WO2009040290A1 - Quinoline derivatives as 5ht5a receptor antagonists - Google Patents

Quinoline derivatives as 5ht5a receptor antagonists Download PDF

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WO2009040290A1
WO2009040290A1 PCT/EP2008/062416 EP2008062416W WO2009040290A1 WO 2009040290 A1 WO2009040290 A1 WO 2009040290A1 EP 2008062416 W EP2008062416 W EP 2008062416W WO 2009040290 A1 WO2009040290 A1 WO 2009040290A1
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Prior art keywords
benzyl
methoxy
quinoline
diamine
ylmethyl
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PCT/EP2008/062416
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French (fr)
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Sabine Kolczewski
Claus Riemer
Lucinda Steward
Juergen Wichmann
Thomas Woltering
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F. Hoffmann-La Roche Ag
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Priority to KR1020107006399A priority Critical patent/KR101192952B1/en
Priority to CN2008801088436A priority patent/CN101808999B/en
Priority to AU2008303602A priority patent/AU2008303602A1/en
Priority to CA2699697A priority patent/CA2699697A1/en
Priority to JP2010526250A priority patent/JP2010540483A/en
Priority to EP08804358A priority patent/EP2195296A1/en
Priority to BRPI0817245-5A priority patent/BRPI0817245A2/en
Priority to MX2010003001A priority patent/MX2010003001A/en
Publication of WO2009040290A1 publication Critical patent/WO2009040290A1/en

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    • 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
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Definitions

  • the present invention is concerned with 2-Aminoquinoline derivatives as 5-HT SA receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments.
  • R 2 is -Ar 2 , -CHR d -Ar 2 , or -CH 2 CH 2 O-Ar 2 ,
  • R 3 is hydrogen, phenyl, or pyridinyl, optionally substituted with one or more Ci- 4 -alkyl, halo, or Ci- 4 -alkoxy,
  • R e and R f are each independently hydrogen, or -(CH 2 ) m -OR g , wherein m is from 2 to 6,
  • Ar 1 and Ar 2 are each independently aryl or heteroaryl, each optionally substituted by one or more B,
  • Ci-7-alkyl optionally substituted with one or more halo, hydroxy, or cyano,
  • n is from 1 to 3
  • n is from 1 to 3
  • R a , R b , R c , R d , and R g are each independently hydrogen, Ci- 7 -alkyl;
  • R 1 , R 11 , R 111 , R lv , and R v are each independently hydrogen, or Ci-7-alkyl or -(CH 2 ) n -C 3 - 7 -cycloalkyl, wherein n is from 0 to 3;
  • R", RTM, and R" 11 are each independently hydrogen, Ci- 4 -alkyl or halogen;
  • the compounds of formula I may contain some asymmetric carbon atoms.
  • 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. It has been found that the compounds of formula I have a good affinity to the 5- HT 5 A receptor.
  • Compounds with 5-HT 5 A affinity may 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 neurotransmitter 5-hydroxytryptamine (5 -HT, 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). In addition, within the G-protein-coupled receptors, serotonin exerts its actions through an array of signal transduction mechanisms. - A -
  • the 5-HT 5 A 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-HTi B 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 5 A receptors as a therapeutic target.
  • the human 5-HT5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells.
  • Eur. J. Pharmacol. (1998), 361(2-3):299-309.
  • Thomas Pharmacology & Therapeutics, 111, 707-714; 2006 describes the potential therapeutic utility of 5-HT 5 A receptor ligands for the treatment of circadian rhythm, sleep disturbances, mood disorders, schizophrenia, cognitive disorders and autism.
  • the human 5-HT 5 A mRNA is distributed in CNS areas, such as the thalamus, limbic cortex, ventrolateral amygdala, hippocampus, and hypothalamus (Pasqualetti, M., Ori, M., Nardi, L, Castagna, M., Cassano, G. B., & Marazziti, D. (1998). Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. MoI 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, L, 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 5 A receptor in central motor control, nociception and autonomic function such as stress induced urinary incontinence and overactive bladder (DoIy, 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)).
  • stress induced urinary incontinence and overactive bladder DoIy, 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)).
  • 5-HT 5 A receptor is expressed in the hamster suprachiasmatic nucleus a region known to be involved in circadian timing circuitry (Duncan, MJ., Jennes, L., Jefferson, J. B., Brownfield, M.S. (2000). Localization of serotonin5A receptors in discrete regions of the circadian timing system in the Syrian hamster. Brain Research 869, 178-185). Activation of both 5- HT 5 A and 5-HT 7 receptors can produce phase advances of the circadian clock in-vitro
  • 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 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.
  • the alkyl or Ci-7-alkyl group as defined above may optionally be substituted with one or more halo, hydroxy or cyano, alternatively also referred to as "halo-Ci-7-alkyl", “hydroxy-Ci- 7 -alkyl", or "cyano-Ci- 7 -alkyl".
  • halo-Ci-7-alkyl hydroxy-Ci- 7 -alkyl
  • cyano-Ci- 7 -alkyl cyano-Ci- 7 -alkyl
  • halo-Ci-7-alkyl hence denotes a Ci-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-Ci-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-Ci- 7 -alkyl groups are difluoro- or trifluoro-methyl or -ethyl.
  • hydroxy-Ci- 7 -alkyl hence denotes a Ci- 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-Ci- 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-Ci- 7 -alkyl hence denotes a Ci- 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-Ci- 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 wherein the alkyl residues are as defined above, and which is attached via an oxygen atom, i.e. a group R'-O- wherein R' is alkyl as defined above.
  • halo or halogen denotes fluorine, chlorine, bromine and iodine.
  • 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, or 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 H ⁇ ckel's rule.
  • heterocycloalkyl refers to a monovalent 5 to 7 membered saturated monocyclic ring containing one or two heteroatoms selected from N, O or 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 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.
  • R 2 is -Ar 2 , -CHR d -Ar 2 , or -CH 2 CH 2 O-Ar 2 ,
  • R 3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci- 4 -alkyl, halo, or Ci-4-alkoxy, -NR e R f , wherein R e and R f are each independently hydrogen or
  • Ar 1 and Ar 2 are each independently aryl or heteroaryl, each optionally substituted by one or more B,
  • Ci- 7 -alkoxy Ci- 7 -haloalkoxy, hydroxy, halo,
  • Ci- 7 -alkyl optionally substituted with one or more halo, hydroxy, or cyano,
  • n is from 1 to 3
  • n is from 1 to 3
  • R a , R b , R c , R d , and R g are each independently hydrogen, Ci- 7 -alkyl;
  • R 1 , R 11 , R 111 , R lv , and R v are each independently hydrogen, or Ci- 7 -alkyl or -(CH 2 ) n -C 3 - 7 -cycloalkyl, wherein n is from 0 to 3;
  • R", R" 1 , and R" 11 are each independently hydrogen, Ci- 4 -alkyl or halogen;
  • 2-aminoquinolines of present invention may 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:
  • linker X is selected from -NR a -, -NR b CH 2 -, -CH 2 NR b -, -NR C C(O)-,
  • R a , R b and R c have the meaning as defined herein.
  • linker Z is represented by a single bond, by -CHR -, or by -CH 2 CH 2 O-, with R d being hydrogen or d-y-alkyl, preferably hydrogen.
  • R 3 is as defined herein.
  • R a , R b and R c are each independently hydrogen or C1-7- alkyl; preferably, R a , R , and R c are hydrogen.
  • R of the compound of formula I is
  • R 1 of the compound of formula I is -NHCH 2 -Ar 1 .
  • R 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
  • R of the compound of formula I is -NHSO 2 NH-Ar 1 . In certain embodiments of the invention, R of the compound of formula I is -NHC(O)O-Ar 1 .
  • Ar 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:
  • n is from 1 to 3
  • n is from 1 to 3
  • Ci-7-alkyl optionally substituted with one or more halo, or hydroxy, -CH 2 -O-R V ,
  • R 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 Ci- 7 -alkyl.
  • R is hydrogen.
  • R 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: Ci- 7 -alkoxy
  • Ci- 7 -alkyl optionally substituted with one or more halo, or hydroxy
  • n is from 1 to 3
  • n is from 1 to 3
  • Ci- 7 -alkyl optionally substituted with one or more halo, or two residues B in ortho-position to each other forming a -0-C(R ⁇ ) 2 -O- bridge, wherein R" is as defined above, and preferably is hydrogen.
  • R 3 of the 2-aminoquinoline of the above- mentioned formula I is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci- 4 -alkyl, halo, or
  • Ci- 4 -alkoxy -NR e R f , wherein R e and R f are each independently hydrogen, or -(CH 2 ) m -OR g , wherein m is from 2 to 6, and R g is hydrogen or Ci- 7 -alkyl, preferably R g is hydrogen.
  • R 3 of formula I is hydrogen, or phenyl or pyridinyl, optionally substituted with one or more Ci- 4 -alkyl, halo, or Ci-4-alkoxy.
  • R 3 of formula I is hydrogen
  • R 2 is -Ar 2 , -CH 2 -Ar 2 , or -CH 2 CH 2 O-Ar 2 ,
  • R 3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci- 4 -alkyl, halo, or Ci-4-alkoxy,
  • Ar 1 and Ar 2 are each independently phenyl, naphthyl, aromatic 5- or 6-membered monocyclic heteroaryl or 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, each Ar 1 and Ar 2 optionally and independently substituted by one or more B,
  • Ci-7-alkyl optionally substituted with one or more halo, hydroxy, or cyano,
  • n is from 1 to 3
  • n is from 1 to 3
  • R a , R , R c , and R g are each independently hydrogen, Ci- 7 -alkyl;
  • R 1 , R 11 , R 111 , R lv , and R v are each independently hydrogen, or Ci-7-alkyl or -(CH 2 ) n -C 3 - 7 -cycloalkyl, wherein n is from 0 to 3;
  • R", RTM, and R" 11 are each independently hydrogen, Ci- 4 -alkyl or halogen;
  • Preferred compounds of present invention are those as exemplified in the examples.
  • N2-(2-phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine (2-methoxy-benzyl)-(6-phenethyl-quinolin-2-yl) -amine
  • N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine N2-(2-phenoxy-ethyl)-N6-pyridin-4-ylmethyl-quinoline-2,6-diamine
  • N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine N6-(2-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine
  • N6-(3-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine N6-(3-methoxy-benzyl
  • N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-4-o-tolyl-quinoline-2,6-diamine N-2-(2-methoxy-benzyl)-4-(3-methoxy-phenyl)-N-6-pyridin-3-ylmethyl-quinoline-2,6- diamine, 4-(2,5-difluoro-phenyl)-N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6- diamine,
  • N-6-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-&-pyridin-4-ylmethyl-quinoline-2,6- diamine
  • N-6-2-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-o-tolyl-quinoline-2,6-diamine N-2-(4-fluoro-2-methoxy-benzyl)-N-6-pyridin-4-ylmethyl-4-o-tolyl-quinoline-2,6- diamine
  • N6-(5-cyclopropyl-[ 1,3,4] oxadiazol-2-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine N2-(2-methoxy-benzyl)-N6-(5-trifluoromethyl- [1,3,4] oxadiazol-2-yl)-quinoline-2,6- diamine
  • N2-methoxy-benzyl)-N6-oxazol-2-yl-quinoline-2,6-diamine N2-methoxy-benzyl)-N6-oxazol-2-yl-quinoline-2,6-diamine
  • the present compounds of formula I, their starting materials, their pharmaceutically acceptable salts, and their optical isomers can be prepared by methods known in the art. These methods are described below in routes 1 to 17. As an example, a process may be used to prepare some of the preferred compounds, which comprises one of the following steps:
  • R 1 is -NH-Ar 1 , -NHCH 2 -Ar 1 , -NHCH 2 CH 2 CH 2 -Ar 1 , or -NHCH 2 CH 2 O-Ar 1
  • R 2 is -Ar 2 , -CH 2 -Ar 2 , or -CH 2 CH 2 O-Ar 2
  • R 3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy, and
  • Ar 1 and Ar 2 are as defined above,
  • the compounds of formula I or formula I' and their pharmaceutically acceptable addition salts possess valuable pharmaceutical properties. It has been found that the compounds of the present invention are active on the 5-HT 5 A 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 5 A receptor, in membranes from transiently (cDNA) expressed 5-HT 5 A receptors in Human Embryonic Kidney-EBNA (HEK-EBNA) cells.
  • Assay buffer consisted of Tris (50 mM) buffer containing 1 mM EGTA, 10 mM MgCl2 (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-1-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.
  • the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • 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, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine 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 gelatine 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.
  • the pharmaceutical preparations 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.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • 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 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.
  • Capsule Formulation Item Ingredients mg/capsule
  • 2,6-Dichloroquinoline (1) is reacted with 2 equivalents of an amine Ar 2 ZNH 2 without solvent.
  • Intermediat 2 is reacted with an amine Ar L NH 2 in a palladium catalyzed substitution reaction.
  • Ar 1 L 1 NH 2 in this context means A ⁇ -CH 2 -NH 2 , Ar ⁇ CH 2 CH 2 CH 2 - NH 2 , or Ar ⁇ 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.
  • 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 A ⁇ -CH 2 -NH 2 , Ar 1 - CH 2 CH 2 CH 2 -NH 2 , or Ar ⁇ 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 x 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 reation 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 A ⁇ -CH 2 -NH 2 , A ⁇ -CH 2 CH 2 CH 2 -NH 2 , or Ar ⁇ 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.
  • Aldehyde 19 is reacted with an amine Ar 1 NH 2 in a reductive amination.
  • Intermediat 5 is reacted with an amide Ar 1 CONH 2 in a palladium catalyzed substitution reaction.
  • 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 A ⁇ -CH 2 -NH 2 , A ⁇ -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 Scheme 13: Route 13 described in example 74
  • 2-Chloro-6-nitro-quinoline (cas no.: 29969-57-1) is treated with ortho methoxybenzene to yield compound 40 which is then reduced with H2 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
  • Step B (6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine (150 mg, 0.503 mmol) was dissolved in 2 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (165 mg, 1.53 mmol), sodium tert.-butylate (119 mg, 1.24 mmol) and l,r-2-(dimethylamino)ferrocen-l-yl-palladium(II) chloride dinorbornylphosphine (16 mg, 0.03 mmol) were added. The reaction mixture was stirred in a sealed tube at 115°C for 16 h.
  • 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 0 C for 16 h.
  • the reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 70:30 gradient).
  • Step B (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 2 mL dimethylformamide. 4-Vinylpyridine (80 mg, 0.762 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphin (7 mg, 0.023 mmol) and palladium(II)acetate (3 mg, 0.013 mmol) were added. The reaction mixture was stirred in a sealed tube at 100 0 C for 16 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each).
  • Example 3 (2-Methoxy-benzyl)-[6-(2-pyridin-4-yl-ethyl)-quinolin-2-yl] -amine
  • Step A 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).
  • Step A (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 2, step A, 500 mg,
  • Example 21 N2-(2-Methoxy-benzyl)-N6-(5-methyl-furan-2-ylmethyl)-quinoline- 2,6-diamine
  • Example 26 N6-Pyridin-3-ylmethyl-N2-pyridin-2-ylmethyl-quinoline-2,6-diamine
  • Step B (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (2.0 g, 5.83 mmol) was dissolved in 100 mL tetrahydrofurane. n-Butyllithium solution (1.6 M in hexane, 9.1 mL, 14.6 mmol) was slowly added at -78°C. The reaction mixture was allowed to warm to -10 0 C and stirred at this temperature for 45 min. The reaction mixture was then cooled again to - 78°C and dimethylformamide (1.07 g, 14.6 mmol) was added. The mixture was then slowly warmed up and quenched with 200 mL water at 5°C. The solvent was evaporated off.
  • Example 49 (5-Methyl-furan-2-ylmethyl)- [6-(pyridin-3-ylaminomethyl)-quinolin- 2-yl] -amine (5-Methyl-furan-2-ylmethyl)-[6-(pyridin-3-ylaminomethyl)-quinolin-2-yl] -amine (prepared from 6-bromo-2-chloro-quinoline, 5-methyl-2-furanmethanamine and dimethylformamide as described in example 43, step A and B, 200 mg, 0.752 mmol) was dissolved in 5 mL dichloromethane. 3-Aminopyridine (85 mg, 0.904 mmol) and acetic acid (90 mg, 1.50 mmol) were added.
  • Example 55 N6-Benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4,6-triamine
  • Example 65 (5-Methyl-furan-2-ylmethyl)-[6-(2-pyridin-2-yl-ethyl)-quinolin-2-yl]- amine
  • Step A 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.
  • Step B 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) and acetic acid (72 mg, 1.2 mmol) were added. The reaction mixture was stirred at 40 0 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).
  • Example 73 N2-Benzo [ 1,3] dioxol-4-ylmethyl-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine
  • 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
  • A- 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).
  • Example 83 ⁇ 6-[(4-Fluoro-benzylamino)-methyl]-quinolin-2-yl ⁇ -(2-methoxy- benzyl)-amine
  • Example 87 N6-(2-Ethyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6- diamine
  • the title compound, white solid, MS: m/e 376.4 (M+H + ); m.p. 190 0 C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- ethyl-2H-tetrazole-5-yl-amine.
  • Example 96 N6-(5-Cyclopropyl-[l,3,4]oxadiazol-2-yl)-N2-(2-methoxy-benzyl)- quinoline-2,6-diamine
  • Example 104 N2-(2-Methoxy-benzyl)-N6-(3-piperidin-l-yl-[ 1,2,4] oxadiazol-5-yl)- quinoline-2,6-diamine

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Abstract

The present invention relates to 2-Aminoquinoline derivatives which are represented by the general formula I wherein R1, R2 and R3 are as defined in the specification as 5-HT5A receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments.

Description

Case 24063
QUINOLINE DERIVATIVES AS 5HT5A RECEPTOR ANTAGONISTS
The present invention is concerned with 2-Aminoquinoline derivatives as 5-HTSA receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments.
In particular, the present invention is concerned with compounds of the general formula (I)
Figure imgf000002_0001
wherein
R1 is -NRa-Ar\ -NR15CH2-Ar1, -CH2NRb-Ar\ -NRt(O)-Ar1, -OCH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1,
-NRt(O)O-Ar1, -C(O)NRtH2-Ar1, -CH2NR15CH2-Ar1, -NHC(=N-Ar1)-Ar1, -NR15CH2CH2CH2-Ar1, Or -NR15CH2CH2O-Ar1,
R2 is -Ar2, -CHRd-Ar2, or -CH2CH2O-Ar2,
R3 is hydrogen, phenyl, or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy,
-NReRf, wherein Re and Rf are each independently hydrogen, or -(CH2)m-ORg, wherein m is from 2 to 6,
Ar1 and Ar2 are each independently aryl or heteroaryl, each optionally substituted by one or more B,
B is Ci-7-alkoxy,
Ci-7-haloalkoxy, hydroxy, HD/07.07.2008 halo,
Ci-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano,
-S(O)2-Ci.7-alkyl,
-NR1R11, -NR111S(O)2R",
-NRmC(O)Rlv,
-C(O)NRmRlv,
-S(O)2-NRmRlv,
-CH2-O-RV, -(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-C(O)RV, cyano, nitro, allyl,
C3-7-cycloalkyl,
5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula -CH2CH2CH2-, -CH2CH2CH2CH2-, -0-C(R^)2-O-, -OCH2CH2O-, -OCH(R^)CH(R"11)-,
Ra, Rb, Rc, Rd, and Rg, are each independently hydrogen, Ci-7-alkyl;
R1, R11, R111, Rlv, and Rv are each independently hydrogen, or Ci-7-alkyl or -(CH2)n-C3-7-cycloalkyl, wherein n is from 0 to 3;
R", R™, and R"11, are each independently hydrogen, Ci-4-alkyl or halogen;
or a pharmaceutically acceptable salt thereof.
The compounds of formula I may 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. It has been found that the compounds of formula I have a good affinity to the 5- HT5A receptor.
Compounds with 5-HT5A affinity may 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 dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders and gastrointestinal disorders such as irritable bowel syndrome.
The neurotransmitter 5-hydroxytryptamine (5 -HT, 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- HT3) and the G-protein-coupled 7-transmembrane receptors (thirteen distinct receptors cloned to date). In addition, within the G-protein-coupled receptors, serotonin exerts its actions through an array of signal transduction mechanisms. - A -
The 5-HT5A receptor is one of 13 G-protein coupled 5-HT receptors and is Gi-α- 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-HTiB 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-HT5A); Barnes, N.M., & Sharp, T. (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083-1152; Thomas D. R. 5-HT5A receptors as a therapeutic target. Pharmacol Ther. (2006), l l l(3):707-14; Francken BJ., Jurzak M., Vanhauwe J. F., Luyten W.H., Leysen J.E. The human 5-HT5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur. J. Pharmacol. (1998), 361(2-3):299-309. A recent review by Thomas (Pharmacology & Therapeutics, 111, 707-714; 2006) describes the potential therapeutic utility of 5-HT5A receptor ligands for the treatment of circadian rhythm, sleep disturbances, mood disorders, schizophrenia, cognitive disorders and autism.
The human 5-HT5A mRNA is distributed in CNS areas, such as the thalamus, limbic cortex, ventrolateral amygdala, hippocampus, and hypothalamus (Pasqualetti, M., Ori, M., Nardi, L, Castagna, M., Cassano, G. B., & Marazziti, D. (1998). Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. MoI 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, L, 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. 278, 9—12) and the spinal cord dorsal horn which may indicate the involvement of the 5-HT5A receptor in central motor control, nociception and autonomic function such as stress induced urinary incontinence and overactive bladder (DoIy, 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)). Gene association studies investigating the occurrence of several common polymorphisms within the 5-HT5A receptor gene, such as -19G/C which shows allelic association with bipolar affective disorder, unipolar depression and schizophrenia (Birkett, J.T., Arranz, MJ., Munro, J., Osbourn, S., Kerwin, R. W., Collier, D.A., 2000. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport 11, 2017-2020). In addition, an allelic association of the polymorphism Pro- 15-Ser was found within a large proportion of Japanese schizophrenic patients (Iwata, N., Ozaki, N., Inada, T., & Goldman, D. (2001). Association of a 5-HT5A receptor polymorphism, Prol5Ser, to schizophrenia. MoI Psychiatry 6, 217-219).
Until recently, pharmacological characterisation of the 5-HT5A receptor has been limited due to lack of available selective ligands. However, in 2006 Garcia- Ladona, FJ. et al. 36th Annu. Meet. Soc. Neurosci. (2006), Oct 14-18, Atlanta, Abstract 33.1 (see also WO 2005082871) reported preclinical evidence that certain selective 5-HT5A receptor antagonists have an antipsychotic profile in animal models of schizophrenia by antagonizing methamphetamine and MK-801 -induced hyperlocomotion, apomorphine- induced climbing and mescaline-induced scratching, while reversing disrupted social interaction (Jongen-Relo et al., 2006). Supporting evidence included, a reduction in the number of spontaneously active midbrain dopaminergic neurons observed after subchronic A- 763079 treatment, suggesting potential antipsychotic-like activity. Data indicating that their 5-HT5A receptor antagonists increase ACh levels in mPFC (Drescher, K.U. et al. 36th Annu. Meet. Soc. Neurosci. (2006), Oct 14-18, Atlanta, Abstr. 33.2), and suggesting the potential efficacy of 5-HT5A receptor antagonists against the cognitive deficits associated with different psychiatric disorders, in particular schizophrenia and psychosis were also presented. Thomas et al. (2006), (SB-699551-A (3-cyclopentyl-N-[2- (dimethylamino)ethyl]-N-[(40-{ [(2 phenylethyl)amino]methyl}-4 biphenylyl) methyl] propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain. Neuropharmacology. 2006 Sep;51(3):566-77) recently published microdialysis data demonstrating 5-HT5A receptor antagonism of 5-CT-induced guinea-pig raphe neuronal firing and implying that the receptor may also act as an autoreceptor, with similar effects of those produced by anxiolytics and antidepressants. No behavioural data has been provided mainly due to species limitations. Furthermore, 5- HT5A receptor is expressed in the hamster suprachiasmatic nucleus a region known to be involved in circadian timing circuitry (Duncan, MJ., Jennes, L., Jefferson, J. B., Brownfield, M.S. (2000). Localization of serotonin5A receptors in discrete regions of the circadian timing system in the Syrian hamster. Brain Research 869, 178-185). Activation of both 5- HT5A and 5-HT7 receptors can produce phase advances of the circadian clock in-vitro
(Sprouse J, Reynolds L, Braselton J, Schmidt A. Serotonin-induced phase advances of SCN neuronal firing in vitro: a possible role for 5-HT5A receptors? Synapse 2004 Nov; 54(2):l l l-8).
The preferred indications with regard to the present invention are the treatment of anxiety, depression, sleep disorders and schizophrenia.
As used herein, the term "alkyl" denotes a saturated straight- or branched-chain 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.
The alkyl or Ci-7-alkyl group as defined above may optionally be substituted with one or more halo, hydroxy or cyano, alternatively also referred to as "halo-Ci-7-alkyl", "hydroxy-Ci-7-alkyl", or "cyano-Ci-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.
The term "halo-Ci-7-alkyl" hence denotes a Ci-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. Examples of halo-Ci-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. Among the preferred halo-Ci-7-alkyl groups are difluoro- or trifluoro-methyl or -ethyl.
The term "hydroxy-Ci-7-alkyl" hence denotes a Ci-7-alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Examples of hydroxy-Ci-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.
The term "cyano-Ci-7-alkyl" hence denotes a Ci-7-alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cyano group. Examples of cyano-Ci-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.
The term "alkoxy" denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom, i.e. a group R'-O- wherein R' is alkyl as defined above.
The term "halo" or "halogen" denotes fluorine, chlorine, bromine and iodine.
The term "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.
The term "heteroaryl" denotes an aromatic monocyclic or bicyclic ring containing one, two, three or four heteroatoms selected from N, O, or S, the remaining ring atoms being C. Preferably, 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. Examples for 9-or 10- membered bicyclic heteroaryl 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.
The term "aromatic" in the above sense means the presence of an electron sextet in the ring, according to Hϋckel's rule.
The term "heterocycloalkyl" refers to a monovalent 5 to 7 membered saturated monocyclic ring containing one or two heteroatoms selected from N, O or S. Examples for heterocycloclakyl moieties are tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazinyl and piperazin-2-one. A preferred heterocycloalkyl moiety is piperidinyl.
The term "cycloalkyl" refers to a monovalent carbocyclic radical of 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferred is cyclopropyl.
The term "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.
The term "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.
In detail, the present invention relates to compounds of the general formula (I)
Figure imgf000009_0001
wherein R1 is -NRa-Ar\ -NR15CH2-Ar1, -CH2NRb-Ar\ -NRCC(O)-Ar\ -OCH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, -NRCC(O)O-Ar\ -C(O)NRCCH2-Ar\ -CH2NR15CH2-Ar1, -NHCt=N-Ar1) -Ar1, -NR15CH2CH2CH2-Ar1, Or -NR15CH2CH2O-Ar1,
R2 is -Ar2, -CHRd-Ar2, or -CH2CH2O-Ar2,
R3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy, -NReRf, wherein Re and Rf are each independently hydrogen or
-(CH2)m-ORg, wherein m is from 2 to 6, Ar1 and Ar2 are each independently aryl or heteroaryl, each optionally substituted by one or more B,
B is Ci-7-alkoxy, Ci-7-haloalkoxy, hydroxy, halo,
Ci-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano,
-S(O)2-C1-7-alkyl, -NR1R11,
-NR111S(O)2R",
-NRmC(O)Rlv,
-C(O)NRmRlv,
-S(O)2-NRmRlv, -CH2-O-RV,
-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-C(O)RV, cyano, nitro, allyl,
C3-7-cycloalkyl,
5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula -CH2CH2CH2-, -CH2CH2CH2CH2-, -0-C(R^)2-O-,
-OCH2CH2O-, -OCH(R^)CH(R"11)-,
Ra, Rb, Rc, Rd, and Rg, are each independently hydrogen, Ci-7-alkyl;
R1, R11, R111, Rlv, and Rv are each independently hydrogen, or Ci-7-alkyl or -(CH2)n-C3-7-cycloalkyl, wherein n is from 0 to 3;
R", R"1, and R"11, are each independently hydrogen, Ci-4-alkyl or halogen;
or a pharmaceutically acceptable salt thereof. As indicated above, the 2-aminoquinolines of present invention may 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 Ar1 and Ar2, respectively, attached to the core with or without a linker X and Z:
Figure imgf000011_0001
Thereby, the linker X is selected from -NRa-, -NRbCH2-, -CH2NRb-, -NRCC(O)-,
-OCH2-, -CH2O-, -CH2CH2-, -CH=CH-, -NHC(O)NH-, -NHSO2NH-, -NRCC(O)O-, -C(O)NRCCH2-, -CH2NRbCH2-, -NHCt=N-Ar1)-, -NRbCH2CH2CH2-, or -NRbCH2CH2O- and Ar1 as well as Ra, Rb and Rc have the meaning as defined herein.
Further, the linker Z is represented by a single bond, by -CHR -, or by -CH2CH2O-, with Rd being hydrogen or d-y-alkyl, preferably hydrogen.
R3 is as defined herein.
In the following, the compounds of present invention are described by way of formula I:
Figure imgf000011_0002
In certain embodiments of the invention, R of the 2-aminoquinoline of the above- mentioned formula I is -NRa-Ar\ -NR15CH2-Ar1, -CH2NRb-Ar\ -NRt(O)-Ar1, -OCH2- Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, -NRt(O)O-Ar1, -C(O)NRtH2-Ar1, -CH2NR15CH2-Ar1, -NHC(=N-Ar1)-Ar1, - NR15CH2CH2CH2-Ar1, or -NR15CH2CH2O-Ar1.
In preferred embodiments of the invention, R of the 2-aminoquinoline of formula I is -NRa-Ar\ -NR15CH2-Ar1, -CH2NRb-Ar\ -OCH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, -NR0C(O)O-Ar1, -NR15CH2CH2CH2-Ar1, or -NR15CH2CH2O-Ar1.
Also preferred embodiments of the invention encompass the compound of formula I with R1 being -NRa-Ar\ -NR15CH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, or -NR0C(O)O-Ar1.
Also preferred embodiments of the invention encompass the compound of formula I with R1 being -NRa-Ar\ -NR15CH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHSO2NH-Ar1, or -NR0C(O)O-Ar1.
In all these embodiments, Ra, Rb and Rc are each independently hydrogen or C1-7- alkyl; preferably, Ra, R , and Rc are hydrogen.
In certain embodiments of the invention, R of the compound of formula I is
-NH-Ar1.
In certain embodiments of the invention, R1 of the compound of formula I is -NHCH2-Ar1.
In certain embodiments of the invention, R of the compound of formula I is -CH2O-Ar1.
In certain embodiments of the invention, R1 of the compound of formula I is -CH2CH2-Ar1.
In certain embodiments of the invention, R of the compound of formula I is -CH=CH-Ar1.
In certain embodiments of the invention, R1 of the compound of formula I is
-NHC(O)NH-Ar1.
In certain embodiments of the invention, R of the compound of formula I is -NHSO2NH-Ar1. In certain embodiments of the invention, R of the compound of formula I is -NHC(O)O-Ar1.
It is to be understood that all combinations of these embodiments are encompassed with present invention.
In certain embodiments of the invention, Ar is an aryl or heteroaryl moiety as defined herein, each optionally substituted by one or more B, also as defined herein.
Preferably, Ar1 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. Again, Ar1 is optionally substituted by one or more B as defined herein.
Examples for Ar1 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 as defined herein.
Preferred examples for Ar1 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:
Ci-7-alkoxy,
Ci-7-haloalkoxy, halo, Ci-7-alkyl, optionally substituted with one or more halo, or hydroxy,
-CH2-O-PJ,
-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
C3-7-cycloalkyl, 5- to 7-membered monocyclic heterocycloalkyl, preferably piperidinyl, or two residues B in ortho-position to each other forming a -Q-C(R^)2-O- bridge; wherein Rv is as defined above, preferably Rv is methyl; and wherein R" is as defined above, preferably R" is hydrogen. Even more preferred optional substituents B are: Ci-7-alkoxy, Ci-7-haloalkoxy, halo,
Ci-7-alkyl, optionally substituted with one or more halo, or hydroxy, -CH2-O-RV,
-(OCH2CH2)n-ORv, wherein n is from 1 to 3, -CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
C3-7-cycloalkyl, or piperidinyl; wherein Rv is as defined above, preferably Rv is methyl.
In certain embodiments of the invention, R of the 2-aminoquinoline of the above- mentioned formula I is -Ar2, -CHRd-Ar2, or -CH2CH2O-Ar2. Thereby, Rd is selected from hydrogen or Ci-7-alkyl. Preferably, R is hydrogen.
In a preferred embodiment of the invention, R of the 2-aminoquinoline of the above-mentioned formula I is -CH2-Ar2 or -CH2CH2O-Ar2.
In certain embodiments of the invention, Ar2 is an aryl or heteroaryl moiety as defined herein, each optionally substituted by one or more B, also as defined herein.
Preferably, Ar2 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. Again, Ar2 is optionally substituted by one or more B as defined herein.
Examples for Ar2 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 as defined herein. Preferred examples for Ar2 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.
Even more preferred examples for Ar2 are phenyl, pyridinyl, or furanyl, each optionally substituted with one or more B as defined herein.
Preferred optional substituents B are: Ci-7-alkoxy,
Ci-7-haloalkoxy, halo,
Ci-7-alkyl, optionally substituted with one or more halo, or hydroxy,
-CH2-O-RV, -(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
C3-7-cycloalkyl,
5- to 7-membered monocyclic heterocycloalkyl, preferably piperidinyl, or two residues B in ortho-position to each other forming a -0-C(R^)2-O- bridge; wherein Rv is as defined above, preferably Rv is methyl; and wherein R" is as defined above, preferably R" is hydrogen.
Even more preferred optional substituents B are: Ci-7-alkoxy, halo,
Ci-7-alkyl, optionally substituted with one or more halo, or two residues B in ortho-position to each other forming a -0-C(R^)2-O- bridge, wherein R" is as defined above, and preferably is hydrogen.
In certain embodiments of the invention, R3 of the 2-aminoquinoline of the above- mentioned formula I is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or
Ci-4-alkoxy, -NReRf, wherein Re and Rf are each independently hydrogen, or -(CH2)m-ORg, wherein m is from 2 to 6, and Rg is hydrogen or Ci-7-alkyl, preferably Rg is hydrogen. In preferred embodiments of the invention, R3 of formula I is hydrogen, or phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy.
In a preferred embodiment of the invention, R3 of formula I is hydrogen.
It is understood that all of the embodiments described above may be combined with each other.
As an example for such a combination, one of the preferred embodiments of the invention is concerned with compounds of formula I
Figure imgf000016_0001
wherein
R1 is -NRa-Ar\ -NR15CH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, or -NRt(O)O-Ar1.
R2 is -Ar2, -CH2-Ar2, or -CH2CH2O-Ar2,
R3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy,
Ar1 and Ar2 are each independently phenyl, naphthyl, aromatic 5- or 6-membered monocyclic heteroaryl or 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, each Ar1 and Ar2 optionally and independently substituted by one or more B,
B is Ci-7-alkoxy,
Ci-7-haloalkoxy, hydroxy, halo,
Ci-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano,
-S(O)2-Ci.7-alkyl, -NR1R11,
-NRmS(O)2Rlv,
-NRmC(O)Rlv,
-C(O)NRmRlv,
-S(O)2-NRmRlv, -CH2-O-RV,
-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3,
-C(O)RV, cyano, nitro, allyl,
C3-7-cycloalkyl,
5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula -CH2CH2CH2-, -CH2CH2CH2CH2-, -0-C(R^)2-O-,
-OCH2CH2O-, -OCH(R^)CH(R"11)-,
Ra, R , Rc, and Rg, are each independently hydrogen, Ci-7-alkyl;
R1, R11, R111, Rlv, and Rv are each independently hydrogen, or Ci-7-alkyl or -(CH2)n-C3-7-cycloalkyl, wherein n is from 0 to 3;
R", R™, and R"11, are each independently hydrogen, Ci-4-alkyl or halogen;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of present invention are those as exemplified in the examples.
Even more preferred are compounds selected from N2-(2-phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, (2-methoxy-benzyl)-(6-phenethyl-quinolin-2-yl) -amine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N2-(2-phenoxy-ethyl)-N6-pyridin-4-ylmethyl-quinoline-2,6-diamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine,
N2-(2-methoxy-benzyl)-4-phenyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, (2-methoxy-benzyl)- [6-( (E) -2-pyridin-3-yl-vinyl)-quinolin-2-yl] -amine, N2,N6-bis-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(2-trifluoromethoxy-benzyl)-quinoline-2,6-diamine, (2-methoxy-benzyl)- [6-(2-pyridin-3-yl-ethyl)-quinolin-2-yl] -amine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N2,N6-bis-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(3-methyl-3H-imidazol-4-ylmethyl)-quinoline-2,6-diamine, N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-pyridin-3-ylmethyl-quinoline-2,6- diamine,
N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-4-o-tolyl-quinoline-2,6-diamine, N-2-(2-methoxy-benzyl)-4-(3-methoxy-phenyl)-N-6-pyridin-3-ylmethyl-quinoline-2,6- diamine, 4-(2,5-difluoro-phenyl)-N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6- diamine,
N-6-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-&-pyridin-4-ylmethyl-quinoline-2,6- diamine, N-6-2-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-o-tolyl-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-N-6-pyridin-4-ylmethyl-4-o-tolyl-quinoline-2,6- diamine,
(2-methoxy-benzyl) -(6-phenoxymethyl-quinolin-2-yl) -amine, N6-benzyl-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(4-fluoro-2-methoxy-benzyl)-N6-(2-methoxy-benzyl)-quinoline-2,4,6-triamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2,N6-bis-(2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4,6-triamine, N6-benzyl-N2-(3-methoxy-benzyl)-quinoline-2,6-diamine,
N2-(3-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-benzyl-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(5-fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-(5-fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N2-(5-methyl-furan-2-ylmethyl)-N6-(3-trifluoromethyl-phenyl)-quinoline-2,6-diamine, N2-benzo [ 1,3] dioxol-4-ylmethyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, l-[2-(2-methoxy-benzylamino)-quinolin-6-yl]-3-(4-methoxy-phenyl)-urea, [2-(2-methoxy-benzylamino)-quinolin-6-yl]-carbamic acid 4-methoxy-phenyl ester, N-(4-fluorophenyl)-N'-{2-[(2-methoxybenzyl)amino]quinolin-6-yl}sulfamide, N2-(2-methoxy-benzyl)-N6-pyrimidin-2-yl-quinoline-2,6-diamine,
N2-(2-methoxy-benzyl)-N6-(5-methyl-[ 1,3,4] oxadiazol-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(3-methyl-[ 1,2,4] oxadiazol-5-yl)-quinoline-2,6-diamine, N6-(2-ethyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(5-methyl-isoxazol-3-yl)-quinoline-2,6-diamine, N6-(4,6-dimethyl-pyrimidin-2-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-methyl-pyrimidin-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-pyridin-2-yl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(6-methyl-pyridin-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-trifluoromethyl-pyrimidin-2-yl)-quinoline-2,6-diamine, N6-(2-tert-butyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine,
N6-(5-cyclopropyl-[ 1,3,4] oxadiazol-2-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(5-trifluoromethyl- [1,3,4] oxadiazol-2-yl)-quinoline-2,6- diamine, N2-(2-methoxy-benzyl)-N6-(5-trifluoromethyl-oxazol-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-oxazol-2-yl-quinoline-2,6-diamine,
N2-(2-methoxy-benzyl)-N6-(6-trifluoromethyl-pyridin-2-yl)-quinoline-2,6-diamine, 2-{3- [2-(2-methoxy-benzylamino)-quinolin-6-ylamino] -phenyl} -ethanol, or N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-N6-(6-methyl-pyridin- 2-yl) -quinoline-2,6-diamine. The present compounds of formula I, their starting materials, their pharmaceutically acceptable salts, and their optical isomers can be prepared by methods known in the art. These methods are described below in routes 1 to 17. As an example, a process may be used to prepare some of the preferred compounds, which comprises one of the following steps:
A process to prepare the compound of formula I,
Figure imgf000020_0001
wherein
R1 is -NH-Ar1, -NHCH2-Ar1, -NHCH2CH2CH2-Ar1, or -NHCH2CH2O-Ar1, R2 is -Ar2, -CH2-Ar2, or -CH2CH2O-Ar2, R3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy, and
Ar1 and Ar2 are as defined above,
comprising the steps of
(a) reacting a compound of formula 1
Figure imgf000020_0002
wherein Hal is Cl or Br, with an amine R2-NH2 to give a compound of formula 2
Figure imgf000020_0003
(b) followed by palladium catalyzed substitution reaction with the amines Ar1NH2, Ar1- CH2-NH2, Ar^CH2CH2CH2-NH2, or Ar^OCH2CH2-NH2; and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
Biological Tests:
As mentioned earlier, the compounds of formula I or formula I' and their pharmaceutically acceptable addition salts possess valuable pharmaceutical properties. It has been found that the compounds of the present invention are active on the 5-HT5A 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.
Test description
A [3H]LSD radioligand binding assay was used to determine the affinity of the compounds for the recombinant human 5-HT5A receptor, in membranes from transiently (cDNA) expressed 5-HT5A receptors in Human Embryonic Kidney-EBNA (HEK-EBNA) cells. Assay buffer consisted of Tris (50 mM) buffer containing 1 mM EGTA, 10 mM MgCl2 (pH 7.4) and 10 μM pargyline. The binding assay was carried out in 96-well-plates in the presence of [3H]LSD (approximately 1 nM), approximately 2 μg/well of membrane protein, and 0.5 mg of Ysi-poly-1-lysine SPA beads in a final volume of 200 μl of buffer. Non-specific binding was defined using methiothepin 2μM. 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. IC5O values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
The affinity towards the human 5-HT5A receptor of the compounds according to the invention is exemplified in the table below:
Figure imgf000021_0001
Figure imgf000022_0001
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. 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, dragees and hard gelatine capsules. Suitable carriers for soft gelatine 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 gelatine 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.
The pharmaceutical preparations 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.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
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 can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration 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 (Wet Granulation)
Item Ingredients mg/ tablet
5 mg 25 mg 100 mg 500
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
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 500C.
3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.
Capsule Formulation Item Ingredients mg/capsule
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
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
Compounds of formula I may be prepared as shown in the following description:
Chemical Synthesis of the Compounds
In examples 1 - 104 and in the following schemes 1 to 17 the preparation of the compounds of formula I or formula I' are described in more detail. The starting materials are known compounds or may be prepared according to methods known in the art.
Compounds of formula I may be prepared in accordance with the following routes:
Scheme 1: Route 1 described in example 1
Figure imgf000025_0001
2,6-Dichloroquinoline (1) is reacted with 2 equivalents of an amine Ar2ZNH2 without solvent. Intermediat 2 is reacted with an amine Ar L NH2 in a palladium catalyzed substitution reaction. Ar1L1NH2 in this context means A^-CH2-NH2, Ar^CH2CH2CH2- NH2 , or Ar^OCH2CH2-NH2. Scheme 2: Route 2 described in example 2
Figure imgf000026_0001
6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar2ZNH2 without solvent. Intermediat 5 is reacted with an alkene Ar1CH=CH2 in a palladium catalyzed substitution reaction.
Scheme 3: Route 3 described in example 3
Figure imgf000026_0002
Compounds of the general structure 6 are reacted with hydrogen in presence of a palladium catalyst.
Scheme 4: Route 4 described in example 13
Figure imgf000026_0003
6-Chloro-4-phenyl-quinolin-2-ylamine (8) is reacted with 2 equivalents of an amine Ar2ZNH2 without solvent. Intermediate 8 is reacted with an aldehyde Ar2CHO in a reductive amination. Intermediate 9 is reacted with an amine Ar1L1NH2 in a palladium catalyzed substitution reaction. Ar1L1NH2 in this context means A^-CH2-NH2, Ar1- CH2CH2CH2-NH2, or Ar^OCH2CH2-NH2.
Scheme 5: Route 5 described in example 14 Ar2ZNH2 Bu3SnCHCH2
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar2ZNH2 without solvent. Intermediate 5 is reacted with vinyltributyltin in a palladium catalyzed substitution reaction. Intermediate 11 is reacted with with an arylbromide or aryliodide Arxhal in a palladium catalyzed substitution reaction.
Scheme 6: Route 6 described in example 30
Figure imgf000027_0004
12 13
Figure imgf000027_0005
14
15
Ar1L1NH,
Figure imgf000027_0006
2-Amino-6-chloro-4-hydroxyquinoline (12) is brominated with PBr3 to the intermediate 13 which is reacted with an aldehyde Ar2CHO in a reductive amination. The bromide 14 is used for a suzuki reation to introduce the substituent Y. Intermediate 15 is reacted with an amine Ar1L1NH2 in a palladium catalyzed substitution reaction. Ar1L1NH2 in this context means A^-CH2-NH2, A^-CH2CH2CH2-NH2, or Ar^OCH2CH2-NH2.
Scheme 7: Route 7 described in example 40
Figure imgf000028_0001
Intermediate (14) is sequentially reacted with an amine RNH2 and an amine Ar1L1NH2 in a palladium catalyzed substitution reaction using two different catalyst systems. Ar1L1NH2 in this context means A^-CH2-NH2, Ar^CH2CH2CH2-NH2, or Ar1- OCH2CH2-NH2.
Scheme 8: Route 8 described in example 43 ArZZNH2
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
6-Bromo-2-chloroquinoline (4) is reacted with 2 equivalents of an amine Ar2ZNH2 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 Ar1OH.
Scheme 9: Route 9 described in example 44
Figure imgf000029_0004
Intermediate (22) is reacted with an amine Ar IT L IT NH2 in a palladium catalyzed substitution reaction. The allyl protecting group is lost during this reaction. Ar1L1NH2 in this context means A^-CH2-NH2, A^-CH2CH2CH2-NH2, or Ar^OCH2CH2-NH2. Scheme 10: Route 10 described in example 49
Figure imgf000030_0001
Aldehyde 19 is reacted with an amine Ar1NH2 in a reductive amination.
Scheme 11: Route 11 described in example 61
Figure imgf000030_0002
Intermediat 5 is reacted with an amide Ar1CONH2 in a palladium catalyzed substitution reaction.
Scheme 12: Route 12 described in example 69
Figure imgf000030_0003
2,6-Dichloroquinoline (1) is reacted with 2 equivalents of allylamine without solvent. Intermediate 26 is reacted with an amine Ar1L1NH2 in a palladium catalyzed substitution reaction. Ar1L1NH2 in this context means A^-CH2-NH2, A^-CH2CH2CH2-NH2, or Ar1- OCH2CH2-NH2. The allyl protecting group is lost in this transformation. Intermediate 27 is reacted with an aldehyde Ar2CHO in a reductive amination Scheme 13: Route 13 described in example 74
Figure imgf000031_0001
2-Chloro-6-hydroxy-quinolin (29, CAS-RN 577967-89-6) is reacted with benzyl bromides in acetone under potassium carbonate conditions to yield 6-benzyloxy derivative (30). In a subsequent step benzyl amines are introduced in position 2.
Scheme 14: Route 14 described in example 82
Figure imgf000031_0002
34
Figure imgf000031_0003
35 36
Intermediates 5 (see route 2) are reacted with zinc cyanide in a palladium catalyzed substitution reaction. The cyano group in 34 is reduced with hydrogen to the amines 35. Amines 35 are reacted with a benzoyl chloride (Ar1COCl).
Scheme 15: Route 15 described in example 83
Figure imgf000032_0001
35 37
Reductive amination of benzaldehydes Ar1CHO with amines 35.
Scheme 16: Route 16 described in example 84
Figure imgf000032_0002
5 38
Intermediates 5 (see route 2) are reacted with hetero- aromatic amines in a palladium catalyzed substitution reaction.
Scheme 17: Route 17 described in example 77-81
Figure imgf000033_0001
Figure imgf000033_0002
or
O R" = COR
C(NHR)NR' CONRR' or COOR
R' ,°4 SO2NRR'
Figure imgf000033_0003
2-Chloro-6-nitro-quinoline (cas no.: 29969-57-1) is treated with ortho methoxybenzene to yield compound 40 which is then reduced with H2 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. Likewise reaction with a carbodiimide led to guanidines, with carbamoyl chlorides led to urea derivatives, with formic acid esters to carbamates and with sulfamoyl chlorides to sulfamides.
Examples:
Example 1: N2-(2-Phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine
Step A
2,6-Dichloroquinoline (1.0 g, 5.1 mmol) and 2-phenoxyethylamine (1.5 g, 11 mmol) were micro waved at 1200C for 1 h. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 70:30 gradient). (6- Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine was obtained as a light yellow solid (1.1 g, 73%), MS: m/e = 299.3 (M+H+).
Step B (6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine (150 mg, 0.503 mmol) was dissolved in 2 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (165 mg, 1.53 mmol), sodium tert.-butylate (119 mg, 1.24 mmol) and l,r-2-(dimethylamino)ferrocen-l-yl-palladium(II) chloride dinorbornylphosphine (16 mg, 0.03 mmol) were added. The reaction mixture was stirred in a sealed tube at 115°C for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0 -> 90:10 gradient). The title compound was obtained as a light brown solid (108 mg, 58%), MS: m/e = 371.1 (M+H+).
Example 2: (2-Methoxy-benzyl)-[6-((E)-2-pyridin-4-yl-vinyl)-quinolin-2-yl]-amine
Step A
6-Bromo-2 chloroquinoline (727 mg, 3.0 mmol) and 2-methoxybenzylamine (823 mg, 6.0 mmol were stirred in a sealed tube at 1200C for 16 h. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 70:30 gradient). (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a light yellow solid (868 mg, 84%), MS: m/e = 343.1 (M+H+).
Step B (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 2 mL dimethylformamide. 4-Vinylpyridine (80 mg, 0.762 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphin (7 mg, 0.023 mmol) and palladium(II)acetate (3 mg, 0.013 mmol) were added. The reaction mixture was stirred in a sealed tube at 1000C for 16 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0 -> 90:10 gradient). The title compound was obtained as a light yellow solid (65 mg, 30%), MS: m/e = 368.1 (M+H+).
Example 3: (2-Methoxy-benzyl)-[6-(2-pyridin-4-yl-ethyl)-quinolin-2-yl] -amine (2-Methoxy-benzyl)- [6-((E)-2-pyridin-4-yl-vinyl)-quinolin-2-yl] -amine (example 2, 51 mg, 0.139 mmol) was dissolved in 20 mL ethanol. Palladium on charcoal (10%, 15 mg, 0.014 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a yellow oil (40 mg, 78%), MS: m/e = 370.1 (M+H+).
Example 4: (2-Methoxy-benzyl)-(6-phenethyl-quinolin-2-yl)-amine
The title compound, MS: m/e = 369.1 (M+H+), was prepared in accordance with the general method of example 2 and 3 from 6-bromo-2-chloroquinoline, 2- methoxybenzylamine and styrene.
Example 5: N2,N6-Bis-(2-phenoxy-ethyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 400.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline and 2-phenoxyethylamine.
Example 6: N2-(2-Methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 371.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3- ( aminomethyl) pyridine.
Example 7: N2-(2-Phenoxy-ethyl)-N6-pyridin-4-ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 371.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and A- ( aminomethyl) pyridine.
Example 8: N6-Benzyl-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 369.9 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and benzylamine. Example 9: N6-(2-Methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 400.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 2- methoxybenzylamine.
Example 10: N6-(3-Methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 400.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 3- methoxybenzylamine.
Example 11: N6-(4-Methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 400.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 4- methoxybenzylamine.
Example 12: N6-Methyl-N2-(2-phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine
The title compound, MS: m/e = 385.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and N- methyl-3-picolylamine.
Example 13: N2-(2-Methoxy-benzyl)-4-phenyl-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine
Step A 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). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 80:20 gradient). (6-Chloro-4-phenyl-quinolin-2-yl)-(2- methoxy-benzyl) -amine was obtained as an off- white solid (595 mg, 54%), MS: m/e = 375.1 (M+H+).
Step B
The title compound, MS: m/e = 447.3 (M+H+), was prepared in accordance with the general method of example 1 B from (6-chloro-4-phenyl-quinolin-2-yl)-(2-methoxy- benzyl) -amine and 3-picolylamine.
Example 14: (2-Methoxy-benzyl)-[6-((E)-2-pyridin-3-yl-vinyl)-quinolin-2-yl]- amine
Step A (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 2, step A, 500 mg,
1.46 mmol) was dissolved in 20 mL toluene. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Vinyltributyltin (462 mg, 1.46 mmol) and tetrakis(triphenylphosphin)palladium(0) (34 mg, 0.029 mmol) were added. The reaction mixture was refluxed overnight and evaporated. The residue was poured into 50 mL acetonitrile and extracted three times with heptane (50 mL each) to remove the tin products. The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 80:20 gradient). (2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine was obtained as a yellow oil (478 mg), MS: m/e = 291.1 (M+H+).
Step B
(2-Methoxy-benzyl)-(6-vinyl-quinolin-2-yl)-amine (240 mg, 0.828 mmol) was reacted with 3-bromopyridine (170 mg, 1.08 mmol) as described in example 2 step B. The title compound was obtained as a yellow waxy solid (100 mg, 33%), MS: m/e = 368.0 (M+H+).
Example 15: N2,N6-Bis-(2-methoxy-benzyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 400.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline and 2-methoxybenzylamine. Example 16: N6-(3-Methoxy-benzyl)-N2-(2-methoxy-benzyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 400.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3- methoxybenzylamine.
Example 17: N2-(2-Methoxy-benzyl)-N6-(2-trifluoromethoxy-benzyl)-quinoline- 2,6-diamine
The title compound, MS: m/e = 454.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 2- (trifluoromethoxy)benzylamine.
Example 18: (2-Methoxy-benzyl)-[6-(2-pyridin-3-yl-ethyl)-quinolin-2-yl]-amine
The title compound, MS: m/e = 370.0 (M+H+), was prepared in accordance with the general method of example 3 from (2-methoxy-benzyl)-[6-((E)-2-pyridin-3-yl-vinyl)- quinolin-2-yl] -amine (example 14).
Example 19: N6-(3-Methoxy-benzyl)-N2-(2-methoxy-benzyl)-4-phenyl-quinoline- 2,6-diamine
The title compound, MS: m/e = 476.0 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478- 40), 2-methoxybenzaldehyde and 3-methoxybenzylamine.
Example 20: N2,N6-Bis-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine
The title compound, MS: m/e = 476.3 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478- 40), 2-methoxybenzaldehyde and 2-methoxybenzylamine.
Example 21: N2-(2-Methoxy-benzyl)-N6-(5-methyl-furan-2-ylmethyl)-quinoline- 2,6-diamine The title compound, MS: m/e = 374.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 5- methyl-2-furanmethanamine.
Example 22: N2-(2-Methoxy-benzyl)-N6-(3-methyl-3H-imidazol-4-ylmethyl)- quinoline-2,6-diamine
The title compound, MS: m/e = 374.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and (1- methyl- lH-imidazol-5-yl)methylamine.
Example 23: N6-(3-Imidazol-l-yl-propyl)-N2-(2-methoxy-benzyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 388.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 1- ( 3 -aminopropyl) imidazole.
Example 24: (2-Methoxy-benzyl)-{6-[2-(2-methoxy-phenyl)-ethyl]-quinolin-2-yl}- amine
The title compound, MS: m/e = 399.3 (M+H+), was prepared in accordance with the general method of example 14 and 3 from 6-bromo-2-chloroquinoline, 2- methoxybenzylamine, vinyltributyltin and 2-bromoanisole.
Example 25: N2-(5-Methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine
The title compound, MS: m/e = 345.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-picolylamine.
Example 26: N6-Pyridin-3-ylmethyl-N2-pyridin-2-ylmethyl-quinoline-2,6-diamine The title compound, MS: m/e = 342.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-picolylamine and 3- picolylamine.
Example 27: N6-(2-Methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-
2,6-diamine
The title compound, MS: m/e = 374.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxybenzylamine.
Example 28: N6-(3-Methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline- 2,6-diamine
The title compound, MS: m/e = 374.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-methoxybenzylamine.
Example 29: N6-Benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 344.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and benzylamine.
Example 30: N2-(2-Methoxy-benzyl)-4-pyridin-3-yl-N6-pyridin-3-ylmethyl- quinoline-2,6-diamine
Step A
2-Amino-6-chloro-4-hydroxyquinoline (CAS 64319-84-2, 6.0 g, 31 mmol) were added portionswise to phosphorus tribromide (25 g, 92 mmol). Phosphorus oxybromide (10 g, 37 mmol) were added and the mixture was stirred at 1500C for 16 h. The mixture was poured into 300 mL ice water and the pH was adjusted to 11 by addition of 32% sodium hydroxide solution. The solid was filtered off and washed with water and cyclohexane. 4-Bromo-6-chloro-quinolin-2-ylamine was obtained as a yellow solid (7.8 g, 98%), MS: m/e = 258.9 (M+H+). Step B
4-Bromo-6-chloro-quinolin-2-ylamine (3.12 g, 12 mmol) was dissolved in 100 mL 1,2-dichloroethane. 2-Methoxybenzaldehyde (1.98 g, 15 mmol) and acetic acid (2.91 g, 48 mmol) were added. The reaction mixture was stirred at 400C for 3 h. Sodium triacetoxy borohydride (5.99 g, 25 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched by addition of 200 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 80:20 gradient). (4-Bromo-6-chloro-quinolin-2-yl)-(2-methoxy-benzyl)- amine was obtained as an off-white solid (2.2 g, 48%), MS: m/e = 379.1 (M+H+).
Step C
(4-Bromo-6-chloro-quinolin-2-yl)-(2-methoxy-benzyl)-amine (530 mg, 1.4 mmol) and pyridine-3-boronic acid (224 mg, 1.8 mmol) were dissolved in 16 mL dimethoxyethane and 8 mL 2N sodium carbonate solution. The reaction mixture was evacuated and backfilled with argon for three times. Triphenylphosphine (37 mg, 0.141 mmol) and palladium acetate (16 mg, 0.071 mmol) were added and the mixture was refluxed overnight. The mixture was extracted three times with ethyl acetate (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 30:70 gradient). (6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a white foam (500 mg, 94%), MS: m/e = 376.4 (M+H+).
Step D
(6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (185 mg, 0.492 mmol) was dissolved in 5 mL toluene and 1 mL tert. butanol. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (160 mg, 1.48 mmol), sodium tert.-butylate (95 mg, 0.99 mmol), palladium acetate (6 mg, 0.027 mmol) and 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 23 mg, 0.05 mmol) were added. The reaction mixture was stirred in a sealed tube at 1300C for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0 -> 90:10 gradient). The title compound was obtained as a yellow foam (105 mg, 47%), MS: m/e = 448.3 (M+H+). Example 31: N-2-(4-Fluoro-2-methoxy-benzyl)-4-phenyl-N-6-pyridin-3-ylmethyl- quinoline-2,6-diamine
The title compound, MS: m/e = 465.4 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478- 40), 4-fluoro-2-methoxybenzaldehyde and 3-picolylamine.
Example 32: N2-(2-Methoxy-benzyl)-N6-pyridin-3-ylmethyl-4-o-tolyl-quinoline- 2,6-diamine
The title compound, MS: m/e = 461.5 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), o-tolyl-phenylboronic acid, 2-methoxybenzaldehyde and 3-picolylamine.
Example 33: N-2-(2-Methoxy-benzyl)-4-(3-methoxy-phenyl)-N-6-pyridin-3- ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 477.4 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), 3-methoxyphenylboronic acid, 2-methoxybenzaldehyde and 3-picolylamine.
Example 34: N-2,N-6-Bis-(2-methoxy-benzyl)-4-(3-methoxy-phenyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 506.4 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), 3-methoxyphenylboronic acid, 2-methoxybenzaldehyde and 2-methoxy- benzylamine.
Example 35: 4-(2,5-Difluoro-phenyl)-N2-(2-methoxy-benzyl)-N6-pyridin-3- ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 483.5 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), 2,5-difluorophenylboronic acid, 2-methoxybenzaldehyde and 3-picolylamine. Example 36: N-6-Benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-quinoline-2,6- diamine
The title compound, MS: m/e = 464.1 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478- 40), 4-fluoro-2-methoxybenzaldehyde and benzylamine.
Example 37: N-2-(4-Fluoro-2-methoxy-benzyl)-4-phenyl-N-6-&-pyridin-4- ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 465.3 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478- 40), 4-fluoro-2-methoxybenzaldehyde and 4-picolylamine.
Example 38: N-6-2-Benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-o-tolyl-quinoline-
2,6-diamine
The title compound, MS: m/e = 478.4 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), o-tolyl-phenylboronic acid, 4-fluoro-2-methoxybenzaldehyde and benzylamine.
Example 39: N-2-(4-Fluoro-2-methoxy-benzyl)-N-6-pyridin-4-ylmethyl-4-o-tolyl- quinoline-2,6-diamine
The title compound, MS: m/e = 479.3 (M+H+), was prepared in accordance with the general method of example 30 from 2-amino-6-chloro-4-hydroxyquinoline (CAS 64319- 84-2), o-tolyl-phenylboronic acid, 4-fluoro-2-methoxybenzaldehyde and 4-picolylamine.
Example 40: N2-(4-Fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)-N6-pyridin-3- ylmethyl-quinoline-2,4,6-triamine
Step A
(4-Bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl) -amine (prepared from 2-amino-6-chloro-4-hydroxyquinoline and 4-fluoro-2-methoxybenzaldehyde as described in example 30, step A and B, 328 mg, 0.828 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 2- Methoxyethylamine (187 mg, 2.49 mmol), sodium tert.-butylate (159 mg, 1.66 mmol), l,r-bis(diphenylphosphino)ferrocene (69 mg, 0.125 mmol) and 1,1'- bis(diphenylphosphino)ferrocene palladium (II) chloride (34 mg, 0.042 mmol) were added. The reaction mixture was stirred in a sealed tube at 1000C for 2 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel
(dichloromethane/methanol/ammonia 100:0:0 -> 110:10:1 gradient). 6-Chloro-N2-(4- fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)-quinoline-2,4-diamine was obtained as an off-white foam (285 mg, 88%), MS: m/e = 390.0 (M+H+).
Step B
The title compound, MS: m/e = 462.5 (M+H+), was prepared in accordance with the general method of example 30, step D from 6-chloro-N2-(4-fluoro-2-methoxy-benzyl)- N4-(2-methoxy-ethyl)-quinoline-2,4-diamine and 3-picolylamine.
Example 41: N2-(2-Methoxy-benzyl)-N6-(l-methyl-lH-imidazol-4-ylmethyl)- quinoline-2,6-diamine
The title compound, MS: m/e = 374.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and (1- methyl- lH-imidazol-4-yl)methylamine.
Example 42: N6-Benzyl-N2-(4-fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)- quinoline-2,4,6-triamine
The title compound, MS: m/e = 461.1 (M+H+), was prepared in accordance with the general method of example 40 from (4-bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2- methoxy-benzyl) -amine, methoxyethylamine and benzylamine.
Example 43: (2-Methoxy-benzyl)-(6-phenoxymethyl-quinolin-2-yl)-amine
Step A
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was prepared from 6-bromo-2- chloroquinoline and 2-methoxybenzylamine as described in example 2 step A.
Step B (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (2.0 g, 5.83 mmol) was dissolved in 100 mL tetrahydrofurane. n-Butyllithium solution (1.6 M in hexane, 9.1 mL, 14.6 mmol) was slowly added at -78°C. The reaction mixture was allowed to warm to -100C and stirred at this temperature for 45 min. The reaction mixture was then cooled again to - 78°C and dimethylformamide (1.07 g, 14.6 mmol) was added. The mixture was then slowly warmed up and quenched with 200 mL water at 5°C. The solvent was evaporated off. The residue was extracted three times with ethyl acetate (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 50:50 gradient). 2-(2-Methoxy-benzylamino)-quinoline-6-carbaldehyde was obtained as a light yellow solid (683 mg, 40%), MS: m/e = 293.1 (M+H+).
Step C
2-(2-Methoxy-benzylamino)-quinoline-6-carbaldehyde (663 mg, 2.27 mmol) was dissolved in 25 mL methanol and sodium borohydride (343 mg, 9.03 mmol) was added. The reaction mixture was refluxed for 3 h. The solvent was evaporated off. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from dichloromethane. [2-(2-Methoxy-benzylamino)-quinolin- 6-yl] -methanol was obtained as a white solid (369 mg, 59%), MS: m/e = 295.3 (M+H+).
Step D
[2-(2-Methoxy-benzylamino)-quinolin-6-yl] -methanol (200 mg, 0.680 mmol) was dissolved in 13 mL tetrahydrofurane. Phenol (70 mg, 0.745 mmol) and triphenylphosphine (200 mg, 0.763 mmol) were added at room temperature. Diisopropyl azodicarboxylate (159 mg, 0.787 mmol) was slowly added at 00C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL 2N sodium carbonate. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 50:50 gradient). The title compound was obtained as an off-white solid (105 mg, 41%), MS: m/e = 371.4 (M+H+).
Example 44: N6-Benzyl-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine 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 decribed in example 40, step A) was coupled with benzylamine as described in example 30, step D. The title compound was obtained as a light brown foam (16%), MS: m/e = 403.4 (M+H+).
Example 45: N2-(2-Methoxy-benzyl)-N6-(2-methoxymethyl-benzyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 414.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3- methoxymethyl-benzylamine (CAS 148278-90-4).
Example 46: N2-(4-Fluoro-2-methoxy-benzyl)-N6-(2-methoxy-benzyl)-quinoline- 2,4,6-triamine
The title compound, MS: m/e = 433.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(4-fluoro-2-methoxy-benzyl)- quinoline-2,4-diamine and 2-methoxybenzylamine
Example 47: N6-Benzyl-N2-(2-methoxy-benzyl)-quinoline-2,4,6-triamine
The title compound, MS: m/e = 385.3 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline- 2,4-diamine and benzylamine
Example 48: N2,N6-Bis-(2-methoxy-benzyl)-quinoline-2,4,6-triamine
The title compound, MS: m/e = 415.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline- 2,4-diamine and 2-methoxybenzylamine
Example 49: (5-Methyl-furan-2-ylmethyl)- [6-(pyridin-3-ylaminomethyl)-quinolin- 2-yl] -amine (5-Methyl-furan-2-ylmethyl)-[6-(pyridin-3-ylaminomethyl)-quinolin-2-yl] -amine (prepared from 6-bromo-2-chloro-quinoline, 5-methyl-2-furanmethanamine and dimethylformamide as described in example 43, step A and B, 200 mg, 0.752 mmol) was dissolved in 5 mL dichloromethane. 3-Aminopyridine (85 mg, 0.904 mmol) and acetic acid (90 mg, 1.50 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (318 mg, 1.5 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 50 mL water. The mixture was extracted three times with dichloromethane (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0 -> 90:10 gradient). The title compound was obtained as an off-white solid (55 mg, 21%), MS: m/e = 345.1 (M+H+).
Example 50: (5-Methyl-furan-2-ylmethyl)-(6-phenylaminomethyl-quinolin-2-yl)- amine
The title compound, MS: m/e = 344.3 (M+H+), was prepared in accordance with the general method of example 49 from (5-methyl-furan-2-ylmethyl)-[6-(pyridin-3- ylaminomethyl)-quinolin-2-yl] -amine and aniline.
Example 51: N2-(2-Methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6- triamine
The title compound, MS: m/e = 386.4 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline- 2,4-diamine and 3-picolylamine
Example 52: N2-(2-Methoxy-benzyl)-N6-[3-(2-methoxy-ethoxymethyl)-benzyl]- quinoline-2,6-diamine
The title compound, MS: m/e = 458.5 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3- (2-methoxy-ethoxymethyl)-benzylamine.
Synthesis of 3-(2-methoxy-ethoxymethyl)-benzylamine: Step 1
Sodium hydride (55% in mineral oil, 1.76 g, 40.5 mmol) was suspended in 100 mL tetrahydrofurane. 3-(Hydroxymethyl)benzonitrile (5.0 g, 36.5 mmol), dissolved in 200 mL tetrahydrofuran was added drop wise. The reaction mixture was stirred at room temperature for 1 h. 2-Bromoethylmethylether (7.0 mL, 76 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched with 3 mL 2N sodium carbonate solution and the solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ ethyl acetate 100:0 -> 50:50 gradient). 3-(2-Methoxy-ethoxymethyl)-benzonitrile was obtained as a yellow liquid (2.63 g, 38%).
Step 2 3-(2-Methoxy-ethoxymethyl)-benzonitrile (2.58 g, 13.5 mmol) was dissolved in 50 mL tetrahydrofuran. Lithiumaluminium hydride (660 mg, 17.5 mmol) was added portionwise at 00C. The reaction mixture was stirred at room temperature overnight and quenched by sequential addition of 0.66 mL water, 0.66 mL 15% sodium hydroxide solution and 1.98 mL water. The solid was filtered off and the filtrate was evaporated. The title compound was obtained as a yellow liquid (2.63 g, 97%), MS: m/e = 196.3 (M+H+).
Example 53: N2-(2-Methoxy-benzyl)-N6-[3-(2-methoxy-ethoxy)-benzyl]-quinoline- 2,6-diamine
The title compound, MS: m/e = 444.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3- (2-methoxy-ethoxy)-benzonitrile (CAS 80407-67-6).
Example 54: N2-(5-Methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline- 2,4,6-triamine
The title compound, MS: m/e = 360.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-methyl-furan-2-ylmethyl)- quinoline-2,4-diamine and 3-picolylamine.
Example 55: N6-Benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4,6-triamine The title compound, MS: m/e = 359.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-methyl-furan-2-ylmethyl)- quinoline-2,4-diamine and benzylamine.
Example 56: N6-Benzyl-N2-(3-methoxy-benzyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 370.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-methoxybenzylamine and benzylamine.
Example 57: N2-(3-Methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-dianiine
The title compound, MS: m/e = 371.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-methoxybenzylamine and 3- picolylamine.
Example 58: N2-(3-Fluoro-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine
The title compound, MS: m/e = 359.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and 3- picolylamine.
Example 59: N6-Benzyl-N2-(3-fluoro-benzyl)-quinoline-2,6-diamine
The title compound, MS: m/e = 358.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and benzylamine.
Example 60: N2-(3-Fluoro-benzyl)-N6-(3-trifluoromethyl-phenyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 412.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and 3- aminobenzotrifluoride. Example 61: N-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-6-yl}-benzamide
(6-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (prepared from 6- bromo-2-chloroquinoline and 5-methyl-2-furanmethanamine as described in example 43, step A, 200 mg, 0.631 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. Benzamide (107 mg, 0.884 mmol), cesium carbonate (308 mg, 0.948 mmol) bis(dibenzylideneacetone)palladium (29 mg, 0.032 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55 mg, 0.095 mmol) were added. The reaction mixture was stirred in a sealed tube at 1000C for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ ethyl acetate 100:0 -> 60:40 gradient). The title compound was obtained as a white solid ( 110 mg, 49%), MS: m/e = 358.3 (M+H+).
Example 62: (5-Methyl-furan-2-ylmethyl)- [6-((E)-2-pyridin-2-yl-vinyl)-quinolin-2- yl] -amine
The title compound, MS: m/e = 342.3 (M+H+), was prepared in accordance with the general method of example 2 from 6-bromo-2-chloroquinoline, 5-methyl-2- furanmethanamine and 2-vinylpyridine.
Example 63: N2-(5-Methyl-furan-2-ylmethyl)-N6-(2-trifluoromethoxy-benzyl)- quinoline-2,6-diamine
The title compound, MS: m/e = 428.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-(trifluoromethoxy)benzylamine.
Example 64: N2-(5-Methyl-furan-2-ylmethyl)-N6-pyridin-4-ylmethyl-quinoline- 2,6-diamine
The title compound, MS: m/e = 345.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 4-(aminomethyl)pyridine.
Example 65: (5-Methyl-furan-2-ylmethyl)-[6-(2-pyridin-2-yl-ethyl)-quinolin-2-yl]- amine The title compound, MS: m/e = 344.0 (M+H+), was prepared in accordance with the general method of example 3 from (5-methyl-furan-2-ylmethyl)-[6-((E)-2-pyridin-2-yl- vinyl)-quinolin-2-yl] -amine (example 63).
Example 66: N6-Benzyl-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine
The title compound, MS: m/e = 403.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)- quinoline-2,4-diamine and benzylamine
Example 67: N6-Pyridin-3-ylmethyl-N2-(3-trifluoromethyl-phenyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 395.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, ( 3 -trifluoromethyl) aniline and 3 - ( aminomethyl) pyridine.
Example 68: N2-(5-Fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline- 2,4,6-triamine
The title compound, MS: m/e = 404.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)- quinoline-2,4-diamine and 3-picolylamine
Example 69: N2-(5-Fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine
Step A 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.
Step B 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) and acetic acid (72 mg, 1.2 mmol) were added. The reaction mixture was stirred at 400C 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). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0 -> 90:10 gradient). The title compound was obtained as a yellow gum (17 mg, 7%), MS: m/e = 389.3 (M+H+).
Example 70: N2-(5-Methyl-furan-2-ylmethyl)-N6-(3-trifluoromethyl-phenyl)- quinoline-2,6-diamine
The title compound, MS: m/e = 398.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-(trifluoromethyl)aniline.
Example 71: N6-(4-Fluoro-phenyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6- diamine
The title compound, MS: m/e = 348.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 4-fluoroaniline.
Example 72: N2-(5-Methyl-furan-2-ylmethyl)-N6-pyridin-3-yl-quinoline-2,6- diamine
The title compound, MS: m/e = 331.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-aminopyridine.
Example 73: N2-Benzo [ 1,3] dioxol-4-ylmethyl-N6-pyridin-3-ylmethyl-quinoline- 2,6-diamine The title compound, MS: m/e = 385.3 (M+H+), was prepared in accordance with the general method of example 69 from 2,6-dichloroquinoline, 3-picolylamine and 2,3- (methylenedioxy)benzaldehyde.
Example 74: (2-Methoxy-benzyl)-[6-(3-methoxy-benzyloxy)-quinolin-2-yl]-amine
Step A
2-Chloro-6-hydroxy-quinoline (CAS RN 577967-89-6, 0.6 g, 3 mMol) and 3- methoxybenzylbromid (0.56 mL, 0.004 MoI) were dissolved in a slurry of potassium carbonate (0.55 g, 4 mMol) in 15 mL acetone and heated to reflux for 3 hr. Then water was added and the mixture extracted with ethyl acetate (3x 20 mL). The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel (heptane/ ethyl acetate 10:0 → 9:1 → 4:1 gradient) to yield 2-chloro-6-(3-methoxy-benzyloxy)-quinoline (0.40 g, 40 %) as a colorless solid; MS: m/e = 300.3 (M+H+).
Step B
The title compound was prepared according to the general method described in step A of example 2 from 2-chloro-6-(3-methoxy-benzyloxy)-quinoline and 3-methoxy- benzylbromide as a yellow oil (0.029 g, 27 %); MS: m/e = 400.3 (M+H+).
Example 75: (2-Methoxy-benzyl)-[6-(pyridin-3-ylmethoxy)-quinolin-2-yl] -amine
The title compound, MS: m/e = 372.3 (M+H+), was prepared in accordance with the general method of example 74 from 2-chloro-6-hydroxy-quinoline, 3-pyridyl-benzyl bromide and 3-methoxy-benzylamine.
Example 76: 2-(2-Methoxy-benzylamino)-quinoline-6-carboxylic acid 2-methoxy- benzylamide
A stirred mixture of 2-chloro-quinoline-6-carboxylic acid ethyl ester [CAS-No. 29969-56-0] (236 mg, 1.0 mmol) and commercially available 2-methoxy-benzylamine (412 mg, 3.0 mmol) was heated in a sealed tube for 16 h at 120 0C. Purification by flash chromatography on silica gel (ethyl acetate/ heptane) and crystallization of each of the two fractions (dichloromethane/ hexane) yielded the title compound as a white solid (40 mg, 9%), MS (ISP) 428.3 [(M+H)+]; m.p. 217°C as well as 2-(2-methoxy-benzylamino)- quinoline-6-carboxylic acid ethyl ester as a white solid (196 mg, 58%), MS (ISP) 337.3 [(M+H)+]; m.p. 1080C.
Example 77: 4-Methoxy-N-[2-(2-methoxy-benzylamino)-quinolin-6-yl]-benzamide
Step A
2-Chloro-6-nitro-quinoline (0.80 g, 4.0 mmol) and 2-methoxybenzylamine (1.5 mL, 12 mmol) were heated at 1300C for 2 h. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate, 9:1, 4:1, 1:1). (2-Methoxy-benzyl)-(6- nitro-quinolin-2-yl) -amine was obtained as a yellow solid (0.5 g, 42%), MS: m/e = 310.5 (M+H+).
Step B
(2-Methoxy-benzyl)-(6-nitro-quinolin-2-yl)-amine (0.5 g, 2.0 mmol) were dissolved in ethyl acetate (25 ml). Upon addition of Pd/C (10%, 0.1 g) the reaction mixture was stirred for 45 min at ambient temperature under an atmosphere of hydrogen. Then the catalyst was filtered off, the filter washed with ethyl acetate and the filtrate evaporated. N-2- (2-Methoxy-benzyl)-quinoline-2,6-diamine was obtained as a yellow foam (0.40 g, 87%); MS: m/e = 280.5 (M+H+).
Step C
N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (40 mg, 0.14 mmol) and p-anisoyl chloride (0.022 mL, 0.16 mmol) were dissolved in toluene (2 mL). 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). The title compound (15 mg, 25%) was obtained as a yellow solid; MS: m/e = 414.7 (M+H+).
Example 78: N-[2-(2-Methoxy-benzylamino)-quinolin-6-yl]-N,N-di-p-tolyl- guanidine
N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (40 mg, 0.14 mmol) and 1,3-di-p- tolylcarbodiimid (0.035 mg, 0.16 mmol) were dissolved in toluene (2 mL). The reaction mixture was heated to 100° C for 7 h. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate, 4:1, 1:1, 0:1). The title compound (10 mg, 14%) was obtained as a yellow solid; MS: m/e = 502.7 (M+H+). Example 79: l-[2-(2-Methoxy-benzylamino)-quinolin-6-yl]-3-(4-methoxy-phenyl)- urea
N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (40 mg, 0.14 mmol) and A- methoxyphenyl isocyanat (0.021 mg, 0.14 mmol) were dissolved in toluene (1 mL). 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. The title compound (21 mg, 34%) was obtained as a grey solid; MS: m/e = 429.7 (M+H+).
Example 80: [2-(2-Methoxy-benzylamino)-quinolin-6-yl]-carbamic acid 4-methoxy- phenyl ester
N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (50 mg, 0.18 mmol), triethylamine (0.030 mL, 0.22 mmol) and 4-methoxyphenylchloroformat (0.027 mL, 0.18 mmol) were dissolved in toluene (3 mL). 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). The title compound (15 mg, 20%) was obtained as an off-white solid; MS: m/e = 430.7 (M+H+).
Example 81: N-(4-fluorophenyl)-N'-{2-[(2-methoxybenzyl)amino]quinolin-6- yljsulfamide
N-2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (40 mg, 0.14 mmol) and 4- fluorphenylsulfamoylchloride (0.039 mg, 0.18 mmol) were dissolved in pyridine (1 mL). 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). The title compound (12 mg, 19%) was obtained as a yellow foam; MS: m/e = 453.7 (M+H+).
Example 82: 4-Fluoro-N-[2-(2-methoxy-benzylamino)-quinolin-6-ylmethyl]- benzamide
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 1600C for 15 min in a microwave reactor. The reaction mixture was poured into water (30 ml) and extracted with diethyl ether (2 x 50 ml). The combined organic layers were washed with brine (2 x 30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/ heptane) on silica gel to yield 2-(2-methoxy- benzylamino)-quinoline-6-carbonitrile as light red oil (400 mg, 95%). MS: m/e = 290.1 (M+H+).
Step B
Hydrogenation of 2-(2-methoxy-benzylamino)-quinoline-6-carbonitrile (395 mg, 1.365 mmol) dissolved in MeOH (20 ml) and 7N MeOH-NH3 (10 ml) on Ra-Ni (395 mg) for 17 h at room temperature yielded after removal of the catalyst by filtration and evaporation a yellow oil which was further purified by flash chromatography (dichloromethane/ MeOH/ NH4OH 15 : 1 : 0.1) on silica gel to yield (6-aminomethyl- quinolin-2-yl)-(2-methoxy-benzyl)-amine as colorless oil (400 mg, 100%). MS: m/e = 294.2 (M+H+).
Step C
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(2- methoxy-benzyl) -amine (200 mg, 0.68 mmol) and triethyl amine (75 mg, 0.76 mmol) in THF (4 ml) was added 4-fluorobenzoyl chloride (119 mg, 0.75 mmol) and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (15 ml) and extracted with diethyl acetate (2 x 20 ml). The combined organic layers were washed with brine (1 x 20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/ heptane) on silica gel and crystallization (dichloromethane/ hexane) to yield the title compound as white foam (250 mg, 88%). MS: m/e = 416.4 (M+H+).
Example 83: {6-[(4-Fluoro-benzylamino)-methyl]-quinolin-2-yl}-(2-methoxy- benzyl)-amine
A solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 85, step B) (390 mg, 1.33 mmol), 4-fluorobenzaldehyde (181.5 mg, 1.46 mmol) and acetic acid (319.3 mg, 5.32 mmol) in 1,2-dichloroethane (15 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (657 mg, 2.79 mmol) was added, the reaction mixture was allowed to stir for 60 h at room temperature, poured into ice/ saturated NaHCO3 solution (30 ml) and extracted with dichloromethane (2 x 40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO/0 and evaporated. The crude product was purified by flash chromatography (ethyl acetate/ heptane) on silica gel to yield the title compound as colorless oil (284 mg, 53%). MS: m/e = 402.5 (M+H+).
Example 84: N2-(2-Methoxy-benzyl)-N6-pyrimidin-2-yl-quinoline-2,6-diamine
A mixture of (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) (171.6 mg, 0.5 mmol), commercially available 2-amino-pyrimidine (95.1 mg, 1.0 mmol), tert.-butyl-XPhos (34 mg, 0.08 mmol), Pd2dba3 (18.3 mg, 0.02 mmol), sodium tet- butylate (52.9 mg, 0.55 mmol) and dioxane (3 ml) was heated in a sealed tube at 1000C for 17 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/ heptane) and crystallization (dichloromethane/ hexane) yielded the title compound (65 mg, 36%) as a light yellow solid. MS: m/e = 358.3 (M+H+); m.p. 175°C.
Example 85: N2-(2-Methoxy-benzyl)-N6-(5-methyl-[l,3,4]oxadiazol-2-yl)- quinoline-2,6-diamine
The title compound, off-white solid, MS: m/e = 362.3 (M+H+); m.p. 183°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 5- methyl- l,3,4-oxadiazole-2-yl-amine.
Example 86: N2-(2-Methoxy-benzyl)-N6-(3-methyl-[l,2,4]oxadiazol-5-yl)- quinoline-2,6-diamine
The title compound, light brown solid, MS: m/e = 362.3 (M+H+); m.p. 175°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 3- methyl-l,2,4-oxadiazole-5-yl-amine [CAS-No. 3663-39-6].
Example 87: N6-(2-Ethyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6- diamine The title compound, white solid, MS: m/e = 376.4 (M+H+); m.p. 1900C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- ethyl-2H-tetrazole-5-yl-amine.
Example 88: N2-(2-Methoxy-benzyl)-N6-(5-methyl-isoxazol-3-yl)-quinoline-2,6- diamine
The title compound, light yellow solid, MS: m/e = 361.3 (M+H+); m.p. 132°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 5- methyl-isoxazole-3-yl-amine.
Example 89: N6-(4,6-Dimethyl-pyrimidin-2-yl)-N2-(2-methoxy-benzyl)-quinoline-
2,6-diamine
The title compound, off-white solid, MS: m/e = 386.2 (M+H+); m.p. 157.5°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-4,6-dimethyl-pyrimidine.
Example 90: N2-(2-Methoxy-benzyl)-N6-(4-methyl-pyrimidin-2-yl)-quinoline-2,6- diamine
The title compound, off-white solid, MS: m/e = 372.2 (M+H+); m.p. 125°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-4-methyl-pyrimidine.
Example 91: N2-(2-Methoxy-benzyl)-N6-(3-methyl-pyridin-2-yl)-quinoline-2,6- diamine
The title compound, light yellow solid, MS: m/e = 371.2 (M+H+); m.p. 163°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-3-methyl-pyridine.
Example 92: N2-(2-Methoxy-benzyl)-N6-pyridin-2-yl-quinoline-2,6-diamine
The title compound, light brown solid, MS: m/e = 357.2 (M+H+); m.p. 134°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-pyridine.
Example 93: N2-(2-Methoxy-benzyl)-N6-(6-methyl-pyridin-2-yl)-quinoline-2,6- diamine
The title compound, light brown solid, MS: m/e = 371.2 (M+H+); m.p. 134°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-6-methyl-pyridine.
Example 94: N2-(2-Methoxy-benzyl)-N6-(4-trifluoromethyl-pyrimidin-2-yl)- quinoline-2,6-diamine
The title compound, light yellow solid, MS: m/e = 426.1 (M+H+); m.p. 114°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-4-trifluoromethyl-pyrimidine.
Example 95: N6-(2-tert-Butyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline- 2,6-diamine
The title compound, light yellow solid, MS: m/e = 404.5 (M+H+); m.p. 156°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- tert.-butyl-2H-tetrazole-5-yl-amine.
Example 96: N6-(5-Cyclopropyl-[l,3,4]oxadiazol-2-yl)-N2-(2-methoxy-benzyl)- quinoline-2,6-diamine The title compound, off-white solid, MS: m/e = 388.4 (M+H+); m.p. 199°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 5- cyclopropyl- l,3,4-oxadiazole-2-yl-amine.
Example 97: N2-(2-Methoxy-benzyl)-N6-(5-trifluoromethyl-[ 1,3,4] oxadiazol-2-yl)- quinoline-2,6-diamine
The title compound, off-white solid, MS: m/e = 416.3 (M+H+); m.p. 198°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 5- trifluoromethyl-l,3,4-oxadiazole-2-yl-amine.
Example 98: N2-(2-Methoxy-benzyl)-N6-(4-trifluoromethyl-oxazol-2-yl)-quinoline-
2,6-diamine
The title compound, light brown solid, MS: m/e = 415.3 (M+H+); m.p. 144°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 4- trifluoromethyl-oxazole-2-yl-amine.
Example 99: N2-(2-Methoxy-benzyl)-N6-(5-trifluoromethyl-oxazol-2-yl)-quinoline- 2,6-diamine
The title compound, light brown solid, MS: m/e = 415.3 (M+H+); m.p. 166°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and 5-trifluoromethyl-oxazole-2- yl-amine [CAS-No. 714972-00-6].
Example 100: N2-(2-Methoxy-benzyl)-N6-oxazol-2-yl-quinoline-2,6-diamine
The title compound, light yellow solid, MS: m/e = 347.3 (M+H+); m.p. 2050C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available oxazole-2-yl-amine [CAS-No. 4570-45-0]. Example 101: N2-(2-Methoxy-benzyl)-N6-(6-trifluoromethyl-pyridin-2-yl)- quinoline-2,6-diamine
The title compound, off-white solid, MS: m/e = 425.1 (M+H+); m.p. 151°C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 2- amino-5-trifluoromethyl-pyridine.
Example 102: N2-(2-Methoxy-benzyl)-N6-(5-methyl-benzooxazol-2-yl)-quinoline-
2,6-diamine
The title compound, off-white solid, MS: m/e = 411.3 (M+H+); m.p. 2200C, was prepared in accordance with the general method of example 84 from (6-bromo-quinolin- 2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) and commercially available 5- methyl-benzoxazol-2-yl-amine [CAS-No. 64037-15-6].
Example 103: 2-{3-[2-(2-Methoxy-benzylamino)-quinolin-6-ylamino]-phenyl}- ethanol
The title compound, yellow oil, MS: m/e = 400.3 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2- methoxy-benzyl) -amine (see example 2, step A) and commercially available 3-(2- hydroxyethyl) -aniline.
Example 104: N2-(2-Methoxy-benzyl)-N6-(3-piperidin-l-yl-[ 1,2,4] oxadiazol-5-yl)- quinoline-2,6-diamine
The title compound, light brown foam, MS: m/e = 431.3 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2- methoxy-benzyl) -amine (see example 2, step A) and 3-(piperidin-l-yl)-[l,2,4]oxadiazol-5- yl-amine [CAS-No. 75565-19-4].
Example 105: N -(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-ΛT-(6-methyl- pyridin-2-yl)-quinoline-2,6-diamine Step A
(6-Bromo-quinolin-2-yl)-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -amine, orange oil, MS: m/e = 371.2 (M+H+), was prepared in accordance with the general method of example 2, step A, from 6-bromo-2 chloroquinoline and (2,2-dimethyl-2,3-dihydro- benzofuran-7-yl) -amine [CAS No. 68298-46-4].
Step B
The title compound, yellow foam, MS: m/e = 397.2 (M+H+), was prepared in accordance with the general method of example 84 from (6-bromo-quinolin-2-yl)-(2,2- dimethyl-2,3-dihydro-benzofuran-7-yl) -amine and commercially available 2-amino-6- methyl-pyridine.

Claims

Claims
1. A compound of formula I,
Figure imgf000063_0001
wherein R1 is -NRa-Ar\ -NR15CH2-Ar1, -CH2NRb-Ar\ -NRCC(O)-Ar\ -OCH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, -NR0C(O)O-Ar1, -C(O)NRCCH2-Ar\ -CH2NR15CH2-Ar1, -NHC(=N-Ar1)-Ar1, -NR15CH2CH2CH2-Ar1, Or -NR15CH2CH2O-Ar1,
R2 is -Ar2, -CHRd-Ar2, or -CH2CH2O-Ar2,
R3 is hydrogen, phenyl, or pyridinyl, optionally substituted with one or more Ci-4-alkyl, halo, or Ci-4-alkoxy, -NReRf, wherein Re and Rf are each independently hydrogen, or
-(CH2)m-ORg, wherein m is from 2 to 6,
Ar1 and Ar2 are each independently aryl or heteroaryl, each optionally substituted by one or more B,
B is Ci-7-alkoxy,
Ci-7-haloalkoxy, hydroxy, halo, Ci-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano,
-S(O)2-C1-7-alkyl, -NR1R11, -NRmS(O)2Rlv, -NRmC(O)Rlv, -C(O)NRmRlv,
-S(O)2-NRmRlv, -CH2-O-RV,
-(OCH2CH2)n-ORv, wherein n is from 1 to 3, -CH2-(OCH2CH2)n-ORv, wherein n is from 1 to 3, -C(O)RV, cyano, nitro, allyl,
C3-7-cycloalkyl,
5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula -CH2CH2CH2-, -CH2CH2CH2CH2-, -0-C(R^)2-O-, -OCH2CH2O-, -OCH(R^)CH(R"11)-,
Ra, Rb, Rc, Rd, and Rg, are each independently hydrogen, or Ci-7-alkyl;
R1, R11, R111, Rlv, and Rv are each independently hydrogen, or Ci-7-alkyl or -(CH2)n-C3-7-cycloalkyl, wherein n is from 0 to 3;
R", R"1, and R"11, are each independently hydrogen, Ci-4-alkyl or halogen;
or a pharmaceutically acceptable salt thereof.
2. A compound of formula I according to claim 1, wherein
R1 is -NRa-Ar\ -NR15CH2-Ar1, -CH2O-Ar1, -CH2CH2-Ar1, -CH=CH-Ar1, -NHC(O)NH-Ar1, -NHSO2NH-Ar1, or -NR0C(O)O-Ar1;
Ra, Rb, and Rc are each hydrogen and Ar1 is as defined in claim 1.
3. A compound of formula I according to claim 1 or 2, wherein
Ar1 and Ar2 are each independently phenyl, naphthyl, aromatic 5- or 6-membered monocyclic heteroaryl or 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, each Ar1 and Ar2 optionally and independently substituted by one or more B as defined in claim 1.
4. A compound of formula I according to any one of claims 1 to 3, wherein R2 is -CH2-Ar2 or -CH2CH2O-Ar2.
5. A compound of formula I according to any one of claims 1 to 4, wherein R3 is hydrogen.
6. A compound of formula I according to any one of claims 1 to 5, wherein the compound is selected from N2-(2-phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine,
N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-4-phenyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine,
N2,N6-bis-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(2-trifluoromethoxy-benzyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N2,N6-bis-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine,
N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-pyridin-3-ylmethyl-quinoline-2,6- diamine,
N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-4-o-tolyl-quinoline-2,6-diamine, N-2-(2-methoxy-benzyl)-4-(3-methoxy-phenyl)-N-6-pyridin-3-ylmethyl-quinoline- 2,6-diamine, 4-(2,5-difluoro-phenyl)-N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-
2,6-diamine,
N-6-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-&-pyridin-4-ylmethyl-quinoline- 2,6-diamine, N-6-2-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-o-tolyl-quinoline-2,6-diamine,
N6-benzyl-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4,6-triamine, N2-(3-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine,
N6-benzyl-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(5-fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-benzo [ 1,3] dioxol-4-ylmethyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, l-[2-(2-methoxy-benzylamino)-quinolin-6-yl]-3-(4-methoxy-phenyl)-urea, N-(4-fluorophenyl)-N'-{2-[(2-methoxybenzyl)amino]quinolin-6-yl}sulfamide,
N6-(2-ethyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(5-methyl-isoxazol-3-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-methyl-pyrimidin-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-pyridin-2-yl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-trifluoromethyl-pyrimidin-2-yl)-quinoline-2,6- diamine,
N6-(5-cyclopropyl-[ 1,3,4] oxadiazol-2-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6- diamine,
N2-(2-methoxy-benzyl)-N6-(6-trifluoromethyl-pyridin-2-yl)-quinoline-2,6-diamine, 2-{3- [2-(2-methoxy-benzylamino)-quinolin-6-ylamino] -phenyl} -ethanol, or
N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-N6-(6-methyl-pyridin- 2-yl) -quinoline-2,6-diamine.
7. A process to prepare the compound of formula I,
Figure imgf000066_0001
wherein
R1 is -NH-Ar1, -NHCH2-Ar1, -NHCH2CH2CH2-Ar1, or -NHCH2CH2O-Ar1,
R2 is -Ar2, -CH2-Ar2, or -CH2CH2O-Ar2,
R3 is hydrogen, phenyl or pyridinyl, optionally substituted with one or more Q-4-alkyl, halo, or
Ci-4-alkoxy, and Ar1 and Ar2 are as defined in claim 1, comprising the steps of
(a) reacting a compound of formula 1
Figure imgf000067_0001
wherein Hal is Cl or Br, with an amine R2-NH2 to give a compound of formula 2
Figure imgf000067_0002
(b) followed by palladium catalyzed substitution reaction with the amines Ar1NH2,
A^-CH2-NH2, Ar^CH2CH2CH2-NH2, or Ar^OCH2CH2-NH2;
and optionally converting the compound obtained into pharmaceutically acceptable acid addition salt.
8. A compound obtainable by the process of claim 7.
9. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1 to 6, and a pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9, wherein it is useful for the prevention or 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.
11. A compound of formula I according to any one of claims 1 to 6, for the use in the prevention or 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.
12. The use of a compound of formula I, according to any one of claims 1 to 6, for the manufacture of a medicament.
13. The use according to claim 12, wherein the medicament is useful for the prevention or 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.
14. The invention as described herein above.
PCT/EP2008/062416 2007-09-27 2008-09-18 Quinoline derivatives as 5ht5a receptor antagonists WO2009040290A1 (en)

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