WO2003066604A2 - Nouvelles aryl- et heteroarylpiperazines - Google Patents

Nouvelles aryl- et heteroarylpiperazines Download PDF

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Publication number
WO2003066604A2
WO2003066604A2 PCT/DK2003/000071 DK0300071W WO03066604A2 WO 2003066604 A2 WO2003066604 A2 WO 2003066604A2 DK 0300071 W DK0300071 W DK 0300071W WO 03066604 A2 WO03066604 A2 WO 03066604A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound according
aryl
compound
alkoxy
Prior art date
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PCT/DK2003/000071
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English (en)
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WO2003066604A3 (fr
Inventor
Rolf Hohlweg
Florencio Zaragoza DÖRWALD
Henrik Stephensen
Ingrid Pettersson
Bernd Peschke
Original Assignee
Novo Nordisk A/S
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Priority to AU2003203148A priority Critical patent/AU2003203148A1/en
Priority to EP03701482A priority patent/EP1474401A2/fr
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to CA002474214A priority patent/CA2474214A1/fr
Priority to UA20040705946A priority patent/UA83187C2/ru
Priority to JP2003565978A priority patent/JP4607458B2/ja
Priority to MXPA04007612A priority patent/MXPA04007612A/es
Priority to IL16285903A priority patent/IL162859A0/xx
Priority to KR10-2004-7011995A priority patent/KR20040081177A/ko
Priority to BR0307429-3A priority patent/BR0307429A/pt
Priority to US10/383,310 priority patent/US20030236259A1/en
Publication of WO2003066604A2 publication Critical patent/WO2003066604A2/fr
Publication of WO2003066604A3 publication Critical patent/WO2003066604A3/fr
Priority to ZA2004/05694A priority patent/ZA200405694B/en
Priority to NO20043709A priority patent/NO328714B1/no
Priority to US12/367,952 priority patent/US20090264435A1/en
Priority to AU2010200135A priority patent/AU2010200135A1/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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Definitions

  • the present invention relates to novel aryl- and heteroarylpiperazines, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions.
  • the present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.
  • histamine H3 receptor The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments. Recently, the human histamine H3 receptor has been cloned.
  • the histamine H3 receptor is a presynaptic autorecep- tor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist. Compounds acting as inverse agonists can inhibit this activity.
  • the histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
  • a his- tamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain.
  • a histamine H3 receptor agonist leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
  • novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art.
  • the present invention provides such a contribution to the art being based on the finding that a novel class of aryl- and heteroarylpiperazines has a high and specific affinity to the histamine H3 receptor.
  • the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial.
  • the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
  • halogen means F, Cl, Br or I.
  • alkyl as used herein represents a saturated, branched or straight hydrocarbon group having the indicated number of carbon atoms.
  • C 1-3 -alkyl represents saturated, branched or straight hydrocarbon groups having from 1 to 3 carbon atoms, 1 to 8 carbon atoms and from 1 to 10 carbon atoms, respectively.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, hexyl and the like.
  • alkenyl represents a branched or straight hydrocarbon group having the indicated number of carbon atoms and at least one double bond.
  • C 2-8 -alkenyl and C 2-10 -alkenyl represents a branched or straight hydrocar- bon group having from 2 to 8 carbon atoms, and from 2 to 10 carbon atoms respectively, and at least one double bond
  • groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1 ,3-butadienyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2- nonenyl, 2-decenyl and the like.
  • alkynyl as used herein represents a branched or straight hydrocarbon group having the indicated number of carbon atoms and at least one triple bond.
  • C 2-8 -alkynyl as used herein represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond.
  • branched C ⁇ e-alkyl represents a saturated, branched hydrocarbon group having from 4 to 6 carbon atoms. Typical branched C .
  • 8 -alkyl groups include, but are not limited to, 1-methylpropyl, ferf-butyl, 1 -ethyl propyl, 1,1-(dimethyl)propyl, isopentyl 1- ethylbutyl, 1,1-(dimethyl)butyl, 1,1-(dimethyl)pentyl, 1-ethylpentyl, 1,1-(dimethyl)hexyl, 1- ethylhexyl and the like.
  • branched C . 6 -alkenyl represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one double bond.
  • Typical branched C 4-6 -alkenyl groups include, but are not limited to, 1-ethylprop-2-enyl, 1 ,1-(dimethyl)prop-2-enyl; 1- ethylbut-3-enyl, 1,1-(dimethyl)but-2-enyl, 1,1-(dimethyl)pent-3-enyl, 1-ethylpent-2-enyl, 1 ,1- (dimethyl)pent-3-enyl, 1,1-(dimethyl)hex-3-enyl, 1-ethylhex-4-enyl and the like.
  • branched C ⁇ e-alkynyl represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one triple bond.
  • Typical branched C 4-6 -alkynyl groups include, but are not limited to, 1-ethylprop-2-ynyl, 1,1-(dimethyl)prop-2-ynyl, 1- ethylbut-3-ynyl, 1,1-(dimethyl)but-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1 -ethyl pent-2-ynyl, 1,1- (dimethyl)pent-3-ynyl, 1,1-(dimethyl)hex-3-ynyl, 1-ethylhex-4-ynyl and the like.
  • C 1-6 -alkoxy refers to the radical -O-C 1-6 -alkyl, wherein C 1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, fetf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 1-6 -alkylamino refers to the radical -NH-C 1-6 -alkyl, wherein C 1-6 - alkyl is as defined above.
  • Representative examples are methylamino, ethylamino, isopro- pylamino, n-propylamino, butylamino, pentylamino, hexylamino and the like.
  • di-C 1-6 -alkylamino refers to the radical -N(C ⁇ -6 -alkyl) 2 , wherein C 1-6 - alkyl is as defined above. It should be understood that the C ⁇ -6 -alkyl groups may be the same or different. Representative examples are dimethylamino, methylethylamino, diethylamino, diisopropylamino, di-n-propylamino, dibutylamino, dipentylamino, dihexylamino and the like.
  • C 3-5 -cycloalkyl represents a monocyclic, carbocyclic group having from from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • C 3-6 -cycloalkyl and “C 3-8 -cycloalkyl” as used herein represent monocyclic, carbocyclic groups having from 3 to 6 carbon atoms and from 3 to 8 carbon atoms, respectively.
  • C 3-7 -cycloalkenyl represents a monocyclic, carbocyclic, non- aromatic group having from 3 to 7 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
  • C 3- 6-cycloalkenyl represents a monocyclic, carbocyclic, non- • aromatic group having from 3 to 6 carbon atoms and at least one double bond.
  • C 3-6 -cycloalkyl-C ⁇ -3 -alkyl refers to the radical -C ⁇ -alkyl-Cs-e-cyclo- alkyl where C 3-6 -cycloalkyl and C 1-3 -alkyl are as defined above.
  • Cs-e-cycloalkenyl-C ⁇ -alkyl refers to the radical -C 1-3 -alkyl- C 3 . 6 -cycloalkenyl where C 3-6 -cycloalkenyl and C ⁇ . 3 -alkyl are as defined above.
  • C 3-8 -cycloalkyloxy refers to the radical -O-C 3-8 -cycloalkyl where C 3-8 -cycloalkyl is as defined above. Representative examples are cyclopropyloxy, cyclobuty- loxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctyl- carbonyl and the like.
  • Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like.
  • C ⁇ . 6 -alkylsulfanyl refers to the radical -S-C 1-6 -alkyl, wherein C 1-6 - alkyl is as defined above. Representative examples are methylsulfanyl, ethylsulfanyl, isopro- pylsulfanyl, n-propylsulfanyl, butylsulfanyl, pentylsulfanyl and the like.
  • C 3 . 8 -heterocyclyl refers to a saturated 3 to 8 membered monocyc- lie ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tet- rahydrofuranyl and the like.
  • Representative exam- pies are aziridinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl,' piperazinylcarbonyl, tetrahydrofuranylcarbonyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • aryloxy refers to the radical -O-aryl, wherein aryl is as defined above.
  • Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyloxyi fluorenyloxy, indenyloxy and the like.
  • arylamino refers to the radical -NH-aryl, wherein aryl is as defined above. Non-limiting examples are phenylamino, naphthylamino, anthracenylamino, phe- • nantrenylamino, fluorenylamino, indenylamino and the like.
  • heteroaryl as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-tri- azinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4-oxadi- azolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1, 1,
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above.
  • partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • heteroaryloxy refers to the radical -O-heteroaryl, wherein heteroaryl is as defined above.
  • heteroarylamino refers to the radical -NH-heteroaryl, wherein heteroaryl is as defined above.
  • Aryl-C 1-6 -alkyl means C-i-e-alkyl or C 1-6 -alkoxy as defined above, substituted by aryl as defined above, for example:
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the present invention relates to a compound of the general formula (I):
  • A represents
  • R 1 represents ethyl, n-propyl or isopropyl
  • A represents
  • R 2a , R 2b , R 3 , and R 4 independently represent
  • aryl, aryl-C 1-6 -alkyl ) aryl-C 1-6 -alkoxy or heteroaryl which may optionally be substituted with one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1-6 -alkoxy, C 1-6 -alkyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, cyano, aryl, heteroaryl and C 3-8 -cycloalkyl,
  • aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino which may optionally be substituted with one or more substituents selected from aryl, heteroaryl, C 1-10 -alkyl, C 3 ⁇ -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 -alkoxy, cyano, amino, C 1-6 -alkylamino, di-Ci-e-alkylamino and hydroxy,
  • R is branched C4-8-alkyl, C3-5-cycloalkyl or C3-6-cycloalkyl-C1-3-alkyl, which may optionally be substituted with one or more halogen substituents.
  • R 1 is branched C4-8-alkyl, C3-5-cycloalkyl or C3-6-cycloalkyl- C1-3-alkyl.
  • R 1 is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclo- propyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.
  • R 1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.
  • R 1 is branched C4-8-alkyl or C3-5-cycloalkyl, which may optionally be substituted with one or more halogen substituents.
  • R 1 is branched C4-8-alkyl or C3-5-cycloalkyl.
  • R 1 is 1-ethylpropyl, cyclopropyl or cyclopentyl.
  • R 1 is isopropyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R , R R ⁇ and R 4 are as defined for formula (I).
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R , R and R are as defined for formula (I).
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R , R and R are as defined for formula (I).
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R , R , R and R 4 are as defined for formula (I).
  • R 2a , R 2b , R 3 and R 4 are independently selected from
  • R 2a , R 2b , R 3 and R 4 are independently selected from
  • R 2a , R 2b and R 4 are hydrogen and R 3 is different from hydrogen.
  • R 3 is halogen, trifluoromethyl or trifluoromethoxy.
  • the invention relates to a compound of the general formula ( ):
  • A is as defined for formula (I) or in any one of the above embodiments.
  • the invention relates to a compound of the general formula (l 2 ):
  • R 2a , R 2b , R 3 and R 4 are as defined for formula (I).
  • the present invention relates to a compound of the general formula (I"):
  • R 1 represents
  • A represents
  • R 2 , R 3 , and R 4 independently represent • hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1-10 -alkyl, C 2- ⁇ o-alkenyl, C 3-8 -cycloalkyl, C 1-6 -alkoxy, aryl-C 1-6 -alkyl, amino, C 1-6 -alkylamino, di- C 1-6 -alkylamino, C 3-8 -cycloalkyloxy or cyano, or
  • aryl, aryl-C 1-6 -aikyl, aryl-C 1-6 -alkoxy or heteroaryl which may optionally be substituted with one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C ⁇ -6 -alkoxy, C ⁇ _ ⁇ -alkyl, amino, C 1-6 -alkylamino, di-C ⁇ -6 -alkylamino, cyano, aryl, heteroaryl and C 3-8 -cycloalkyl, or .
  • R 1 is branched C 4-8 -alkyl, C 3-5 -cycloalkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl, which may optionally be substituted with one or more halogen substituents.
  • R 1 is branched C 4-8 -alkyl, C 3-5 -cycloalkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl, such as 1 ,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or cyclopentyl, eg 1-ethylpropyl, cyclopropylmethyl or cyclopentyl.
  • R 1 is branched C 4-8 -alkyl or C 3-5 -cycloalkyl, which may optionally be substituted with one or more halogen substituents, such as branched C 4-8 -alkyl or C 3-5 -cycloalkyl, eg 1-ethylpropyl or cyclopentyl.
  • R 2 , R 3 and R 4 are as defined for formula (I").
  • R 2 , R 3 and R 4 are as defined for formula (I").
  • R 2 , R 3 and R 4 are independently selected from
  • R 2 , R 3 and R 4 are independently selected from
  • R 2 and R 4 are both hydrogen and R 3 is different from hydrogen.
  • the invention relates to a compound of the general formula ( ):
  • the invention relates to a compound of the general formula (l 2 ):
  • the present invention relates to a compound of the general formula (I) as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. Furthermore, the invention relates to the use of a compound of the general formula (I'):
  • R 1 represents
  • A represents
  • R 2a , R 2b , R 3 , and R 4 independently represent
  • R 4a and R 4b independently are hydrogen, C 1-6 -alkyl or aryl-
  • aryl, aryl-C 1-6 -alkyl, aryl-C 1-6 -alkoxy or heteroaryl which may optionally be substituted with one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C -6 -alkoxy, C 1-6 -alkyl, amino,
  • R 2 is hydrogen or C 1-4 -alkyl, (i) R 1 represents
  • R and R 2 together form a C . 6 -alkylene bridge
  • A represents
  • R 1 and R 2 together form a C 3-6 -alkylene bridge
  • A represents
  • R is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1-10 -alkyl, C 2-10 -alkenyl, C 3 . 8 -cycloalkyl, C 1-6 -alkoxy, aryl, aryl-C 1-6 -alkyl, amino, C 1-6 -alkylamino, di-C ⁇ -6 -alkylamino, C 3 . 8 -cycloalkyl, C 3-8 -cycloalkyloxy, cyano, nitro, C 1-6 -alkylsulfanyl, or C 1-6 -alkylsulfonyl,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 1 , R 12 and R 13 independently represent
  • R 14 and R 5 are independently hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl or R 14 and R 15 may together form a C 3-6 -alkylene bridge
  • R 16 is independently selected from aryl, heteroaryl, C 3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19 R 20 and C 1-6 -alkoxy,
  • R 17 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1-6 - alkoxy, C ⁇ . ⁇ -alkyl, amino, C 1-6 -alkylsulfonyl, C 1-6 -alkylamino, di-C 1-6 -alkylamino, cyano, aryl, heteroaryl and C 3-8 -cycloalkyl,
  • R 18 is independently selected from aryl, heteroaryl, C 1-10 -alkyl, C 3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 -alkoxy, cyano, amino, C 1-6 -alkylamino, di- C ⁇ -6 -alkylamino and hydroxy,
  • R 19 and R 20 are independently hydrogen or C ⁇ e-alky!, R 19 and R 20 may together form a C 3-6 alkylene-bridge
  • R 1 is branched C ⁇ -alkyl, C 3-5 -cycloalkyl or C 3-6 -cycloalkyl- C 1-3 -alkyl with the proviso that R 1 is not isobutyl.
  • R 1 is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1 -cyclopropyl-1 -methylethyl.
  • R 1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.
  • R 1 is branched C ⁇ -alkyl or C 3-5 -cycloalkyl with the proviso that R 1 is not isobutyl.
  • R 1 is 1-ethylpropyl, cyclopropyl or cyclopentyl.
  • R 2 is hydrogen
  • R 2 is C 1-4 -alkyl.
  • R 2 is methyl or ethyl.
  • R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C-i.io-alkyl, C 1-6 -alkoxy, aryl, aryl-C 1-6 -alkyl, amino, C 3-8 -cycloalkyl, C 3-8 -cycloalkyloxy, cyano or nitro.
  • R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, C 1-10 -alkyl, C- ⁇ . 6 -alkoxy, cyano or nitro.
  • R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, C- ⁇ - 6 -alkyl, or cyano.
  • R 3 is hydrogen, halogen, or C 1-6 -alkyl.
  • R 3 is hydrogen or methyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • Aryl or aryl-Ci-e-alkyl which may optionally be substituted with one or more substituents selected from R 17 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent • hydrogen, halogen, or cyano
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-d-e-alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-d- 6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent • hydrogen, halogen, or cyano
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1-6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent • hydrogen, halogen, or cyano
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C -6 -alkylene bridge' or an - O-C 1-6 -alkylene-O- bridge.
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent
  • Aryl optionally substituted with one or more substituents selected from R
  • Aroyl or -O-phenyl which may optionally be substituted with one or more substituents selected from R 18 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a d -6 -alkylene bridge or an - O-C 1-6 -alkylene-O- bridge.
  • R 1 is ethyl or isopropyl.
  • R 1 is isopropyl
  • R 1 is ethyl
  • R 1 and R 2 together form a C 3- -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a C 1-6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a C 1-6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a d -6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a C 1-6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a C 1-6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 10 , R 11 , R 12 and R 13 in adjacent positions together form a d -6 -alkylene bridge.
  • R 10 , R 11 , R 12 and R 13 independently represent
  • R 14 and R 15 are independently methyl, ethyl or benzyl.
  • R 16 is halogen, trifluoromethyl, trifluoromethoxy and C 1-6 - alkoxy.
  • R 17 is halogen, hydroxy, trifluoromethyl, d -6 -alkoxy, d. 6 -alkyl, C -6 -alkylsulfonyl, or cyano.
  • R 17 is halogen, trifluoromethyl, C 1-6 -aIkoxy or C 1-6 - alkylsulfonyl.
  • R 18 is C 1-10 -alkyl, halogen, trifluoromethyl, C 1-6 -alkoxy, cyano, amino and hydroxy.
  • R 18 is halogen, C 1-6 -alkoxy and hydroxy.
  • the invention provides the use of a compound according to formula (II) or (III) as a pharmaceutical composition.
  • the pharmaceutical composition may in another aspect of the invention comprise, as an active ingredient, at least one compound according to formula (II) or (III) together with one or more pharmaceutically acceptable carriers or excipi- ents.
  • the invention provides such a pharmaceutical composition in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to formula (II) or (III)
  • R 2 is hydrogen or C 1-4 -alkyl
  • R 1 represents
  • A represents
  • R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, d. 10 -alkyl, C 2-10 -alkenyl, C 3-8 -cycloalkyl, C 1-6 -alkoxy, aryl, aryl-d-e-alkyl, amino, C 1-6 -alkylamino, di-d. 6 -alkylamino, C 3-8 -cycloalkyl, C 3-8 -cycloalkyloxy, cyano, nitro, C 1-6 -alkylsulfanyl, or C 1-6 -alkylsulfonyl,
  • R 14 and R 15 are independently hydrogen, C -6 -alkyl, aryl-C 1-6 -alkyl or R 14 and R 15 may together form a C 3-6 -alkylene bridge
  • R 16 is independently selected from aryl, heteroaryl, C 3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19 R 20 and d-e-alkoxy,
  • R 17 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1-6 - alkoxy, C 1-6 -alkyI, amino, C 1-6 -alkylsulfonyl, C 1-6 -alkylamino, di-C 1-6 -alkylamino, cyano, aryl, heteroaryl and C 3-8 -cycloalkyl,
  • R 18 is independently selected from aryl, heteroaryl, d. 10 -alkyl, C 3-8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 -alkoxy, cyano, amino, C 1-6 -alkylamino, di- C 1-6 -alkylamino and hydroxy,
  • R 19 and R 20 are independently hydrogen or C 1-6 -alkyl, R 19 and R 20 may together form a C 3 . 6 -alkylene bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the reduction of weight.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety induction.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
  • the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of IGT.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • the invention provides the use of a compound of the general formula .(II') as defined above for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the delaying or pre- vention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition having histamine H3 agonistic activity.
  • the invention provides the use of a compound of the general formula (IT) as defined above for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia.
  • the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.
  • the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula (II') as defined above or a pharmaceutical composition comprising such a compound.
  • the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor wherein the effective amount of the compound of the general formula (IT) as defined above is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
  • the invention relates to a method for the treatment of diseases and disorders related to the histamine H3 receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the invention relates to compounds with histamine H3 receptor antagonistic i activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
  • the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
  • the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
  • the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.
  • the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, os- teoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
  • disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, os- teoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
  • the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • Such treatment includes inter alia treatment for the purpose of delaying or prevention of the progression from IGT to type 2 diabetes as well as delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the compounds of the present invention may also be used for the treatment of airway disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion.
  • the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.
  • the compounds of the invention may be used as CNS stimulants or as sedatives.
  • the present compounds may also be used for the treatment of conditions associated with epilepsy.
  • the present compounds may be used for the treatment of motion sickness and vertigo.
  • they may be useful as regulators of hypothalamo- hypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
  • the compounds of the present invention may be used for the treatment of dementia and Alzheimer's disease.
  • the compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
  • the compounds of the present invention may furthermore be useful for the treatment of migraine, see McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see Mackins et al., Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.
  • treatment of a patient with the present compounds is combined with diet and/or exercise.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratio(s).
  • Such further active agents may be selected from antiobesity agents, antidiabetics, antidyslipidemic agents, antihyper- tensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.
  • the present compounds are administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (***e amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL- 316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita
  • the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine. In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxet- ine, bupropion, topiramate or ecopipam.
  • the present compounds are administered in combination with one or more antidiabetic agents.
  • antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 0792290 (Novo Nordisk A/S), eg N ⁇ B29 -tetradecanoyl des (B30) human insu- lin, EP 0 214826 and EP 0705275 (Novo Nordisk A/S), eg Asp 828 human insulin, US 5,504,188 (Eli Lilly), eg Lys 828 Pro 629 human insulin, EP 0368 187 (Aventis), eg Lantus®, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A S), which is incorporated herein by reference, as well as ⁇ orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ⁇ - glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the ⁇ -cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 828 human insulin, Lys 828 Pro 829 human insulin, Lantus®, or a mix- preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulfonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • the present compounds are administered in combination with a biguanide eg metformin. In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
  • the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
  • a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41
  • the present compounds may be administered in combination with an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX- 0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr.
  • an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX- 0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191,
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbu- tamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
  • a sulfonylurea such as glyburide
  • a sulfonylurea and acarbose such as glyburide
  • a sulfonylurea and acarbose such as glyburide
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alpre- nolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni- modipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ⁇ -blockers such as alpre- nolol, atenolol, timolol
  • the compounds of the present invention may be chiral, and it is intended that any enanti- omers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule di- astereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the inven- , tion. Furthermore, some of the compounds of the present invention may exist in different tauto- , meric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharma- ceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition saltsjn clude salts of inorganic acids as well as organic acids. Representative examples of j. suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, , acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, probably lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane- sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • Exam- . pies of metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, di- methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethyl- ammonium, butylammonium, tetramethylammonium salts and the like.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present . compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharma- ; ceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accor- dance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcuta- neous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition , ⁇ and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release ac- cording to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non- aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile pow- ders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids.
  • a pharmaceutically acceptable acid for example, inorganic and organic acids.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suit- able for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phosphol- ipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • a solid carrier is used for oral administration, the preparation may be tabletted; placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques, may contain: Core:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • DIPEA diisopropylethylamine
  • DMSO dimethyl sulphoxide
  • -CH(R 20 R 21 ) represents ethyl, isopropyl, branched C 4-6 -alkyl, branched O ⁇ e-alkenyl, branched C ⁇ -alkynyl, C 3-5 -cycloalkyl, C 3-7 -cycloalkenyl, C 3-6 -cycloaIkyl-C 1-3 -alkyl or C 3-6 - cycloalkenyl-C 1-3 -alkyl, which may optionally be substituted with one or more halogen substituents.
  • the residue may be converted into an appropriate salt, such as the hydrochloride salt by co-evaporation with an acid, such as 1 molar aqueous hydrochloric acid, ethanol and toluene, and the residue is then purified by recrystallization.
  • an appropriate salt such as the hydrochloride salt by co-evaporation with an acid, such as 1 molar aqueous hydrochloric acid, ethanol and toluene
  • a mixture of a monosubstituted piperazine (2.00 mmol), DMSO (1.0 ml), a suitable aryl or heteroaryl halide (2.00 mmol), and a base such as DIPEA (0.20 ml) is stirred for one hour at 100 °C and then for 18 hours at 120 °C.
  • Water and potassium carbonate are added and the mixture is extracted with a solvent such as ethyl acetate (3 x 20 ml). Isolation and purification are done as in General Procedure (A).
  • Non-commercially available substituted 2-chloroquinolines were prepared as described in the literature: F. Effenberger, W. Hartmann, Chemische Berichte 1969, 102, 3260-3267.
  • the compounds of the general formula (I) may be prepared by the general procedure (C):
  • a compound of formula I may be prepared from a suitable monosubstituted piperazine and a suitable aryl bromide in the presence of a suitable catalyst such as e. g. tris(dibenzylideneacetone)dipalladium in a suitable solvent such as toluene at a suitable temperature between 0°C and 150°C.
  • a suitable catalyst such as e. g. tris(dibenzylideneacetone)dipalladium in a suitable solvent such as toluene at a suitable temperature between 0°C and 150°C.
  • This compound was prepared as described in Example 1, starting from 1-(4-acetylphenyl)- piperazine.
  • This compound was prepared as described in Example 1, starting from 1-(3,4-dichloro- phenyl)piperazine and 3-pentanone.
  • This compound was prepared as described in Example 6, starting from 4-fluorophenyl-(2- chlorophenyl)ketone.
  • This compound was prepared as described in Example 6, starting from 4,4'-difluorobenzo- phenone.
  • This compound was prepared as described in Example 1, starting from 1-(5-trifluoromethyl- pyridin-2-yl)piperazine.
  • This compound was prepared as described in Example 1, starting from 1-(3-trifluoromethyl- pyridin-2-yl)piperazine.
  • This compound was prepared as described in Example 6, starting from 4'-fluoro-3,4- dimethoxybenzophenone.
  • This compound was prepared as described in Example 6, starting from 3,4,5-trifluorobenzo- phenone.
  • This compound was prepared as Example 6, starting from 2-chloroquinoxaline and using propionitrile as solvent.
  • This compound was prepared from 2-chloro-6-fluoro-4-methylquinoline, which was prepared by acetoacetylation of 4-fluoroaniline, followed by acid-mediated ring-closure and conversion of the resulting carbostyryl into the chloroquinoline by treatment with phosphorus oxychlo- ride.
  • This compound was prepared according to General Procedure (B), starting from 1- isopropylpiperazine and 3-chloro-6-phenylpyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).
  • This compound was prepared according to General Procedure (B), starting from 1- cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonyl-phenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).
  • This compound was prepared according to General Procedure (B), starting from 1- cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonyl-phenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).
  • This compound was prepared according to General Procedure (B), starting from 1- isopropylpiperazine and 3-chloro-6-(4-methanesulfonyI-phenyl)-pyridazine, prepared as de- scribed in J. Heterocycl. Chem., 15, 881 (1978).
  • This compound was prepared according to General Procedure (B), starting from 1- cyclopentylpiperazine and 6-chloro-3-(4-chloro-phenyl)-4-methyl-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2,7-dichloroquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-fluoroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine - and 2 ; 6-dichloroquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-isopropylquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6,8-difluoroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-fluoroquinoline.
  • This compound was prepared using the General Procedure (B) from (9a-R)- octahydropyrido[1 ,2-a]pyrazine and 2-chloroquinoline.
  • This compound was prepared using the General Procedure (B) from (9a-R)- octahydropyrido[1 ,2-a]pyrazine and 2,6-dichloroquinoline.
  • This compound was prepared using the General Procedure (B) from (9a-R)- octahydropyrido[1 ,2-a]pyrazine and 2-chloro-6-propylquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloroquinoxaline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 4-fluorobenzophenone.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3,4,5-trifluorobenzophenone.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-5,6,7-trimethoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chIoro-5,6,7-trimethoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2,7-dichloro-6-methoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2,5,7-trichloroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(4-trifluorornethylphenyl)pyridazine.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 6-chloro[1 ,3]dioxolo[4,5-g]quinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-cyclohexylquinoline.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-cyclohexylquinoline.
  • This anilide (2.1 g, 10.0 mmol) was mixed with DMF (1.1 ml, 15 mmol), and to this mixture POCI 3 (6.5 ml, 70 mmol) was dropwise added at room temperature. When the addition is fin- ished the mixture is stirred at 75 oC for 2 h. The mixture was poured into ice-water (100 ml), stirred for 30 min, and filtered. The solid was stripped with toluene and acetonitrile, to yield 1.60 g (67%) of 2-chloro-6,7-dimethoxy-3-methylquinoline as a solid. This product was treated with 1-cyclopropylpiperazine as described in General Procedure (B) to yield the title compound.
  • This compound was prepared using the General Procedure (B) by reaction of 1- isopropylpiperazine with 3,4,5-trifluorobenzoic acid piperidide. This reaction yielded two products, namely the current example and example 121.
  • This compound was prepared using the General Procedure (B) from (9a-f?)- octahydropyrido[1 ,2-a]pyrazine and 2-chloro-6,7-dimethoxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-5,6,7,8-tetrahydroquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 5,6-dichloronicotinic acid piperidide.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 6-chloronicotinic acid piperidide.
  • This compound was prepared using the General Procedure (B) by reaction of 1- isopropylpiperazine with 3,4,5-trifluorobenzoic acid piperidide. This reaction yielded two products, namely the current example and example 115
  • This compound was prepared by reductive cyclopropylation of 6,7-dimethoxy-2-(3- methylpiperazin-1-yl)quinoline as described by Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; and Hoover, D. J. in Tetrahedron Lett. 1995, 36 (41), 7399-7402.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 6-chloronicotinic acid pyrrolidide.
  • This product (58.8 g; 218 mmol) was mixed with ice-cold concentrated sulfuric acid (390 ml) and the mixture was stirred first at 0 oC for 15 min (until almost all acrylamide had dissolved) and then at room temperature for 4 h. The mixture was then poured into ice water (3 I) and allowed to stand overnight. The mixture was filtered, and the solid was washed with water. The solid was transferred into a flask with the aid of acetonitrile, ethanol, and dichloromethane, and the suspension was concentrated under reduced pressure. The residue was resuspended in acetonitrile (300 ml), heated to reflux, and allowed to stand at room tempera- ture overnight. Filtration and drying of the solid under reduced pressure yielded 31.3 g (64%) of 6-bromo-2-quinolone as a yellow solid.
  • This quinolone (6.28 g, 28.0 mmol) was mixed with copper(l) cyanide (5.02 g, 56.1 mmol) and NMP (15 ml), and the mixture was stirred under reflux (202 oC) for 6 h, and then at room temperature overnight. Water (150 ml) was added, the mixture was filtered, and the solid was washed with water. The solid was resuspended in 1N hydrochloric acid (200 ml) and iron(lll) chloride hexahydrate (17.8 g) was added.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-phenylpyridazine.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine.
  • This compound was prepared by reductive cyclopropylation of 2-(3-methylpiperazin-1- yl)quinoline as described by Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; and Hoover, D. J. in Tetrahedron Lett. 1995, 36 (41), 7399-7402.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-(cyclopropylmethyloxy)quinoline.
  • the required 2-chloro-6- (cyclopropylmethyloxy)quinoline was prepared by treatment of 6-(cyclopropylmethyloxy)-2- quinolone with POCI 3 .
  • 6-(Cyclopropylmethyloxy)-2-quinolone was prepared from the corre- sponding 6-hydroxyquinolone by treatment with (bromomethyl)cycylopropane and potassium carbonate in dimethyl formamide in the presence of catalytic amounts of sodium iodide.
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-(1-pyrazolyl)quinoline.
  • the required 2-chloro-6-(1-pyrazolyl)quinoline was prepared by treatment of 6-(1-pyrazolyl)-2-quinolone with POCI 3 .
  • 6-(1-Pyrazolyl)-2-quinolone was prepared in the following way:
  • This compound was prepared using the General Procedure (B) from 1 -isopropylpiperazine and 2-chloro-6-hydroxyquinoline.
  • This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-cyanoquinoline.

Abstract

L'invention concerne de nouvelles aryl- et hétéroarylpiperazines, l'utilisation de ces composés comme compositions pharmaceutiques, les compositions pharmaceutiques comprenant les composés ainsi qu'une méthode thérapeutique utilisant ces composés et compositions. Les composés font preuve d'une forte affinité de liaison sélective avec le récepteur de l'histamine H3 indiquant une activité antagoniste du récepteur H3, agoniste inverse ou agoniste. Par conséquent, les composés sont utilisés dans le traitement de maladies et de troubles associés au récepteur de l'histamine H3.
PCT/DK2003/000071 2002-02-05 2003-02-05 Nouvelles aryl- et heteroarylpiperazines WO2003066604A2 (fr)

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BR0307429-3A BR0307429A (pt) 2002-02-05 2003-02-05 Composto, uso do mesmo, composição farmacêutica, e, método para o tratamento de distúrbios ou doenças relacionadas com receptor de histamina h3
KR10-2004-7011995A KR20040081177A (ko) 2002-02-05 2003-02-05 신규 아릴- 및 헤테로아릴피페라진
CA002474214A CA2474214A1 (fr) 2002-02-05 2003-02-05 Nouvelles aryl- et heteroarylpiperazines
EP03701482A EP1474401A2 (fr) 2002-02-05 2003-02-05 Nouvelles aryl- et heteroarylpiperazines
JP2003565978A JP4607458B2 (ja) 2002-02-05 2003-02-05 新規なアリールおよびへテロアリールピペラジン
MXPA04007612A MXPA04007612A (es) 2002-02-05 2003-02-05 Aril- y heteroarilpiperazinas novedosas.
IL16285903A IL162859A0 (en) 2002-02-05 2003-02-05 Novel aryl-and heteroarylpiperazines
AU2003203148A AU2003203148A1 (en) 2002-02-05 2003-02-05 Novel aryl- and heteroarylpiperazines
UA20040705946A UA83187C2 (en) 2002-02-05 2003-02-05 Aryl- and heteroarylpiperazines
US10/383,310 US20030236259A1 (en) 2002-02-05 2003-03-07 Novel aryl- and heteroarylpiperazines
ZA2004/05694A ZA200405694B (en) 2002-02-05 2004-07-16 Novel aryl-and heteroarylpiperazines
NO20043709A NO328714B1 (no) 2002-02-05 2004-09-03 Aryl- og heteroarylpiperaziner, farmasoytiske preparater som omfatter minst en slik forbindelse, samt anvendelser av slike forbindelser til fremstilling av farmasoytiske preparater
US12/367,952 US20090264435A1 (en) 2002-02-05 2009-02-09 Novel Aryl- and Heteroarylpiperazines
AU2010200135A AU2010200135A1 (en) 2002-02-05 2010-01-13 Novel aryl-and heteroarylpiperazines

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DKPA200200168 2002-02-05
DKPA200200168 2002-02-05
US35663002P 2002-02-08 2002-02-08
US60/356,630 2002-02-08
US39930402P 2002-07-26 2002-07-26
US60/399,304 2002-07-26
DKPA200201142 2002-07-26
DKPA200201142 2002-07-26

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JP (1) JP4607458B2 (fr)
CN (1) CN1628109A (fr)
AU (2) AU2003203148A1 (fr)
BR (1) BR0307429A (fr)
CA (1) CA2474214A1 (fr)
IL (1) IL162859A0 (fr)
MX (1) MXPA04007612A (fr)
NO (1) NO328714B1 (fr)
PL (1) PL372390A1 (fr)
WO (1) WO2003066604A2 (fr)
ZA (1) ZA200405694B (fr)

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