US20090088451A1 - Quinolines - Google Patents

Quinolines Download PDF

Info

Publication number
US20090088451A1
US20090088451A1 US12/233,625 US23362508A US2009088451A1 US 20090088451 A1 US20090088451 A1 US 20090088451A1 US 23362508 A US23362508 A US 23362508A US 2009088451 A1 US2009088451 A1 US 2009088451A1
Authority
US
United States
Prior art keywords
benzyl
methoxy
quinoline
diamine
ylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/233,625
Other languages
English (en)
Inventor
Sabine Kolczewski
Claus Riemer
Lucinda Steward
Juergen Wichmann
Thomas Woltering
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOLCZEWSKI, SABINE, RIEMER, CLAUS, STEWARD, LUCINDA, WICHMANN, JUERGEN, WOLTERING, THOMAS
Assigned to HOFFMANN-LA ROCHE, INC. reassignment HOFFMANN-LA ROCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Publication of US20090088451A1 publication Critical patent/US20090088451A1/en
Priority to US13/359,933 priority Critical patent/US8399674B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D17/00—Detergent materials or soaps characterised by their shape or physical properties
    • C11D17/0047—Detergents in the form of bars or tablets
    • C11D17/0065—Solid detergents containing builders
    • C11D17/0073—Tablets
    • C11D17/0086—Laundry tablets
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/0005—Other compounding ingredients characterised by their effect
    • C11D3/001—Softening compositions
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/50—Perfumes
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/50—Perfumes
    • C11D3/502—Protected perfumes
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D2111/00—Cleaning compositions characterised by the objects to be cleaned; Cleaning compositions characterised by non-standard cleaning or washing processes
    • C11D2111/10—Objects to be cleaned
    • C11D2111/12—Soft surfaces, e.g. textile

Definitions

  • 5-hydroxytryptamine 5-hydroxytryptamine
  • 5-HT 5-hydroxytryptamine
  • serotonin modulates a wide range of physiological and pathological processes in the central nervous system and periphery, including anxiety, sleep regulation, aggression, feeding and depression (Hoyer et al., Pharmacol. Rev. 46, 157-204, 1994).
  • Both pharmacological characterization and molecular cloning of several 5-HT receptor genes has revealed that 5-HT mediates its diverse physiological actions through a multiplicity of receptor subtypes. These receptors belong to at least two different protein superfamilies: ligand-gated ion channel receptor (5-HT 3 ) and the G-protein-coupled 7-transmembrane receptors (thirteen distinct receptors cloned to date).
  • serotonin exerts its actions through an array of signal transduction mechanisms.
  • the 5-HT 5A receptor is one of 13 G-protein coupled 5-HT receptors and is Gi- ⁇ -coupled, inhibiting adenylate cyclase.
  • the receptor protein DNA sequence is not closely related to that of any previously known serotonin receptor, with the best homology being 35% to the human 5-HT 1B receptor. It encodes a predicted 357 amino-acid protein, with seven putative transmembrane domains, consistent with that of a G-protein coupled receptor.
  • the sequence is characterized by containing an intron between transmembrane domains V and VI (5-HT 5A ; Barnes, N. M., & Sharp, T. (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083-1152; Thomas D. R.
  • 5-HT 5A receptors as a therapeutic target.
  • the human 5-HT5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells.
  • Thomas Pharmacology & Therapeutics, 111, 707-714; 2006 describes the potential therapeutic utility of 5-HT 5A receptor ligands for the treatment of circadian rhythm, sleep disturbances, mood disorders, schizophrenia, cognitive disorders and autism.
  • the human 5-HT 5A mRNA is distributed in CNS areas, such as the thalamus, limbic cortex, ventrolateral amygdala, hippocampus, and hypothalamus (Pasqualetti, M., Ori, M., Nardi, I., Castagna, M., Cassano, G. B., & Marazziti, D. (1998). Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol Brain Res 56, 1-8). All of these CNS areas are implicated in either the pathology or treatment of schizophrenia and anxiety.
  • the receptor has not been detected in peripheral organs (Rees, S., Dendaas, I., Foord, S., Goodson, S., Bull, D., Kilpatrick, G., et al. (1994). Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett 355, 242-246), although it is expressed in rat superior cervical ganglia (Wang, Z. Y., Keith, I. M., Beckman, M. J., Brownfield, M. S., Vidruk, E. H. and Bisgard, G. E. (2000) 5-HT5A receptors in the carotid body chemoreception pathway of rat. Neurosci. Lett.
  • the spinal cord dorsal horn which may indicate the involvement of the 5-HT 5A receptor in central motor control, nociception and autonomic function such as stress induced urinary incontinence and overactive bladder (Doly, S., Fischer, J., Brisorgueil, M.-J., Verge, D. and Conrath M. 5-HT5A Receptor Localization in the Rat Spinal Cord Suggests a Role in Nociception and Control of Pelvic Floor Musculature The Journal of comparative neurology 476:316-329 (2004)).
  • the present invention provides 2-aminoquinolines as 5-HT 5A receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments.
  • the compounds of formula I can contain some asymmetric carbon atoms. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof, i.e. their individual optical isomers and mixtures thereof.
  • the compounds of formula I have a good affinity to the 5-HT 5A receptor.
  • Compounds with 5-HT 5A affinity can be used for the manufacture of medicaments for the treatment of depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorders and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders, (which includes generalized anxiety and social anxiety disorder, panic disorders, agoraphobia, social phobia, obsessive compulsive disorders, post-traumatic stress disorders, psychotic disorders (which includes schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions), pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviors (including nervosa and bulimia nervosa), sexual
  • the preferred indications with regard to the present invention are the treatment of anxiety, depression, sleep disorders and schizophrenia.
  • alkyl denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and the like.
  • Preferred alkyl groups are groups with 1-4 carbon atoms.
  • halo or “halogen” denotes fluorine, chlorine, bromine and iodine.
  • the alkyl or C 1-7 -alkyl group as defined above can optionally be substituted with one or more halo, hydroxy or cyano, alternatively also referred to as “halo-C 1-7 -alkyl”, “hydroxy-C 1-7 -alkyl”, or “cyano-C 1-7 -alkyl”. Thereby, at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, a hydroxy group or a cyano group.
  • halo-C 1-7 -alkyl hence denotes a C 1-7 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
  • halo-C 1-7 -alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as well as those groups specifically illustrated by the examples herein below.
  • the preferred halo-C 1 I 7 -alkyl groups are difluoro- or trifluoro-methyl or -ethyl.
  • hydroxy-C 1-7 -alkyl hence denotes a C 1-7 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group.
  • hydroxy-C 1-7 -alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more hydroxy groups, preferably one hydroxy group, as well as those groups specifically illustrated by the examples herein below.
  • cyano-C 1-7 -alkyl hence denotes a C 1-7 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cyano group.
  • cyano-C 1-7 -alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more cyano groups, preferably one cyano group, as well as those groups specifically illustrated by the examples herein below.
  • alkoxy denotes a group having an alkyl residue as defined above, which is attached via an oxygen atom, i.e. a group R′—O— wherein R′ is alkyl as defined above.
  • C 1 -C 7 haloalkoxy denotes an alkoxy group as defined above which is substituted by one or more halogen.
  • Examples of C 1 -C 7 haloalkoxy include but are not limited to methoxy or ethoxy, substituted by one or more Cl, F, Br or I atom(s) as well as those groups specifically illustrated by the examples herein below.
  • Preferred C 1 -C 7 haloalkoxy are difluoro- or trifluoro-methoxy or ethoxy.
  • aryl denotes a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono- or bicyclic aromatic ring, for example phenyl or naphthyl.
  • Aryl is optionally substituted as described herein.
  • heteroaryl denotes an aromatic monocyclic or bicyclic ring containing one, two, three or four heteroatoms selected from N, O, and S, the remaining ring atoms being C.
  • the monocyclic heteroaryl ring is 5 or 6 membered and the bicylcic heteroaryl ring is 9 or 10 membered.
  • the one, two, three or four heteroatoms of the bicyclic heteroaryl moiety are located in either one or both rings.
  • Examples for 5- or 6-membered monocyclic heteroaryl include but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or tetrazolyl.
  • 9-or 10-membered bicyclic heteroaryl examples include but are not limited to indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxyzolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl, or pteridinyl.
  • Preferred examples for 5- or 6-membered monocyclic heteroaryl are are tetrazolyl, [1,3,4]-oxadiazolyl, [1,2,4]-oxadiazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridinyl, or pyrimidinyl.
  • a preferred example for a 9-membered bicyclic heteroaryl is benzoxazolyl.
  • Heteroaryl is optionally substituted as described herein.
  • aromatic in the above sense means the presence of an electron sextet in the ring, according to Hutckel's rule.
  • heterocycloalkyl refers to a monovalent 5 to 7 membered saturated monocyclic ring containing one or two heteroatoms selected from N, O and S.
  • heterocycloclakyl moieties are tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazinyl and piperazin-2-one.
  • a preferred heterocycloalkyl moiety is piperidinyl.
  • cycloalkyl refers to a monovalent carbocyclic radical of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferred is cyclopropyl.
  • one or more as used herein to describe the number of optional substituents means that so many optional substituents are possible, as hydrogen atoms attached to the ring may be replaced. However, one, two or three optional substituents are preferred, whereas one or two optional substituents are even more preferred.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salt embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the 2-aminoquinolines of present invention can alternatively be described with formula I′, indicating that the 2-amino-position as well as the 6-position of the quinoline core bear aromatic substituents Ar 1 and Ar 2 , respectively, attached to the core with or without a linker X and Z
  • the linker X is selected from —NR a —, —NR b CH 2 —, —CH 2 NR b —, —NR c C(O)—, —OCH 2 —, —CH 2 O—, —CH 2 CH 2 —, —CH ⁇ CH—, —NHC(O)NH—, —NHSO 2 NH—, —NR c C(O)O—, —C(O)NR c CH 2 —, —CH 2 NR b CH 2 —, —NHC( ⁇ N—Ar 1 )—, —NR b CH 2 CH 2 CH 2 —, and —NR b CH 2 CH 2 O—.
  • Ar 1 R a , R b and R c have the meaning as defined herein.
  • linker Z is a single bond, —CHR d —, or —CH 2 CH 2 O—, with R d being hydrogen or C 1-7 -alkyl, preferably hydrogen.
  • R 3 is as defined herein.
  • R 1 of the 2-aminoquinoline of the above-mentioned formula I is —NR a —Ar 1 , —NR b CH 2 —Ar 1 , —CH 2 NR b —Ar 1 , —NR c C(O)—Ar 1 , —OCH 2 —Ar 1 , —CH 2 O—Ar 1 , —CH 2 CH 2 —Ar 1 , —CH ⁇ CH—Ar 1 , —NHC(O)NH—Ar 1 , —NHSO 2 NH—Ar 1 , —NR c C(O)O—Ar 1 , —C(O)NR c CH 2 —Ar 1 , —CH 2 NR b CH 2 —Ar 1 , —NHC( ⁇ N—Ar 1 )—Ar 1 , —NR b CH 2 CH 2 CH 2 —Ar 1 , or —NR b CH 2
  • R 1 of the 2-aminoquinoline of formula I is —NR a —Ar 1 , —NR b CH 2 —Ar 1 , —CH 2 NR b —Ar 1 , —OCH 2 —Ar 1 , —CH 2 O—Ar 1 , —CH 2 CH 2 —Ar 1 , —CH ⁇ CH—Ar 1 , —NHC(O)NH—Ar 1 , —NHSO 2 NH—Ar 1 , —NR c C(O)O—Ar 1 , —NR b CH 2 CH 2 CH 2 —Ar 1 , or —NR b CH 2 CH 2 O—Ar 1 .
  • R 1 being —NR a —Ar 1 , —NR b CH 2 —Ar 1 , —CH 2 O—Ar 1 , —CH 2 CH 2 —Ar 1 , —CH ⁇ CH—Ar 1 , —NHC(O)NH—Ar 1 , —NHSO 2 NH—Ar 1 , or —NR c C(O)O—Ar 1 .
  • R 1 being —NR a —Ar 1 , —NR b CH 2 —Ar 1 , —CH 2 O—Ar 1 , —CH 2 CH 2 —Ar 1 , —CH ⁇ CH—Ar 1 , —NHSO 2 NH—Ar 1 , or —NR c C(O)O—Ar 1 .
  • R a , R b and R c are each independently hydrogen or C 1-7 -alkyl; preferably, R a , R b , and R c are hydrogen.
  • R 1 of the compound of formula I is —NH—Ar 1 .
  • R 1 of the compound of formula I is —NHCH 2 —Ar 1 .
  • R 1 of the compound of formula I is —CH 2 O—Ar 1 .
  • R 1 of the compound of formula I is —CH 2 CH 2 —Ar 1 .
  • R 1 of the compound of formula I is —CH ⁇ CH—Ar 1 .
  • R 1 of the compound of formula I is NHC(O)NH—Ar 1 .
  • R 1 of the compound of formula I is —NHSO 2 NH—Ar 1 .
  • R 1 of the compound of formula I is —NHC(O)O—Ar 1 .
  • Ar 1 is an aryl or heteroaryl moiety as defined herein, each optionally substituted by one or more B, also as defined herein.
  • Ar 1 is phenyl, naphthyl, an aromatic 5- or 6-membered monocyclic heteroaryl or an aromatic 9- or 10-membered bicyclic heteroaryl, each containing one, two, three or four heteroatoms selected from N, O or S, the remaining ring atoms being C.
  • Ar 1 is optionally substituted by one or more B as defined herein.
  • Ar 1 examples are phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxyzolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl, or pteridinyl, each optionally substituted with one or more B
  • Ar 1 Preferred examples for Ar 1 are phenyl, tetrazolyl, [1,3,4]-oxadiazolyl, [1,2,4]-oxadiazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridinyl, pyrimidinyl or benzoxazolyl, each optionally substituted with one of more B as defined herein above.
  • Preferred optional substituents B are:
  • R v is as defined above, preferably R v is methyl
  • R vi is as defined above, preferably R vi is hydrogen.
  • R v is as defined above, preferably R v is methyl.
  • R 2 of the 2-aminoquinoline of the above-mentioned formula I is —Ar 2 , —CHR d —Ar 2 , or —CH 2 CH 2 O—Ar 2 .
  • R d is selected from hydrogen or C 1-7 -alkyl.
  • R d is hydrogen.
  • R 2 of the 2-aminoquinoline of the above-mentioned formula I is —CH 2 —Ar 2 or —CH 2 CH 2 O—Ar 2 .
  • Ar 2 is an aryl or heteroaryl moiety as defined herein, each optionally substituted by one or more B, also as defined herein.
  • Ar 2 is phenyl, naphthyl, an aromatic 5- or 6-membered monocyclic heteroaryl or an aromatic 9- or 10-membered bicyclic heteroaryl, each containing one, two, three or four heteroatoms selected from N, O or S, the remaining ring atoms being C.
  • Ar 2 is optionally substituted by one or more B as defined herein.
  • Ar 2 examples are phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxyzolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl, or pteridinyl, each optionally substituted with one or more B
  • Ar 2 Preferred examples for Ar 2 are phenyl, tetrazolyl, [1,3,4]-oxadiazolyl, [1,2,4]-oxadiazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridinyl, pyrimidinyl or benzoxazolyl, each optionally substituted with one of more B as defined herein, for instance as defined in claim 1 .
  • Ar 2 is phenyl, pyridinyl, or furanyl, each optionally substituted with one or more B as defined herein.
  • Preferred optional substituents B are:
  • R v is as defined above, preferably R v is methyl
  • R vi is as defined above, preferably R vi is hydrogen.
  • R vi is as defined above, and preferably is hydrogen.
  • R 3 of the 2-aminoquinoline of the above-mentioned formula I is
  • phenyl or pyridinyl optionally substituted with one or more C 1-4 -alkyl, halo, or C 1-4 -alkoxy,
  • R e and R f are each independently hydrogen, or —(CH 2 ) m —OR g ,
  • R g is hydrogen or C 1-7 -alkyl, preferably R g is hydrogen.
  • R 3 of formula I is
  • phenyl or pyridinyl optionally substituted with one or more C 1-4 -alkyl, halo, or C 1-4 -alkoxy.
  • R 3 of formula I is hydrogen
  • Preferred compounds of present invention are those as exemplified in the examples.
  • the compounds of formula I or formula I′ and their pharmaceutically acceptable addition salts possess valuable pharmaceutical properties.
  • the compounds of the present invention are active on the 5-HT 5A receptor and therefore suitable for the treatment of depression, anxiety disorders, schizophrenia, panic disorders, agoraphobia, social phobia, obsessive compulsive disorders, post-traumatic stress disorders, pain, memory disorders, dementia, disorders of eating behaviors, sexual dysfunction, sleep disorders, withdrawal from abuse of drugs, motor disorders such as Parkinson's disease, psychiatric disorders or gastrointestinal disorders.
  • a [ 3 H]LSD radioligand binding assay was used to determine the affinity of the compounds for the recombinant human 5-HT 5A receptor, in membranes from transiently (cDNA) expressed 5-HT 5A receptors in Human Embryonic Kidney-EBNA (HEK-EBNA) cells.
  • Assay buffer consisted of Tris (50 mM) buffer containing 1 mM EGTA, 10 mM MgCl 2 (pH 7.4) and 10 ⁇ M pargyline.
  • the binding assay was carried out in 96-well-plates in the presence of [ 3 H]LSD (approximately 1 nM), approximately 2 ⁇ g/well of membrane protein, and 0.5 mg of Ysi-poly-l-lysine SPA beads in a final volume of 200 ⁇ l of buffer. Non-specific binding was defined using methiothepin 2 ⁇ M. Compounds were tested at 10 concentrations. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 120 min at room temperature before centrifugation. Bound ligand was determined using a Packard Topcount scintillation counter. IC 50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
  • the present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose,corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the present invention also provides a method for the manufacture of pharmaceutical compositions. Such process comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the compounds and compositions of the present invention can be administered in a conventional manner, for example, orally, rectally, or parenterally.
  • the pharmaceutical compositions of the invention can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions, or suspensions.
  • the pharmaceutical compositions also can be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injectable solutions.
  • the most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment of anxiety, depression, sleep disorders and schizophrenia.
  • the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831
  • Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600
  • 2,6-Dichloroquinoline (1) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediate 2 is reacted with an amine Ar 1 L 1 NH 2 in a palladium catalyzed substitution reaction.
  • Ar 1 L 1 NH 2 in this context means Ar 1 —CH 2 —NH 2 , Ar 1 —CH 2 CH 2 CH 2 —NH 2 , or Ar 1 —OCH 2 CH 2 —NH 2 .
  • 6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediate 5 is reacted with an alkene Ar 1 CH ⁇ CH 2 in a palladium catalyzed substitution reaction.
  • 6-Chloro-4-phenyl-quinolin-2-ylamine (8) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediate 8 is reacted with an aldehyde Ar 2 CHO in a reductive amination.
  • Intermediate 9 is reacted with an amine Ar 1 L 1 NH 2 in a palladium catalyzed substitution reaction.
  • Ar 1 L 1 NH 2 in this context means Ar 1 —CH 2 —NH 2 , Ar 1 —CH 2 CH 2 CH 2 —NH 2 , or Ar 1 —OCH 2 CH 2 —NH 2 .
  • 6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediate 5 is reacted with vinyltributyltin in a palladium catalyzed substitution reaction.
  • Intermediate 11 is reacted with with an arylbromide or aryliodide Ar 1 hal in a palladium catalyzed substitution reaction.
  • 2-Amino-6-chloro-4-hydroxyquinoline (12) is brominated with PBr3 to the intermediate 13 which is reacted with an aldehyde Ar 2 CHO in a reductive amination.
  • the bromide 14 is used for a Suzuki reaction to introduce the substituent Y.
  • Intermediate 15 is reacted with an amine Ar 1 L 1 NH 2 in a palladium catalyzed substitution reaction.
  • Ar 1 L 1 NH 2 in this context means Ar 1 —CH 2 —NH 2 , Ar 1 —CH 2 CH 2 CH 2 —NH 2 , or Ar 1 —OCH 2 CH 2 —NH 2 .
  • 6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediate 5 is reacted with n-butyllithium and quenched with dimethylformamide to produce aldehyde 19 which is reduced with sodium borohydride to the alcohol 20.
  • Alcohol 20 is then reacted in a Mitsunobu reaction with a phenol derivative Ar 1 OH.
  • Ar 1 L 1 NH 2 in this context means Ar 1 —CH 2 —NH 2 , Ar 1 —CH 2 CH 2 CH 2 —NH 2 , or Ar 1 —OCH 2 CH 2 —NH 2 .
  • Aldehyde 19 is reacted with an amine Ar 1 NH 2 in a reductive amination.
  • 2,6-Dichloroquinoline (1) is reacted with 2 equivalents of allylamine without solvent.
  • Intermediate 26 is reacted with an amine Ar 1 L 1 NH 2 in a palladium catalyzed substitution reaction.
  • Ar 1 L 1 NH 2 in this context means Ar 1 —CH 2 —NH 2 , Ar 1 —CH 2 CH 2 CH 2 —NH 2 , or Ar 1 —OCH 2 CH 2 —NH 2 .
  • the allyl protecting group is lost in this transformation.
  • Intermediate 27 is reacted with an aldehyde Ar 2 CHO in a reductive amination
  • 2-Chloro-6-nitro-quinoline (cas no.: 29969-57-1) is treated with ortho methoxybenzene to yield compound 40 which is then reduced with H 2 and Pd/C under normal pressure to yield 6-amino-quinoline derivative 41.
  • Acylation of the 6-amino group with a carboxyl chloride leads to carboxamide 42.
  • reaction with a carbodiimide led to guanidines
  • carbamoyl chlorides led to urea derivatives
  • formic acid esters to carbamates and with sulfamoyl chlorides to sulfamides
  • 6-Bromo-2 chloroquinoline (727 mg, 3.0 mmol) and 2-methoxybenzylamine (823 mg, 6.0 mmol were stirred in a sealed tube at 120° C. for 16 h.
  • the reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0 ⁇ 70:30 gradient).
  • 6-Chloro-4-phenyl-quinolin-2-ylamine (CAS 51478-40-1, 750 mg, 2.94 mmol) was dissolved in 40 mL dichloromethane.
  • 2-Methoxybenzaldehyde (481 mg, 3.54 mmol) and acetic acid (354 mg, 5.9 mmol) were added.
  • the reaction mixture was stirred at room temperature for 2 h.
  • Sodium triacetoxy borohydride (1.39 g, 6.59 mmol) was added and stirring was continued overnight.
  • the reaction mixture was quenched by addition of 100 mL sat. sodiumbicarbonate solution.
  • the mixture was extracted three times with dichloromethane (100 mL each).
  • N4-Allyl-6-chloro-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine (prepared from (4-bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl)-amine and allylamine as described in example 40, step A) was coupled with benzylamine as described in example 30, step D.
  • N6-Pyridin-3-ylmethyl-quinoline-2,6-diamine MS: m/e 251.5 (M+H + ), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, allylamine and 3-(aminomethyl)pyridine. The allyl protecting group was lost in the palladium catalyzed substitution reaction.
  • N6-Pyridin-3-ylmethyl-quinoline-2,6-diamine 150 mg, 0.6 mmol was dissolved in 10 mL dichloromethane.
  • 5-Fluoro-2-methoxybenzaldehyde 111 mg, 0.72 mmol
  • acetic acid 72 mg, 1.2 mmol
  • the reaction mixture was stirred at 40° C. for 3 h.
  • Sodium triacetoxy borohydride (254 mg, 1.2 mmol) was added and stirring was continued at room temperature overnight.
  • the reaction mixture was quenched by addition of 20 mL sat. sodiumbicarbonate solution.
  • the mixture was extracted three times with dichloromethane (20 mL each).
  • N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine 40 mg, 0.14 mmol
  • p-anisoyl chloride 0.022 mL, 0.16 mmol
  • the reaction mixture was heated to 50° C. for 3 h. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate, 4:1, 1:1, 1:2).
  • N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine 40 mg, 0.14 mmol
  • 1,3-di-p-tolylcarbodiimid 0.035 mg, 0.16 mmol
  • N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine 40 mg, 0.14 mmol
  • 4-methoxyphenyl isocyanat 0.021 mg, 0.14 mmol
  • the reaction mixture was heated to 60° C. for 16 h. Then the solvent was removed and a precipitate formed which was filtered, washed with toluene and dried under high vacuum.
  • N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine 50 mg, 0.18 mmol
  • triethylamine 0.030 mL, 0.22 mmol
  • 4-methoxyphenylchloroformat 0.027 mL, 0.18 mmol
  • the reaction mixture was heated to 90° C. for 6 h. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate, 9:1, 4:1, 1:1, 1:2).
  • N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine 40 mg, 0.14 mmol
  • 4-fluorphenylsulfamoylchloride 0.039 mg, 0.18 mmol
  • the reaction mixture was heated to 90° C. for 6 h. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate, 9:1, 4:1, 1:1, 1:2).
  • step A A mixture of of (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) (500 mg, 1.46 mmol), zinc cyanide (188 mg, 1.6 mmol) and tetrakis-(triphenylphosphine)-palladium (168 mg, 0.145 mmol) in DMF (5 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (30 ml) and extracted with diethyl ether (2 ⁇ 50 ml). The combined organic layers were washed with brine (2 ⁇ 30 ml), dried (MgSO 4 ) and evaporated.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Wood Science & Technology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Detergent Compositions (AREA)
  • Quinoline Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US12/233,625 2007-09-27 2008-09-19 Quinolines Abandoned US20090088451A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/359,933 US8399674B2 (en) 2007-09-27 2012-01-27 Quinolines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07117420.5 2007-09-27
EP07117420 2007-09-27

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/359,933 Continuation US8399674B2 (en) 2007-09-27 2012-01-27 Quinolines

Publications (1)

Publication Number Publication Date
US20090088451A1 true US20090088451A1 (en) 2009-04-02

Family

ID=40336429

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/233,625 Abandoned US20090088451A1 (en) 2007-09-27 2008-09-19 Quinolines
US13/359,933 Expired - Fee Related US8399674B2 (en) 2007-09-27 2012-01-27 Quinolines
US14/022,712 Abandoned US20140107010A1 (en) 2007-09-27 2013-09-10 Fragrance tablet and method
US15/057,922 Abandoned US20170015952A1 (en) 2007-09-27 2016-03-01 Fragrance Tablet and Method

Family Applications After (3)

Application Number Title Priority Date Filing Date
US13/359,933 Expired - Fee Related US8399674B2 (en) 2007-09-27 2012-01-27 Quinolines
US14/022,712 Abandoned US20140107010A1 (en) 2007-09-27 2013-09-10 Fragrance tablet and method
US15/057,922 Abandoned US20170015952A1 (en) 2007-09-27 2016-03-01 Fragrance Tablet and Method

Country Status (14)

Country Link
US (4) US20090088451A1 (zh)
EP (1) EP2195296A1 (zh)
JP (1) JP2010540483A (zh)
KR (1) KR101192952B1 (zh)
CN (1) CN101808999B (zh)
AR (1) AR068547A1 (zh)
AU (1) AU2008303602A1 (zh)
BR (1) BRPI0817245A2 (zh)
CA (1) CA2699697A1 (zh)
CL (1) CL2008002864A1 (zh)
MX (1) MX2010003001A (zh)
PE (1) PE20091204A1 (zh)
TW (1) TW200922580A (zh)
WO (1) WO2009040290A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090227583A1 (en) * 2008-03-07 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US20090227570A1 (en) * 2008-03-05 2009-09-10 Sabine Kolczewski 2-aminoquinolines
JP2014503488A (ja) * 2010-11-12 2014-02-13 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー プロパ−２−エン−１−アミンから出発して２，２−ジフルオロエチルアミンを調製する方法

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101959557A (zh) * 2008-03-12 2011-01-26 弗·哈夫曼-拉罗切有限公司 作为5-ht5a受体拮抗剂的2-氨基喹啉类
TW201116281A (en) 2009-08-06 2011-05-16 Astellas Pharma Inc N atom containing ring acylguanidine derivatives
NZ600857A (en) 2010-01-29 2014-06-27 Boehringer Ingelheim Int Substituted naphthyridines and their use as syk kinase inhibitors
CA2843022C (en) 2011-07-26 2019-09-24 Boehringer Ingelheim International Gmbh Substituted quinolines and their use as medicaments
KR20140088194A (ko) 2011-11-04 2014-07-09 에프. 호프만-라 로슈 아게 아릴-퀴놀린 유도체
EP3285594B1 (en) 2015-04-24 2021-03-17 International Flavors & Fragrances Inc. Delivery systems and methods of preparing the same
US10226544B2 (en) 2015-06-05 2019-03-12 International Flavors & Fragrances Inc. Malodor counteracting compositions
US20170204223A1 (en) 2016-01-15 2017-07-20 International Flavors & Fragrances Inc. Polyalkoxy-polyimine adducts for use in delayed release of fragrance ingredients
CN108697591B (zh) 2016-02-18 2022-06-17 国际香料和香精公司 聚脲胶囊组合物
ES2950434T3 (es) 2016-09-16 2023-10-10 Int Flavors & Fragrances Inc Composiciones de microcápsula estabilizadas con agentes de control de la viscosidad
US20180085291A1 (en) 2016-09-28 2018-03-29 International Flavors & Fragrances Inc. Microcapsule compositions containing amino silicone
US20180346648A1 (en) 2017-05-30 2018-12-06 International Flavors & Fragrances Inc. Branched polyethyleneimine microcapsules
US12012394B2 (en) 2018-02-19 2024-06-18 Washington University Alpha-synuclein ligands
BR112021011903A2 (pt) 2018-12-18 2021-08-31 International Flavors & Fragrances Inc. Composição de microcápsula, produto de consumo, e, processo para preparar uma composição de microcápsula
US11946026B2 (en) 2020-06-04 2024-04-02 International Flavors & Fragrances Inc. Fabric care composition and method for improving fragrance intensity with isopropyl myristate
EP3970690A3 (en) 2020-06-05 2022-07-06 International Flavors & Fragrances Inc. Consumer products with improved aesthetics
EP4124383A1 (en) 2021-07-27 2023-02-01 International Flavors & Fragrances Inc. Biodegradable microcapsules

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6897220B2 (en) * 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
US20070299074A1 (en) * 2004-02-19 2007-12-27 Astrid Netz Guanidine Compounds, and Use Thereof as Binding partners for 5-Ht5 Receptors
US20090227583A1 (en) * 2008-03-07 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US20090227570A1 (en) * 2008-03-05 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US20090233927A1 (en) * 2008-03-12 2009-09-17 Sabine Kolczewski 2-aminoquinolines

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4434086A (en) * 1982-06-04 1984-02-28 International Flavors & Fragrances, Inc. Process for augmenting or enhancing the fresh air aroma of clothing
DE3911363B4 (de) * 1989-04-07 2005-02-03 Freytag Von Loringhoven, Andreas Verfahren zur Herstellung von mit Duftstoffen anzureichernder Wasch- oder Spüllauge und Duftstoffzugabemittel zur Durchführung des Verfahrens
US20030104969A1 (en) * 2000-05-11 2003-06-05 Caswell Debra Sue Laundry system having unitized dosing
AU2001293826A1 (en) 2000-09-25 2002-04-02 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting quinoline and quinazoline derivatives as farnesyl transferase inhibitors
EP1429765A2 (en) 2001-09-14 2004-06-23 Methylgene, Inc. Inhibitors of histone deacetylase
AU2002352878B2 (en) * 2001-11-27 2007-11-22 Merck Sharp & Dohme Corp. 2-Aminoquinoline compounds
MXPA05009722A (es) * 2003-03-10 2006-03-09 Schering Corp Inhibidores heterociclicos de cinasa: metodos de uso y sintesis.
GB0309781D0 (en) 2003-04-29 2003-06-04 Glaxo Group Ltd Compounds
AU2004281154A1 (en) * 2003-10-16 2005-04-28 Novartis Vaccines And Diagnostics, Inc. 2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines as inhibitors of Raf kinase for treatment of cancer
EP1861102A1 (en) * 2005-03-15 2007-12-05 F. Hoffmann-Roche AG Use of 2-anilino-3,4-dihydro-quinazolines as 5ht5a receptor antagonists
EP1888538B1 (en) * 2005-05-04 2009-11-18 F. Hoffmann-Roche AG (3,4-dihydro-quinazolin-2-yl)-(2-aryloxy-ethyl)-amines having an activity on the 5-ht receptor
CN101208308B (zh) * 2005-06-27 2010-12-08 弗·哈夫曼-拉罗切有限公司 8-烷氧基-4-甲基-3,4-二氢-喹唑啉-2-基胺和它们作为5-ht5a受体配体的用途
CN101208309B (zh) * 2005-06-27 2010-12-08 弗·哈夫曼-拉罗切有限公司 氯取代的胍类化合物
WO2007022946A1 (de) * 2005-08-21 2007-03-01 Abbott Gmbh & Co. Kg Heterocyclische verbindungen und ihre verwendung als bindungspartner für 5-ht5-rezeptoren
EP1917244A2 (de) * 2005-08-24 2008-05-07 Abbott GmbH & Co. KG Hetaryl substituierte guanidinverbindungen und ihre verwendung als bindungspartner für 5-ht5-rezeptoren
ES2347193T3 (es) * 2006-09-28 2010-10-26 F. Hoffmann-La Roche Ag Derivados de quinolina con propiedades de enlace a 5-ht.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6897220B2 (en) * 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
US20070299074A1 (en) * 2004-02-19 2007-12-27 Astrid Netz Guanidine Compounds, and Use Thereof as Binding partners for 5-Ht5 Receptors
US20090227570A1 (en) * 2008-03-05 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US20090227583A1 (en) * 2008-03-07 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US20090233927A1 (en) * 2008-03-12 2009-09-17 Sabine Kolczewski 2-aminoquinolines

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090227570A1 (en) * 2008-03-05 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US8183380B2 (en) * 2008-03-05 2012-05-22 Hoffmann-La Roche Inc. 2-aminoquinolines
US20090227583A1 (en) * 2008-03-07 2009-09-10 Sabine Kolczewski 2-aminoquinolines
US8188284B2 (en) * 2008-03-07 2012-05-29 Hoffman-La Roche Inc. 2-aminoquinolines
JP2014503488A (ja) * 2010-11-12 2014-02-13 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー プロパ−２−エン−１−アミンから出発して２，２−ジフルオロエチルアミンを調製する方法

Also Published As

Publication number Publication date
WO2009040290A1 (en) 2009-04-02
PE20091204A1 (es) 2009-08-26
KR20100047326A (ko) 2010-05-07
US20140107010A1 (en) 2014-04-17
US20120136018A1 (en) 2012-05-31
CL2008002864A1 (es) 2009-08-21
US8399674B2 (en) 2013-03-19
BRPI0817245A2 (pt) 2015-06-16
AR068547A1 (es) 2009-11-18
CA2699697A1 (en) 2009-04-02
EP2195296A1 (en) 2010-06-16
KR101192952B1 (ko) 2012-10-18
US20170015952A1 (en) 2017-01-19
CN101808999B (zh) 2013-02-13
JP2010540483A (ja) 2010-12-24
AU2008303602A1 (en) 2009-04-02
CN101808999A (zh) 2010-08-18
TW200922580A (en) 2009-06-01
MX2010003001A (es) 2010-04-01

Similar Documents

Publication Publication Date Title
US8399674B2 (en) Quinolines
US7923561B2 (en) Quinolines
US7989628B2 (en) 2-aminoquinolines
US20080081907A1 (en) 2-aminoquinoline derivatives
US7994324B2 (en) 2-aminoquinoline derivatives
US8188284B2 (en) 2-aminoquinolines
US8350028B2 (en) 2-aminoquinolines
US8044047B2 (en) 5-substituted benzoxazines

Legal Events

Date Code Title Description
AS Assignment

Owner name: F. HOFFMANN-LA ROCHE AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KOLCZEWSKI, SABINE;RIEMER, CLAUS;STEWARD, LUCINDA;AND OTHERS;REEL/FRAME:021671/0688

Effective date: 20080912

Owner name: HOFFMANN-LA ROCHE, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:F. HOFFMANN-LA ROCHE AG;REEL/FRAME:021671/0818

Effective date: 20080915

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION