WO2010026113A1 - Acyl- et sufonyl-tétrahydronaphtyridines et dérivés aza de celles-ci en tant qu’antagonistes de récepteur d’histamine h3 - Google Patents

Acyl- et sufonyl-tétrahydronaphtyridines et dérivés aza de celles-ci en tant qu’antagonistes de récepteur d’histamine h3 Download PDF

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WO2010026113A1
WO2010026113A1 PCT/EP2009/061159 EP2009061159W WO2010026113A1 WO 2010026113 A1 WO2010026113 A1 WO 2010026113A1 EP 2009061159 W EP2009061159 W EP 2009061159W WO 2010026113 A1 WO2010026113 A1 WO 2010026113A1
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compound
formula
naphthyridine
cyclobutylpiperidin
oxy
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PCT/EP2009/061159
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English (en)
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Adam James Davenport
David James Hallett
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Evotec Neurosciences Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to Histamine H3 receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.
  • the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion.
  • the H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al.
  • H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance.
  • Such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity)
  • cognition e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others
  • sleep e.g., hypersomnia and narcolepsy
  • energy homeostasis e.g. obesity
  • Histamine H3 receptor antagonists are described in the art for the treatment of the above mentioned diseases and disorders.
  • WO-A 2007/080140 cyclohexyl piperazinyl methanone derivatives are disclosed, which are useful as H3 receptor modulators.
  • cyclo butyl derivatives are disclosed as Histamine-3 receptor antagonists.
  • EP-A 1 595 881 describes tetrahydronaphthyridine derivatives useful as histamine H3 receptor ligands.
  • An individual compound as H3 ligand is disclosed in WO-A 2007/052124.
  • an object of the present invention is to provide a new class of compounds as Histamine H3 receptor antagonists which may be effective in the treatment of H3 receptor related diseases.
  • X ! -X la , X 2 -X 2a is C(R la R lb )-C(R x R lx ); and the other is N(R°)-C(R a R b ), provided that N(R 0 ) represents X 1 or X 2 ;
  • R a , R b , R la , R lb , R x , R lx are independently selected from the group consisting of H; halogen; and Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • R 0 is C(O)-R 1 ; C(O)N(R 0 ⁇ -R 1 ; C(O)O-R 1 ; S(O) 2 -R 1 ; or S(O) 2 N(R 0 ⁇ -R 1 ;
  • R Oa is H; or Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • At least one of the pairs R a /R b , R la /R lb , R x /R lx is joined together with the carbon atom to which they are attached to form C 3 _ 5 cycloalkyl, wherein C 3 _ 5 cycloalkyl is optionally substituted with one or more R c , which are the same or different;
  • R 1 is Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl; or T, wherein Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl are optionally substituted with one or more R lc , which are the same or different, provided that R 1 is other than unsubstituted tert-butyl when R 0 is C(O)O-R 1 ;
  • T is phenyl; naphthyl; azulenyl; indenyl; indanyl; C 3 - 7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R ld , which are the same or different;
  • X 3 is N, N-oxide or C(R 2 ) and X 4 is N, N-oxide or CH, provided that at least one of X 3 , X 4 is N or N-oxide;
  • R 2 is H; halogen; CN; CH 3 ; CH 2 F; CHF 2 ; CF 3 ; C(O)N(R 3 R 3a ); CH 2 N(R 3 R 3a ); OMe; OCH 2 F; OCHF 2 ; or OCF 3 ;
  • R 3 , R 3a are independently selected from the group consisting of H; Ci_5 alkyl; and C 3 _5 cycloalkyl;
  • R 3 , R 3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered saturated heterocycle;
  • X 5 is O; S; S(O); S(O) 2 ; N(R 4 ); N*(R 4 )C(0); N* (R 4 ) S (O) 2 ; or S*(O) 2 N(R 4 ), wherein the asterisk indicates the attachment to the aromatic cyclic moiety in formula (I); R 4 is H; Ci_5 alkyl; or C 3 - 6 cycloalkyl;
  • n 0, 1, 2, 3 or 4;
  • R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen; or C 4-6 cycloalkyl, wherein R is optionally substituted with one or more R 5 , which are the same or different, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen or the 4 to 7 membered saturated heterocycle and C 4-6 cycloalkyl are substituted with at least one R 5 selected from the group consisting of N(R 6 R 6a ); and C(O)N(R 6b R 6c ).
  • R ld , R 5 are independently selected from the group consisting of halogen; CN; C(O)OR 6b ; OR 6b ; C(O)R 6b ; C(O)N(R 6b R 6c ); S(O) 2 N(R 6b R 6c ); S(O)N(R 6b R 6c ); S(O) 2 R 6b ; S(O)R 6b ; N(R 6b )S(O) 2 N(R 6c R 6d ); SR 6b ; N(R 6 R 6a ); N(R 6b R 6c ); NO 2 ; OC(O)R 6b ; N(R 6b )C(O)R 6c ; N(R 6b )S(O) 2 R 6c ; N(R 6b )S(O)R 6c ; N(R 6b )C(O)OR 6c ; N(R 6b )C(O)N(R 6c R 6d
  • two R 5 form a bridging group selected from the group consisting of CH 2 ; CH 2 CH 2 ; CH 2 CH 2 CH 2 ; NH; N(CH 3 ); CH 2 NHCH 2 ; CH 2 N(CH 3 )CH 2 ; and O;
  • R 6 , R 6a are independently selected from the group consisting of T 1 ; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more R 8 , which are the same or different;
  • R 6 , R 6a are joined together with the nitrogen atom to which they are attached to form nitrogen containing ring T 2 ;
  • R 6b , R 6c , R 6d are independently selected from the group consisting of H; T 1 ; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more R 8 , which are the same of different; R lc , R 7 , R 8 are independently selected from the group consisting of halogen; CN; C(O)R 9 ; C(O)OR 9 ; OR 9 ; C(O)N(R 9 R 9a ); S(O) 2 N(R 9 R 9a ); S(O)N(R 9 R 9a ); S(O) 2 R 9 ; S(O)R 9 ; N(R 9 )S(O) 2 N(R 9a R 9b ); SR 9 ; N(R 9 R 9a ); NO 2 ; OC(
  • R 9 , R 9a , R 9b are independently selected from the group consisting of H; T 1 ; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same of different;
  • T 1 is phenyl; naphthyl; azulenyl; indenyl; indanyl; C 3 _ 7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T 1 is optionally substituted with one or more R 10 , which are the same or different;
  • T 2 is a nitrogen containing 3 to 7 membered heterocycle, wherein T 2 is optionally substituted with one or more R 10 , which are the same or different;
  • R 11 , R l la , R l lb are independently selected from the group consisting of H; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same of different.
  • Alkyl means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.
  • Alkenyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.
  • Alkynyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.
  • Ci_ 4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, or e.g. -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent as further specified.
  • Ci_ 5 alkyl means an alkyl chain having 1 - 5 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, or e.g.
  • Ci_ 5 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_ 5 alkyl carbon may be replaced by a substituent as further specified.
  • Ci_6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_ 5 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl; tert-butyl, n-pentyl, n-hexyl, or e.g.
  • Ci_6 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified.
  • Ci_ 7 alkyl means an alkyl chain having 1 - 7 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_ 5 alkyl, Ci_6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, n-heptyl, or e.g.
  • Ci_7 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_7 alkyl carbon may be replaced by a substituent as further specified.
  • Each hydrogen of a C 2 -6 alkenyl carbon may be replaced by a substituent as further specified.
  • Each hydrogen of a C 2 - 7 alkenyl carbon may be replaced by a substituent as further specified.
  • C 2 -6 alkynyl means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C ⁇ CH, -CH 2 -C ⁇ CH, CH 2 -CH 2 -C ⁇ CH, CH 2 -C ⁇ C-CH 3 , or e.g. -C ⁇ C- when two moieties of a molecule are linked by the alkynyl group.
  • Each hydrogen of a C 2 -6 alkynyl carbon may be replaced by a substituent as further specified.
  • C2-7 alkynyl means an alkynyl chain having 2 to 7 carbon atoms, e.g. if present at the end of a molecule: C 2 - 6 alkynyl, -C ⁇ CH, -CH 2 -C ⁇ CH, CH 2 -CH 2 -C ⁇ CH, CH 2 -C ⁇ C-CH 3 , or e.g. - C ⁇ C- when two moieties of a molecule are linked by the alkynyl group.
  • Each hydrogen of a C2-7 alkynyl carbon may be replaced by a substituent as further specified.
  • C 3 _ 5 cycloalkyl or "C 3 _ 5 cycloalkyl ring” means a cyclic alkyl chain having 3 to 5 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.
  • C4_6 cycloalkyl or "C 4-6 cycloalkyl ring” means a cyclic alkyl chain having 4 to 6 carbon atoms, e.g. cyclobutyl, cyclopentyl, cyclohexyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.
  • C 3 _6 cycloalkyl or “C 3 _6 cycloalkyl ring” means a cyclic alkyl chain having 3 to 6 carbon atoms, e.g. C 3 _5 cycloalkyl, C 4-6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.
  • C 3 _ 7 cycloalkyl or “C 3 _ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. C 3 _5 cycloalkyl, C 3 _6 cycloalkyl, C 4 _6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • heterocycles examples include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.
  • Each hydrogen of the heterocycle may be replaced by a substituent as further specified.
  • Examples are azetidine, oxetane, thietane, tetrahydrofurane, thiolane, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine, tetrahydropyrane, thiane, piperidine, dioxane, morpholine, or piperazine.
  • Each hydrogen of the heterocycle may be replaced by a substituent as further specified.
  • “4 to 7 membered saturated heterocyclyl” or “4 to 7 membered saturated heterocycle” means a saturated ring with 4, 5, 6 or 7 ring atoms, wherein at least one ring atom up to 3 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -
  • Each hydrogen of the heterocycle may be replaced by a substituent as further specified.
  • Examples for 3 to 7 membered heterocycles are 5 to 6 membered aromatic heterocycle, 4 to 6 membered saturated heterocycle, 4 to 7 membered saturated heterocycle, azeridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, t
  • Examples for 7 to 11 membered heterobicycles are imidazo[2,l-b][l,3]oxazole, imidazo[2,l-b][l,3]thiazole, indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, tetrahydronaphthyridine, benzazepine, purine or pteridine.
  • 7 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • Each hydrogen of the heterobicycle may be replaced by a substituent as further specified.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
  • the substituents X la , X 2a , X 1 to X 5 , n and R of formula (I) independently have the following meaning.
  • one or more of the substituents X la , X 2a , X 1 to X 5 , n and R can have the preferred or more preferred meanings given below.
  • X ! -X la is N(R°)-C(R a R b ) and X 2 -X 2a is C(R la R lb )-C(R x R lx ), provided that N(R 0 ) represents X 1 .
  • X ! -X la is N(R°)-C(R a R b ) and X 2 -X 2a is C(R la R lb )-CH 2 , provided that N(R 0 ) represents X 1 .
  • X 1 , X la , X 2 , X 2a are chosen to give a compound having the formula (Ia)
  • R 0 , R a , R b , X 3 , X 4 , X 5 , n, R have the meaning as indicated above.
  • R 0 is C(O)-R 1 ; C(O)N(R 0 ⁇ -R 1 ; or S(O) 2 -R 1 . More preferred is R 0 C(O)-R 1 ; or C(O)N(R 0 ⁇ -R 1 .
  • R a , R la , R b , R lb are independently selected from the group consisting of H; and Ci_4 alkyl, which is optionally substituted. More preferred are R a , R la , R b , R lb independently selected from the group consisting of H; and methyl. Even more preferred are R a , R la , R b , R lb H.
  • R x , R lx are independently selected from the group consisting of H; and Ci_4 alkyl or joined together with the carbon atom to which they are attached to form an unsubstituted C3-5 cycloalkyl. More preferred are R x , R lx H. Preferably, only one of the pairs R a /R b , R la /R lb , R x /R lx is joined together with the carbon atom to which they are attached to form C 3 _ 5 cycloalkyl, wherein C 3 _ 5 cycloalkyl is optionally substituted with one or more R c , which are the same or different. In case one pair is joined it is preferred that R a /R b is joined.
  • R Oa is H.
  • R 1 is Ci_7 alkyl; or T, wherein R 1 is optionally substituted. More preferred is R 1 methyl; trifluoromethyl; ethyl; propyl; propyl, butyl; pentyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; pyridyl; pyrimidinyl; pyridazinyl; pyrazinyl; morpholinyl; or piperidinyl, wherein R 1 is optionally substituted. Even more preferred is R 1 methyl; ethyl; isopropyl; sec.
  • -butyl isobutyl; dimethylpropyl; cyclpropyl; cyclobutyl; cyclopentyl; phenyl; o-, m-, or p-fluorophenyl; o-, m-, or p- methoxyphenyl; pyridyl; methylpyridyl; piperidinyl; or cyclopropylmethyl.
  • R lc is halogen; CN; OR 9 ; C(O)N(R 9 R 9a ); S(O) 2 R 9 ; N(R 9 R 9a ); N(R 9 )C(O)R 9a ;
  • N(R 9 )SO 2 R 9a ; or T 1 More preferred is R lc halogen; CN; OR 9 ; C(O)N(R 9 R 9a ); S(O) 2 R 9 ; or T 1 .
  • T is phenyl; C3_7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted. More preferred is T phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T is optionally substituted. Even more preferred is T phenyl, cyclopropyl, cyclobutyl; cyclopentyl; pyridyl; pyrimidinyl; pyridazinyl; pyrazinyl; morpholinyl; or piperidinyl, wherein T is optionally substituted.
  • T 1 is phenyl; C3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 1 is optionally substituted. More preferred is T 1 phenyl; or C 3 _ 7 cycloalkyl, wherein T 1 is optionally substituted.
  • R ld halogen CN; OR 6b ; C(O)R 6b ; C(O)N(R 6b R 6c ); S(O) 2 R 6b ; N(R 6 R 6a ); N(R 6b )C(O)R 6c ; or Ci_6 alkyl, wherein Ci_ 6 alkyl is optionally substituted.
  • X 3 is N, or C(R 2 ) and X 4 is N, or N-oxide or CH, provided that at least one of X 3 , X 4 is N or N-oxide.
  • X 3 is C(R 2 ) and X 4 is N, or N-oxide.
  • X 3 is N or C(R 2 ) and X 4 is N or CH, provided that at least one of X 3 , X 4 is N.
  • X 3 is C(R 2 ).
  • X 3 , X 4 are N.
  • X 3 is N or C(R 2 ) and X 4 is N, N oxide or CH, provided that at least one of X 3 , X 4 is N or N-oxide.
  • at least one of X 3 , X 4 is N-oxide.
  • X 3 , X 4 are N; or N-oxide.
  • R 2 is H; halogen; CN; CH 3 ; CH 2 F; CHF 2 ; CF 3 ; C(O)N(R 3 R 3a ); CH 2 N(R 3 R 3a ).
  • R 2 is H; halogen; CH 3 ; CF 3 ; C(O)N(R 3 R 3a ); or CN. More preferably, R 2 is H; or CN. Even more preferably, R 2 is H.
  • X 5 is O; N(R 4 ); S; S(O); S(O) 2 ; or N*(R 4 )C(O). More preferred is X 5 O; or N(R 5 ). Even more preferred X 5 is O.
  • n is O; or 3. More preferred is n O.
  • R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen; or C 4-6 cycloalkyl, wherein R is optionally substituted with one or more R 5 , which are the same or different, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen or the 4 to 7 membered saturated heterocycle and C 4-6 cycloalkyl are substituted with at least one R 5 being N(R 6 R 6a ).
  • R is a cyclopentyl; a cyclohexyl; an azetidine; an azepine; a pyrrolidine; a piperidine; a piperazine; or a morpholine ring; more preferred is R equals pyrrolidine; piperidine; morpholine; or cyclohexyl; even more preferred is piperidine; or pyrrolidine, wherein preferred or more preferred R is optionally substituted with one or more R 5 , which are the same or different, provided that the ring comprises a tertiary nitrogen atom or the ring is substituted with at least one R 5 being N(R 6 R 6a ) or C(O)N(R 6b R 6c ), preferably being N(R 6 R 6a ).
  • R ld , R 5 are independently selected from the group consisting of halogen; CN; C(O)OR 6b ; OR 6b ; C(O)R 6b ; C(O)N(R 6b R 6c ); S(O) 2 N(R 6b R 6c ); S(O)N(R 6b R 6c ); S(O) 2 R 6b ; S(O)R 6b ; N(R 6b )S(O) 2 N(R 6c R 6d ); SR 6b ; N(R 6 R 6a ); NO 2 ; OC(O)R 6b ; N(R 6b )C(O)R 6c ; N(R 6b )S(O) 2 R 6c ; N(R 6b )S(O)R 6c ; N(R 6b )C(O)OR 6c ; N(R 6b )C(O)N(R 6c R 6d ); OC(O)
  • -R is
  • T 1 is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 1 is optionally substituted with one or more R 10 , which are the same or different.
  • R 5 is T 1 , especially C3-7 cycloalkyl; Ci_6 alkyl.
  • T 1 is C3-7 cycloalkyl.
  • R 6b , R 6c are independently selected from the group consisting of H; and Ci_6 alkyl.
  • Preferred specific compounds of the present invention are selected from the group consisting of
  • Prodrugs of the compounds of the invention are also within the scope of the present invention.
  • “Prodrug” means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterif ⁇ ed or amidated.
  • These compounds can be produced from compounds of the present invention according to well-known methods.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the present invention provides compounds of general formula (I) as Histamine H3 receptor antagonists.
  • the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion.
  • the H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al.
  • H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance.
  • Such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity)
  • cognition e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others
  • sleep e.g., hypersomnia and narcolepsy
  • energy homeostasis e.g. obesity
  • the pharmacology of the H3 receptor seems not only to be determined by its localization but appears also to be regulated by differential splicing.
  • the H3 receptor is localized primarily to the central nervous system (CNS), with highest expression, in rodents, in the cerebral cortex, hippocampal formations, striatum, and hypothalamus (Drutel et al. (2001) MoI Pharmacol: 59; 1 - 8).
  • H3 receptor expression is prominent in the basal ganglia, globus pallidus, hippocampus, and cortex (Martinez-Mir et al. (1990) Brain Res: 526; 322 327). Notably, many of these brain regions are critical for cognition (cortex and hippocampus) and sleep and homeostatic regulation (hypothalamus).
  • the H3 receptor has been shown also to localize to regions which might be involved in pain sensation or transmission and therefore might offer treatment opportunities for different pain states (Cannon et al. (2007) Pain: 129; 76 - 92).
  • the H3 receptor is constitutively active and capable of signaling independently of agonist both in vitro and in vivo (Morisset et al. (2000) Nature: 408, 860 - 864).
  • H3 receptor antagonists like the series in this application could be useful in the treatment of cognitive dysfunctions as well as sleeping and energy homeostasis disorders.
  • antagonist also includes inverse agonists.
  • Neurological disorders include behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders) seizure disorders neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis) sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns)
  • behavioral/cognitive syndromes e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders
  • seizure disorders neurodegenerative disorders e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis
  • sleep disorders e.g. hypersomnia and narcol
  • neurological disorders also includes psychiatrical disorders within the meaning of the present invention.
  • neurodegenerative disorders also includes neuro- inflammatory disorders within the meaning of the present invention.
  • disorders affecting energy homeostasis as well as complications associated therewith e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus.
  • Pain e.g. neuropathic pain, inflammatory pain, nociception.
  • Pain includes acute and chronic pain within the meaning of the present invention.
  • Cardiovascular disorders e.g. acute myocardial infarction, and
  • vestibular dysfunction e.g. Morbus Meniere, motion sickness, drug abuse
  • nasal congestion e.g. allergic rhinitis (hay fever), asthma.
  • Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.
  • schizophrenia Foetal Alcohol Syndrome
  • Mild Cognitive Impairment Mild Cognitive Impairment
  • Age-related Memory Dysfunction disease-related cognitive dysfunctions
  • Lewy body dementia vascular dementia
  • Down Syndrome epilepsy
  • convulsion depression
  • More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.
  • Alzheimer's disease Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.
  • one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use as a medicament.
  • Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.
  • Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g.
  • Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.
  • Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), or asthma. More preferred and even more preferred embodiments are those associated with the more preferred and even more preferred disorders as mentioned above
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the H3 receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g.
  • the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. More preferred and even more preferred embodiments are those associated with the more preferred and even more preferred disorders as mentioned above.
  • the mammalian patient is a human patient.
  • Yet another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
  • the one or more bioactive compounds are lipase inhibitors, anorectic agents, selective serotonin uptake inhibitors, neurotransmitter reuptake blocker, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, or histamine Hl receptor antagonists.
  • a combination of one or more histamine H3 receptor antagonists of the present invention and histamine Hl receptor antagonists is preferred, especially for the treatment of allergic rhinitis, allergic congestion or nasal congestion.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Histamine H3 receptor antagonists.
  • the active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • X 1 , X 2 is NH and the other is C(R la R lb ) and X la , X 2a , X 3 , X 4 have the meaning as indicated above;
  • step (b) reacting the resulting compound from step (a) with a compound of formula (VII)
  • X 5 is O; S; or N(R 4 ).
  • compounds of formula (I), wherein X 5 is, e.g., O, S or NR 4 can be prepared in a three step process by reacting 2-chloroethanol with isocyanatosulfuryl chloride in the presence of base to form a compound of formula (XXIX)
  • the method may comprise the further step (d) reacting a compound of formula (I), wherein X 5 is S with an oxidising agent to yield a compound of formula (I), wherein X 5 is S(O); or S(O) 2 .
  • preparation routes for preferred compounds - but not limited to preferred compounds - may be used to prepare compounds of formula (I).
  • the variables have the above described meanings unless otherwise specifically indicated.
  • X 1 is N(R 0 )
  • X la is C(R a R b )
  • X 2 -X 2a is C(R la R lb )-C(R x R lx )
  • X 3 is C(R 2 ) and X 4 is N
  • R 0 is defined as above or as a suitable N-atom protecting group such as Boc, by reacting compounds of formula (II) with pyrrolidine under Dean-Stark conditions followed by treatment of the resulting intermediate with prop-2-ynamide under Dean-Stark conditions to yield compounds of formula (III)
  • Compounds of formula (IVa) are either commercially available or can be prepared by reacting a compound of formula (V) with a sulfonyl chloride (such as methylsulfonyl chloride) in the presence of a suitable base such as DIPEA
  • Compounds of formula (IVb) are either commercially available or can be prepared by reacting a compound of formula (V) with a suitable halagonating agent (such as thionyl chloride or PBr 3 or triphenylphospine and NBS) optionally in the presence of a suitable base such as DIPEA.
  • a suitable halagonating agent such as thionyl chloride or PBr 3 or triphenylphospine and NBS
  • R 0 of formula (I) is a suitable N-atom protecting group such as Boc
  • the resulting compound represented by formula (VI) requires the following additional steps to synthesise a compound of formula (I)
  • compounds of formula (I), wherein X 5 is O, S or NR 4 , can be prepared in a three step process by reacting a compound of formula (XXIX), above, with a compound of formula (I), wherein X 1 or X 2 is NH and the other is C(R la R lb ) and X la is C(R a R b ), X 2a is C(R x R lx ) - followed by reacting the resulting intermediate with a compound of formula HN(R 1 ⁇ R 1 in base such as TEA and at elevated temperature (usually 40 to 85 0 C) to yield a compound of formula (I).
  • compounds of formula (I), wherein X 5 is O, S or NR 4 can be prepared in a two step process starting from a compound of formula (III) above by
  • a reducing agent such as NaBH 4 or borane-THF complex.
  • compounds of formula (I), wherein X 5 is O, S or NR 4 can be prepared in a two step process starting from a commercially available or readily obtainable compound of formula (VIII) and reacting this under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (XXXIV)
  • Another aspect of the present invention is a method for the preparation of a compound according to the present invention, wherein in formula (I) X 5 is O; S; or NR 4 , comprising the steps
  • X 1 , X 2 is NH and the other is C(R la R lb ) and X la , X 2a , X 3 , X 4 have the meaning as indicated above, with
  • X r 5 of formula (I) is S(O) or S(O) 2
  • the compounds represented by formula (I) can be prepared by reacting a compound of formula (I) (where X 5 is S) with an oxidising agent such as OXONE or mCPBA.
  • Another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of
  • X 2 -X 2a is C(R la R lb )-C(R x R lx ) and R 0 can be as defined above or a suitable N- atom protecting group such as Boc with DMF.
  • DMA at high temperature (usually at 100 C) followed by treatment of the resulting intermediate with a compound of formula (X) at high temperature (usually at 80 C) to yield a compound of formula (I).
  • compounds of formula (I), wherein X 3 is N, X 5 is O, S or NR 4 can be prepared in a four step process starting from a commercially available or readily obtainable compound of formula (XII)
  • compounds of formula (I), wherein X 3 is N, X 5 is O, S or NR 4 can be prepared in a two step process starting from a commercially available or readily obtainable compound of formula (XII) and reacting this under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (XXXIV)
  • R a and R b of formula (I) are lower alkyl (C 1-4 alkyl)
  • the compounds can be prepared by reacting a compound of formula (I) (where R a and R b are H and R 0 is Boc) with a strong base such as 1 BuLi and TMEDA at low temperature (usually ⁇ -50 0 C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XIV)
  • another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of removal of the tert-butyl amide of a compound of formula (XVI), which can be obtained in 2 steps from 3-aminopyridine as described in J. Org. Chem., 1983, 48, 3014, with sulphuric acid at high temperature (usually ⁇ 100 0 C) followed by treatment of the resulting intermediate with ethyl acrylate under Heck conditions to yield intermediate compound of formula (XVII)
  • compounds of formula (I), wherein X 1 is N(R 0 ), X 2 is C(R la R lb ), X la is C(R a R b ), X 2a is C(R x R lx ), X 3 is CR 2 , X 4 is N may be prepared starting from compounds of formula (II) by
  • R 0 can be as defined above or a suitable N-atom protecting group such as Boc with DMF.
  • DMA at high temperature (usually at 100 0 C) followed by treatment of the resulting intermediate with a compound of formula H 2 N(CO)CH 2 R 2 and strong base usually NaH at high temperature (usually at 100 0 C) to yield a intermediate compound of formula (XX)
  • compounds of formula (I), wherein X 5 is N(R 4 )C(O) or N(R 4 )S(O) 2 may be prepared starting from compounds of formula (XXII), which are either commercially available or their preparations have been disclosed above herein
  • Another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of
  • compounds of formula (I), wherein X 5 is S(O) 2 N(R 4 ) may be prepared starting from compounds of formula (XXII), which is either commercially available or their preparation has been disclosed herein. Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of
  • R 0 can be as defined above or as a suitable N-atom protecting group such as Boc
  • Another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of
  • another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein in formula (I) X 5 is O; S; or NR 4 ; X 1 is N(R 0 ); X 2 is C(R la R lb ); X la is C(R a R b ); X 2a is C(R x R lx ); and X 3 is CR 2 ; comprising the steps of
  • R 0 has the meaning as indicated above or is a suitable N-atom protecting group (such as Boc), with propargylamine in ethanol solvent, with catalytic sodium tetrachloroaurate (III) dihydrate at high temperature (usually about 100 0 C);
  • R 0 of formula (I) is a suitable N-atom protecting group (such as Boc)
  • step (d2) deprotecting the resulting compound of step (dl) (which is represented by formula (XXXIII) in case Boc is used) and reacting the resulting deprotected compound under either of the reaction steps i) to vii) as indicated above to yield a compound of formula (I).
  • CHO-Kl cell line expressing human H3 receptors were purchased from Euroscreen (Gosselies, Belgium, Cat. no.: ES-392-C) Human H3 receptor-expressing cell-lines were grown in Ham's F12 [Sigma, Cat. no. N6658], supplemented with 10% FBS [Sigma, Cat. no. F9665], 400 ⁇ g/ml G418 [Sigma, Cat. no. Nl 876] and 250 ⁇ g/ml Zeocin [Invitrogen, Cat. no. 46-0509]) according to the protocol provided by Euroscreen.
  • the assay measures the ability of test compounds to inhibit Histamine receptor agonist- induced decrease of intracellular free cAMP (receptor is G 1 coupled).
  • cAMP quantification assay system from Disco veRx (cAMP XS+; Cat. no. 90- 0075) was used.
  • the cAMP assay was performed according to the protocol provided by DiscoveRx.
  • the cell culture medium was removed and the cells washed once with PBS (50 ⁇ l per well).
  • IBMX and 0.03% BSA were added and incubated for 30min at 37°C.
  • hH3 100 nM histamine, 10 ⁇ M forskolin in PBS (containing ImM IBMX and 0.03% BSA)
  • Test compounds were assayed at 8 concentrations in triplicate. Serial 10-fold dilutions in 100% DMSO were made at a 100-times higher concentration than the final concentration and then diluted with a 2 step protocol in assay buffer to reach the required assay concentrations and 1% DMSO.
  • Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following methods.
  • Example compounds and their intermediates were purified by one of or any combination of the following methods.
  • MeOD dueterated methanol m multiplet min(s) minute(s) mL millilitre ml millilitre mol/M mole/molar
  • reaction mixture was basif ⁇ ed with saturated NaHCOs solution (10 ml), extracted with DCM (2 x 20 ml) and the combined organic layers washed with brine (5 ml), dried (Na 2 SO 4 ), filtered and evaporated at reduced pressure to provide the title compound (0.101 g, 90 %) as brown oil.
  • the crude compound was taken on to the next step without further purification.
  • tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridine- 6(5H)-carboxylate can be deprotected using HCl as illustrated in Route 5 General Procedure C.
  • Example 12 Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4- fluorophenyl)carbonyl] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.
  • Example 13 Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(2- fluorophenyl)carbonyl] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.
  • the resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH 3 /MeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (14.1 mg, 28%) as white hygroscopic solid.
  • Example 20 Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- (ethylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.
  • 1,6-naphthyridine hydrochloride salt 40 mg, 0.111 mmol
  • cyclopentanesulfonyl chloride 29 ⁇ l, 0.223 mmol
  • tert-Butyl 7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate 1 -oxide (0.36 g, 1.44 mmol) was dissolved in phosphorus oxychloride (2 ml) and heated at 50 0 C for 16h. The reaction mixture was poured into ice water and stirred for Ih. The aqueous solution was basified by the addition of solid NaHCO 3 then extracted with DCM (3 x 30 ml).
  • Acetic anhydride (0.23 mL, 2.44 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (0.50 g, 2.44 mmol) and DIPEA (0.85 mL, 4.88 mmol) in pyridine (5 mL) at RT.
  • the reaction mixture was heated at 30 0 C for 6 h, then diluted with DCM (60 mL) and washed with saturated aq. NaHCO 3 (3 x 30 mL), dried (MgSO 4 ), filtered and concentrated at reduced pressure.
  • the residue was purified by FCC (eluting with 99:1 to 95:5 DCM/MeOH) to give the title compound (0.394 g, 77%) as brown oil.
  • Trifluoroacetic anhydride (0.86 rnL, 6.19 mmol) was added to a solution of l-(2-chloro-7,8- dihydro-l,6-naphthyridin-6(5H)-yl)ethanone (0.65 g, 3.09 mmol) and urea hydrogen peroxide (0.61 g, 6.49 mmol) in acetonitrile (30 mL) at RT.
  • the reaction was stirred overnight for approximately 16 h, then diluted with DCM (40 mL) and washed with saturated aq. NaHCO 3 (2 x 20 mL), dried (MgSO 4 ), filtered and concentrated at reduced pressure.
  • the residue was purified by FCC (eluting with 99:1 to 95:5 DCM/MeOH) to give the title compound (200 mg, 28%) as white solid.

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle X1 à X5, X1a, X2a, n et R ont la définition comme décrit dans la description et les revendications. Lesdits composés sont utiles en tant qu’antagonistes de récepteur d’histamine H3. L’invention concerne en outre des compositions pharmaceutiques, la préparation de tels composés ainsi que la production et l’utilisation en tant que médicament.
PCT/EP2009/061159 2008-09-03 2009-08-28 Acyl- et sufonyl-tétrahydronaphtyridines et dérivés aza de celles-ci en tant qu’antagonistes de récepteur d’histamine h3 WO2010026113A1 (fr)

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WO2012029070A1 (fr) 2010-09-02 2012-03-08 Suven Life Sciences Limited Composés hétérocyclyle comme ligands des récepteurs h3 de l'histamine
US8912176B2 (en) 2009-02-02 2014-12-16 Evotec Ag Azetidines as histamine H3 receptor antagonists
JP2015507622A (ja) * 2011-12-22 2015-03-12 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ＲＯＲｃモジュレーターとしてのベンジルスルホンアミド誘導体
JP2015516963A (ja) * 2012-04-06 2015-06-18 サノフイ アルツハイマー病の処置における使用のためのｈ３受容体アンタゴニスト
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WO2019151270A1 (fr) 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof

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US8912176B2 (en) 2009-02-02 2014-12-16 Evotec Ag Azetidines as histamine H3 receptor antagonists
WO2012029070A1 (fr) 2010-09-02 2012-03-08 Suven Life Sciences Limited Composés hétérocyclyle comme ligands des récepteurs h3 de l'histamine
US8912179B2 (en) 2010-09-02 2014-12-16 Suven Life Sciences Limited Heterocyclyl compounds as histamine H3 receptor ligands
CN102093356A (zh) * 2011-03-16 2011-06-15 无锡美克赛医药科技有限公司 一种2-氯-5,6,7,8-四氢-1,6-萘啶盐酸盐的制备方法
CN102093356B (zh) * 2011-03-16 2012-12-19 无锡美克赛医药科技有限公司 一种2-氯-5,6,7,8-四氢-1,6-萘啶盐酸盐的制备方法
JP2015507622A (ja) * 2011-12-22 2015-03-12 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ＲＯＲｃモジュレーターとしてのベンジルスルホンアミド誘導体
JP2015516963A (ja) * 2012-04-06 2015-06-18 サノフイ アルツハイマー病の処置における使用のためのｈ３受容体アンタゴニスト
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
US11505550B2 (en) 2015-07-02 2022-11-22 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
CN106674096A (zh) * 2016-12-02 2017-05-17 上海键合医药科技有限公司 一类2，3‑二取代吡啶衍生物的合成方法
WO2019151270A1 (fr) 2018-01-31 2019-08-08 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée
KR20200115491A (ko) 2018-01-31 2020-10-07 도레이 카부시키가이샤 환상 아민 유도체 및 그 의약 용도

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