alkyl groups R 6 and R 7 have the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group OR 9 , SR 9 and NR 8 R 9 , where R 8 and R 9 are hydrogen, C 1 -C 5 -alkyl or (CO ) C 1 -C 5 -alkyl and alkyl is also as defined above.
  • Particularly preferred for R 6 and R 7 is a hydrogen atom and the unsubstituted C 1 -C 3 -alkyl group, most preferably a hydrogen atom and the methyl group.
  • the alkoxy groups can be straight-chain or branched and are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2- Dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group.
  • a methoxy or ethoxy group is preferred.
  • the alkylthio groups may be straight-chain or branched and may be a methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio , 2-methylbutylthio or 3-methylbutylthio group.
  • a methylthio or ethylthio group is preferred.
  • a partially or fully fluorinated alkyl group which may be straight-chain or branched, are, for example, the partially or fully fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1, 2-difluoroethyl, 1, 1 , 1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, C 3 F 7 , C 3 H 2 F 5 , C 4 F 9 , C 5 F 11 .
  • the trifluoromethyl and the pentafluoroethyl group most preferably the trifluoromethyl group.
  • the reagents are commercially available or the published syntheses of the corresponding reagents are state of the art.
  • the aryl substituents R 1 and R 2 may form a ring in which both aryl substituents together represent a chain selected from among
  • the substituent NR 8 R 9 is , for example, NH 2 , NH (CH 3 ), N (CH 3 ) 2 , NH (C 2 H 5 ), N (C 2 Hs) 2 , NH (C 3 H 7 ), N ( C 3 H 7 ) ,, NH (C 4 H 9 ), N (C 4 H 9 ) 2) NH (C 5 H 11 ), N (C 5 Hn) 2 , NH (CO) CH 3 , NH (CO ) C 2 H 5 , NH (CO) C 3 H 7 , NH (CO) C 4 H 9 , NH (CO) C 5 H 11 .
  • the cycloalkyl group means by one or more groups selected from hydroxy, halo, (CrC 5) alkyl, (C 1 - C ⁇ J-alkoxy optionally substituted saturated cyclic group having from 3 to 7 ring carbon atoms, for example cyclopropyl, Methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.
  • the cycloalkylalkyl group means, for example, - (CH 2 ) -cycloalkyl, - (C 2 H 4 ) -cycloalkyl, - (C 3 H 6 ) -cycloalkyl, - (C 4 H 8 ) -cycloalkyl, - (C 5 H 10 ) - Cycloalkyl, wherein cycloalkyl is defined as described above.
  • the heterocyclyl group is not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Come as substituents
  • Heterocyclylalkyl groups are to be understood as meaning heterocyclyl groups which are linked to the skeleton via a C 1 -C 5 -alkyl group, where the alkyl group may be straight-chain or branched.
  • Heterocyclylalkenyl groups are heterocyclyl groups which are linked to the skeleton via an unsaturated C 2 -C 5 -alkyl group, where the alkenyl groups may be straight-chain or branched.
  • the aryl group R 4 and R 5 may be phenyl or naphthyl. Suitable substituents for both groups Ci-C coming 3 alkyl, hydroxy, -C 3 - alkoxy, d-Cs-alkylthio, halogen, cyano, COO (Ci-C 5) alkyl, COOH, NR 9 R 10, nitro, in consideration ,
  • the degree of substitution may be one or more than one, may include several identical or different substituents.
  • Mono- or disubstituted phenyl and naphthyl groups R 4 are preferred.
  • the aryl groups may be partially hydrogenated and then, in addition to or in addition to the abovementioned substituents, keto, (C 1 -C 3 ) - Wear exoalkylidene.
  • partially hydrogenated phenyl is meant, for example, cyclohexadienyl, cyclohexenyl, cyclohexyl.
  • a partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.
  • the arylalkyl group is an aryl group linked to a skeleton via a C 1 -C 8 -alkyl group, where the alkyl group can be straight-chain or branched.
  • alkyl group can be straight-chain or branched.
  • benzyl or phenethylene may be mentioned.
  • An arylalkenyl group is an aryl group which is linked to a skeleton via a C 2 -C 8 -alkenyl group, where the alkenyl group may be straight-chain or branched.
  • the arylalkynyl group is an aryl group which is linked to the skeleton via a C 2 -C 6 -alkynyl group, where the alkynyl group may be straight-chain or branched.
  • R 4 and R 5 which may be hydrogenated at one or more sites, are meant any mono- or bicyclic aromatic ring systems which contain at least one heteroatom and at most seven heteroatoms. Preference is given to ring systems having 1-5 heteroatoms. Suitable heteroatoms are 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms, which can occur in all subcombinations in the ring system as long as they do not exceed the number specified for the respective heteroatom and, in total, the maximum number of seven heteroatoms.
  • R 4 or R 5 is furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl , Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl , Dihydroisoindolonyl, benzofuranyl
  • quinolonyl includes both quinoline-2 (1H) one and quinoline-3 (4H) one and quinoline-4 (1H) one. If the heteroaryl groups are partially or fully hydrogenated then belong
  • R 4 is tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridine 4-ylidenaminyl, chromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1 , 4] oxazinyl, 1, 2-dihydro [1, 3] benzoxazin
  • R 4 is optionally substituted by one or more groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 COOR 10 groups), (CIC 5 ) Alkoxy groups, hydroxy groups,
  • a particularly preferred subject of the invention are compounds of general formula I according to claims 1-5, wherein R 4 is optionally substituted by one or more groups selected from (C 1 -C 5 ) -alkyl groups, hydroxy groups, halogen atoms, optionally substituted 1-2 nitrogen atoms and or bicyclic heteroaryl group containing 1 keto group, which group may be linked via any position with the amine of the ring system and may optionally be hydrogenated at one or more sites.
  • a preferred subject of the invention are compounds of general formula I according to claims 1-5, wherein R 4 is optionally substituted by -C 5 - alkyl, halogen, hydroxy, C r C 5 alkoxy, keto, or (Ci-C 3) substituted Exoalkyliden Phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, , Cinnolinyl, phthalazinyl, 1, 7 or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroiso
  • a preferred object is compounds of general formula I according to claims 1-5, wherein R 4 is a phenyl or naphthyl, phthalidyl, thiophthalidyl, benzoxazinonyl optionally substituted by C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy.
  • a particularly preferred subject of the invention are compounds of the general formula I in which R 4 is a quinolinyl, quinolinyl, quinazolinyl, phthalazinonyl or quinolonyl group which is optionally substituted by C 1 -C 3 -alkyl, halogen, hydroxyl. If it is a heteroarylalkyl group R 5 , it is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is bonded to the skeleton via a C 1 -C 6 -alkyl group which may be straight-chain or branched.
  • a heteroarylalkenyl group is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is bonded to the skeleton via a C 2 -C 8 -alkenyl group, which may be straight-chain or branched.
  • R 5 is a (Ci-CsJ-alkyl group or an optionally partially or fully fluorinated (CrC 5 ) alkyl group, a (C 3 -C 7 ) cycloalkyl, (C 3 -C 7) cycloalkyl (CrC 8) alkyl (C 3 -C 7) cycloalkyl (C 2 -C 8) alkenyl group, a heterocyclyl group, a heterocyclyl (Ci-C 8) alkyl, heterocyclyl ( C 2 -C 8 ) alkenyl group, an aryl group, an aryl (Ci-C 8 ) alkyl group, aryl (C 2 -C 8 ) alkenyl group.
  • R 5 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group, an aryl group, an aryl (C 1 -C 4) alkyl group.
  • R 5 represents a (CrC 3 ) alkyl group or an optionally partially or fully fluorinated (Ci-C 3 ) alkyl group.
  • R 5 is a fully fluorinated (C 1 -C 3 ) -alkyl group, very particularly preferably a CF 3 group.
  • R 4 is a C r Cio-alkyl group which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted
  • Phenyl group an optionally represented by 1-2 keto groups, 1-2 (C 1 -C 5 ) -alkyl groups, 1-2 (C 1 -C 6 -alkoxy groups, 1-3 halogen atoms, 1-2 (C 1 -C 3 ) - Exoalkylidene-substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms containing mono- or bicyclic heteroaryl group, which groups may be linked via any position with the nitrogen atom and may optionally be hydrogenated at one or more sites means.
  • the compounds of the general formula I according to the invention can exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers (eg RRR, RRS, RSR, RSS, SRR, SRS 1 SSR, SSS), both as racemates or mixtures of diastereomers. as well as in enantiomerically pure or diastereomerically pure form.
  • the enantiomers or diastereomers can be obtained by methods known to the person skilled in the art, for example by chromatography of the racemate or the diastereomer mixture on a chiral solid phase.
  • the compounds according to the invention may also be present in the form of salts with physiologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
  • the compounds according to the invention can also be present on the hydroxy group as ether or ester, which can be prepared by methods known to the person skilled in the art.
  • ether methyl ether, ethyl ether, propyl ether,
  • esters are derived from inorganic acids or organic acids.
  • the organic acids may be cyclic, straight-chain or branched, saturated or unsaturated, carbocyclic or heterocyclic, substituted or unsubstituted.
  • the radicals are derived from d-Cg carboxylic acids.
  • acids which are suitable for esterification are sulfuric acid, formic acid, acetic acid, propionic acid, butanoic acid,
  • Pentanoic acid called pivalic acid.
  • Inorganic acids are, for example, H 2 SO 4, H 2 SO 3 , H 2 SO 2 , H 3 PO 4 .
  • the compounds according to the invention are prepared a) by the methods known to those skilled in the art (eg J. Chem. Soc., Perkin Trans.1 (1999) pp. 2911-2922; Org. Lett. 6 (2004) pp. 3047-3050 ) are converted from the corresponding chromanones, thiochromanones, cyclic ketones or cyclic aminoketones cyclic styrenes of the general formula (III) by an optionally enantioselectively led ene reaction with optionally chiral Lewis acids in the compounds of general formula (IV).
  • the imine (V) is produced by methods known to those skilled in the art,
  • Lewis acid under Lewis acid according to the invention are understood as meaning all known to those skilled Lewis acids such as TiCl 4, Ti (OR3) 4, TiCl 2 (OR 3) 2, TiBr 2 (OR 3) 2, PdCl 4, Pd (OR 3) 4, PdCl 2 (OR3) 2, PdBr 2 (OR 3) 2, ZnCl 2, ZnBr 2, SnCl 4, AlCl 3, AlBr 3, AIEtCI 2, AlMe 2 Cl, BBr 3, BCl 3, Bl 3, BF 3, BBrMe 2, Cu Salts z.
  • B. Cu (OTf) 2 , CuCl 2 , CuBr 2 , Yb (OTf) 3 , preferably BBr 3 .
  • a particular subject of the invention are the amines R 4 NH 2 , 5-amino-7-fluoro-2-methylquinazoline, 5-amino-8-fluoro-2-methylquinazoline and 5-amino-7,8-difluoro-2-methylquinazoline , b) according to known instructions, precursors of the type of general formula (VI) can be prepared (J. Med. Chem. 44 (2001) pp. 1085-1098). According to methods known to those skilled in the art, these compounds can be converted into compounds of the general formula (VII) by reducing the double bond, for example with hydrogen over palladium / carbon, reducing the ester, for example with lithium aluminum hydride and oxidizing the resulting alcohols. 1. hydrogenation
  • Suitable catalysts are fluoride salts or basic compounds such as alkali metal carbonates (J. Am. Chem. Soc. 111 (1989) pp.393).
  • Compounds of the general formula (X) can be prepared by reacting compounds of the general formula (IX), for example with TMSCN or MCN, where M can be a metal such as, for example, sodium, potassium or copper (J. Med. Chem. 46 (2003 ) pp. 2494-2501). It may optionally be R 11 is a hydrogen atom or a trialkylsilyl group.
  • Compounds of general formula (XI) can be prepared by reacting compounds of general formula (X) with a suitable reducing agent, e.g. Diisobutylaluminum hydride are obtained.
  • a suitable reducing agent e.g. Diisobutylaluminum hydride
  • Compounds of the general formula (VII) can be obtained by reaction with e.g. an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, in the presence of a suitable copper salt or mixed organo copper (eg Tetrahedron Lett., 31 (1990) pp. 7425-7428; J. Organomet. Chem. 502 (1995) pp. C5-C7 ) and subsequent reduction eg be reacted with diisobutylaluminum hydride to give a compound of formula VII, which are analogous to the preparation process b) into which the compounds of general formula (I) are converted.
  • an alkyl metal compound for example a Grignard reagent or a lithium alkyl
  • a suitable copper salt or mixed organo copper eg Tetrahedron Lett., 31 (1990) pp. 7425-7428; J. Organomet. Chem. 502 (1995) pp. C5-C7
  • subsequent reduction
  • An object of the invention are the intermediates for the processes described above, in particular the compounds of formulas III, IV and V wherein the radicals have the meanings given in claim 1 and the process steps for their preparation.
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays.
  • the substances show a high affinity to the GR.
  • an IC 50 (GR) 20 nM
  • GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is mediated by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (for review see Cato ACB and Wade E, BioEssays 18, 371-378 1996).
  • the compounds of the general formula I according to the invention inhibit lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1.
  • LPS lipopolysaccharide
  • the concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits.
  • the anti-inflammatory activity of the compounds of the general formula I was tested in animal experiments by testing in the croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108).
  • the animals were topically applied croton oil in ethanolic solution to the ears.
  • the test substances were also applied topically or systemically simultaneously or two hours before the croton oil.
  • ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration.
  • the compounds of the general formula I inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.
  • glucocorticoid therapy One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines,
  • TAT tyrosine aminotransferase
  • the compounds of the general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:
  • the term "DISEASE” stands for the following indications:
  • rheumatic diseases especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica - Reactive arthritis
  • Traumatic arthritis - collagenosis of any genesis e.g. systemic lupus erythematosus
  • liver disease associated with inflammatory, allergic and / or proliferative processes (vii) liver disease associated with inflammatory, allergic and / or proliferative processes:
  • acute hepatitis of different origins e.g. viral, toxic, drug-induced - chronic aggressive and / or chronic intermittent hepatitis
  • Severe states of shock eg anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Acquired primary adrenal insufficiency e.g. Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.
  • congenital secondary adrenal insufficiency e.g. congenital hypopitotitarism
  • the invention further relates to combination therapies or combined compositions wherein a glucocorticoid receptor (GR) agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is administered either simultaneously (optionally in the same composition) or sequentially together with one or more drugs for the treatment of any of the above-mentioned conditions.
  • a GR agonist of the present invention may be combined with one or more drugs to treat such a condition.
  • the drug to be combined may be selected from the following list:
  • a PDE4 inhibitor including an isoform PDE4D inhibitor; • a selective ß.sub2.
  • Adrenoceptor agonist such as
  • a muscarinic receptor antagonist for example an M1, M2 or M3 antagonist, such as a selective M3 antagonist
  • a modulator of the chemokine receptor function such as a
  • such combination with a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is employed for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (e.g. for example, aminophylline or theophylline), which may also be administered by inhalation or orally.
  • xanthine e.g. for example, aminophylline or theophylline
  • the compounds of the general formula I according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic glucocorticoids are used today (see Hatz, HJ, Glucocorticoids: Immunological Principles, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart , 1998).
  • the appropriate dose will vary and depends, for example, on the potency of the compound of general formula I, the host, the mode of administration and the nature and severity of the conditions to be treated, as well as the prophylactic use or therapeutic.
  • the invention further provides (i) the use of one of the compounds of the invention of formula I or a mixture thereof for the manufacture of a medicament for the treatment of a DISEASE;
  • a method of treating a DISEASE which method comprises administering a compounding amount according to the invention, wherein the amount suppresses the disease, and wherein the compounding amount is given to a patient in need of such a drug;
  • a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg of body weight.
  • an acute shock e.g., anaphylactic shock
  • single doses well above the above doses may be given.
  • Compounds are prepared in a manner known per se by processing the active ingredient with the carriers customarily used in galenicals, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and converting them into the desired administration form.
  • crystal suspensions For intraarticular injection appropriately prepared crystal suspensions may be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy.
  • these can be used in the form of aerosols and inhalants.
  • the new compounds may be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.
  • formulations in gels, ointments, greases, creams, pastes, powders, milk and tinctures are possible.
  • the dosage of the compounds of general formula I should be in these preparations 0.01% - 20% in order to achieve a sufficient pharmacological effect.
  • the invention also encompasses the compounds of general formula I according to the invention as therapeutic active ingredient. Furthermore, the invention relates to the compounds of general formula I as therapeutic agent together with pharmaceutically acceptable and acceptable excipients and carriers.
  • the invention also includes a pharmaceutical composition containing one of the pharmaceutically active compounds of the invention or their mixture or their pharmaceutically acceptable salt and pharmaceutically acceptable excipients and carriers.
  • the mixture is stirred for a further 3 hours at room temperature. It is diluted with diethyl ether and the reaction mixture is carefully added to a mixture of 4 M hydrochloric acid and ice. The phases are separated, extracted with diethyl ether, washed with water, dried over sodium sulfate and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane / isopropyl ether 0-20%) to give 2.75 g of 4-methylene-chroman.
  • the imine is taken up in 3.4 ml dichloromethane and treated at -50 0 C with 0.83 ml (0.83 mmol) of a 1 M boron tribromide solution.
  • the mixture is allowed to come to 0 0 C for one hour and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 15 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (hexane / 2-propanol 15%) gives 28 mg of the desired product as a mixture of two diastereomers. Diastereomer 1
  • 5-aminoquinoline-2 (1H) -one 4.5 g of 5-nitroquinoline-2 (1 H) -one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) are dissolved in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon Catalyst hydrogenated under normal pressure with hydrogen until complete reaction. The catalyst is removed by filtration through diatomaceous earth and the reaction solution is concentrated in vacuo. 3.8 g of the title compound are obtained as a yellow solid.
  • 2-Hydroxy-3- (2-methylthiochroman-4-yl) -2- (trifluoromethyl) propanal Can be prepared analogously to Example 1 from 6-chloro-2-methylthiochroman-4-one, wherein in the hydrogenation Raney nickel instead of palladium is to be used as a catalyst on carbon.

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Abstract

L'invention concerne des aminoalcools tricycliques de formule (I), des procédés de réalisation associés et leur utilisation en tant qu'anti-inflammatoires.
PCT/EP2005/013943 2004-12-22 2005-12-20 Aminoalcools tricycliques, procedes de realisation associes et utilisation comme anti-inflammatoires WO2006066950A2 (fr)

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JP2007547379A JP2008524300A (ja) 2004-12-22 2005-12-20 三環式アミノアルコール、それらの合成方法および抗炎症薬物としてのそれらの使用
AU2005318354A AU2005318354A1 (en) 2004-12-22 2005-12-20 Tricyclic aminoalcohols, methods for producing the same and their use as anti-inflammatory agents
BRPI0519710-4A BRPI0519710A2 (pt) 2004-12-22 2005-12-20 aminoÁlcoois tricÍclicos, processo para sua preparaÇço e seu emprego como anti-inflamatàrio
CA002586973A CA2586973A1 (fr) 2004-12-22 2005-12-20 Amino-alcools tricycliques, processus de synthese et utilisation comme anti-inflammatoires
MX2007007420A MX2007007420A (es) 2004-12-22 2005-12-20 Aminoalcoholes triciclicos, procedimientos para su preparacion y su uso como inhibidores de inflamacion.
IL183060A IL183060A0 (en) 2004-12-22 2007-05-08 Tricyclic aminoalcohols, methods for producing the same and their use as anti-inflammatory agents

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DE102004063227A DE102004063227A1 (de) 2004-12-22 2004-12-22 Tricylische Aminoalkohole, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102004063227.8 2004-12-22

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EP1917963A1 (fr) * 2006-10-31 2008-05-07 Bayer Schering Pharma Aktiengesellschaft Imidazoles cycliques substitués par un groupe phényle, procédé pour leur préparation et leur utilisation comme des agents anti-inflammatoires
US7402596B2 (en) 2005-03-24 2008-07-22 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
EP2072509A1 (fr) 2007-12-18 2009-06-24 Bayer Schering Pharma Aktiengesellschaft 1-aryl-1H-quinoline-2-ones : leur procédé de fabrication et leur utilisation en tant qu'agents anti-inflammatoires
US7638515B2 (en) 2003-10-08 2009-12-29 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7659297B2 (en) 2003-10-08 2010-02-09 Bayer Schering Pharma, AG Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7662821B2 (en) 2003-10-08 2010-02-16 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7816371B2 (en) 2006-03-16 2010-10-19 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US7880042B2 (en) 2006-03-15 2011-02-01 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, methods for the production thereof, and the use thereof as antiphlogistics
US8097627B2 (en) 2004-04-05 2012-01-17 Bayer Pharma AG Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
WO2013119895A1 (fr) 2012-02-08 2013-08-15 Sunovion Pharmaceuticals Inc. Composés hétéroaryles et procédé d'utilisation correspondant
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
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses 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

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KR102462991B1 (ko) * 2020-11-02 2022-11-04 한국해양과학기술원 남극-유래 진균 균주 아크레모늄(Acremonium sp.) SF-7394에서 분리한 화합물 및 이를 포함하는 항염증, 항암 또는 항당뇨용 조성물

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EA008830B1 (ru) * 2002-03-26 2007-08-31 Бёрингер Ингельхайм Фармасьютиклз, Инк. Миметики глюкокортикоидов, способы их получения, фармацевтические композиции и их применение
DE10215316C1 (de) * 2002-04-02 2003-12-18 Schering Ag Chinolin- und Isochinolin-Derivate, ein pharmazeutisches Mittel und ihre Verwendung als Entzündungshemmer
EP1670458B1 (fr) * 2003-10-08 2006-12-20 Schering Aktiengesellschaft Derives de tetrahydronaphtalene a substitution 1-amino-2-oxy, procedes pour leur production et leur utilisation en tant qu'anti-inflammatoires
GB0418045D0 (en) * 2004-08-12 2004-09-15 Glaxo Group Ltd Compounds
DE102004044680B3 (de) * 2004-09-09 2006-06-08 Schering Ag Alkyliden-Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer sowie diese enthaltende pharmazeutische Präparate

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US7638515B2 (en) 2003-10-08 2009-12-29 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7659297B2 (en) 2003-10-08 2010-02-09 Bayer Schering Pharma, AG Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7662821B2 (en) 2003-10-08 2010-02-16 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US8097627B2 (en) 2004-04-05 2012-01-17 Bayer Pharma AG Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7402596B2 (en) 2005-03-24 2008-07-22 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US7880042B2 (en) 2006-03-15 2011-02-01 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, methods for the production thereof, and the use thereof as antiphlogistics
US7816371B2 (en) 2006-03-16 2010-10-19 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
EP1917963A1 (fr) * 2006-10-31 2008-05-07 Bayer Schering Pharma Aktiengesellschaft Imidazoles cycliques substitués par un groupe phényle, procédé pour leur préparation et leur utilisation comme des agents anti-inflammatoires
WO2008052808A1 (fr) * 2006-10-31 2008-05-08 Bayer Schering Pharma Aktiengesellschaft Indazoles cycliques substitués par un phényle, leur procédé de production et leur utilisation comme agents anti-inflammatoires
EP2072509A1 (fr) 2007-12-18 2009-06-24 Bayer Schering Pharma Aktiengesellschaft 1-aryl-1H-quinoline-2-ones : leur procédé de fabrication et leur utilisation en tant qu'agents anti-inflammatoires
WO2013119895A1 (fr) 2012-02-08 2013-08-15 Sunovion Pharmaceuticals Inc. Composés hétéroaryles et procédé d'utilisation correspondant
US10189825B2 (en) 2012-02-08 2019-01-29 Sunovion Pharmaceuticals Inc. Heteroaryl compounds and methods of use thereof
US10556890B2 (en) 2012-02-08 2020-02-11 Sunovion Pharmaceuticals Inc. Heteroaryl compounds and methods of use thereof
US11332462B2 (en) 2012-02-08 2022-05-17 Sunovion Pharmaceuticals Inc. Heteroaryl 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
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses 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

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CA2586973A1 (fr) 2006-06-29
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CN101087780A (zh) 2007-12-12
JP2008524300A (ja) 2008-07-10
WO2006066950A3 (fr) 2006-08-17
IL183060A0 (en) 2007-09-20
BRPI0519710A2 (pt) 2009-03-10
PA8657801A1 (es) 2006-12-07
KR20070089948A (ko) 2007-09-04
MX2007007420A (es) 2007-07-17
DE102004063227A1 (de) 2006-07-06
AU2005318354A1 (en) 2006-06-29
GT200500385A (es) 2006-08-03

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