EP1474401A2 - Neue aryl- und heteroarylpiperazine - Google Patents

Neue aryl- und heteroarylpiperazine

Info

Publication number
EP1474401A2
EP1474401A2 EP03701482A EP03701482A EP1474401A2 EP 1474401 A2 EP1474401 A2 EP 1474401A2 EP 03701482 A EP03701482 A EP 03701482A EP 03701482 A EP03701482 A EP 03701482A EP 1474401 A2 EP1474401 A2 EP 1474401A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound according
aryl
compound
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03701482A
Other languages
English (en)
French (fr)
Inventor
Rolf Hohlweg
Florencio Zaragoza DÖRWALD
Henrik Stephensen
Ingrid Pettersson
Bernd Peschke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
vTv Therapeutics LLC
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1474401A2 publication Critical patent/EP1474401A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-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
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—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
    • 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
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/033—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C07D295/112—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 with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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 (cocaine 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pulmonology (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pyridine Compounds (AREA)
EP03701482A 2002-02-05 2003-02-05 Neue aryl- und heteroarylpiperazine Withdrawn EP1474401A2 (de)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
DKPA200200168 2002-02-05
DK200200168 2002-02-05
US35663002P 2002-02-08 2002-02-08
US356630P 2002-02-08
US39930402P 2002-07-26 2002-07-26
US399304P 2002-07-26
DKPA200201142 2002-07-26
DK200201142 2002-07-26
PCT/DK2003/000071 WO2003066604A2 (en) 2002-02-05 2003-02-05 Novel aryl- and heteroarylpiperazines

Publications (1)

Publication Number Publication Date
EP1474401A2 true EP1474401A2 (de) 2004-11-10

Family

ID=27739216

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03701482A Withdrawn EP1474401A2 (de) 2002-02-05 2003-02-05 Neue aryl- und heteroarylpiperazine

Country Status (12)

Country Link
EP (1) EP1474401A2 (de)
JP (1) JP4607458B2 (de)
CN (1) CN1628109A (de)
AU (2) AU2003203148A1 (de)
BR (1) BR0307429A (de)
CA (1) CA2474214A1 (de)
IL (1) IL162859A0 (de)
MX (1) MXPA04007612A (de)
NO (1) NO328714B1 (de)
PL (1) PL372390A1 (de)
WO (1) WO2003066604A2 (de)
ZA (1) ZA200405694B (de)

Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
GB0224084D0 (en) 2002-10-16 2002-11-27 Glaxo Group Ltd Novel compounds
US7279491B2 (en) 2002-10-23 2007-10-09 Janssen Pharmaceutica N.V. Phenylpiperidines and phenylpyrrolidines
KR20060054392A (ko) * 2003-07-29 2006-05-22 노보 노르디스크 에이/에스 피리다지닐-피페라진 및 히스타민 ｈ３ 수용체 리간드로서그들의 사용
US7754711B2 (en) * 2003-07-30 2010-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
SG145700A1 (en) 2003-07-30 2008-09-29 Xenon Pharmaceuticals Inc Pyridyl derivatives and their use as therapeutic agents
EP2316827B1 (de) 2003-07-30 2016-01-27 Xenon Pharmaceuticals Inc. Piperazin derivate und deren anwendung als therapeutische wirkstoffe
SG145699A1 (en) * 2003-07-30 2008-09-29 Xenon Pharmaceuticals Inc Pyridazine derivatives and their use as therapeutic agents
WO2005035521A1 (en) * 2003-10-09 2005-04-21 Argenta Discovery Ltd. Substituted quinolines as mcr modulators
GB0324159D0 (en) 2003-10-15 2003-11-19 Glaxo Group Ltd Novel compounds
JP4596792B2 (ja) * 2004-02-24 2010-12-15 あすか製薬株式会社 ５−ｈｔ１ａ作動作用と５−ｈｔ３拮抗作用を併有する薬剤
MXPA06011414A (es) 2004-03-31 2007-04-20 Johnson & Johnson Compuestos heterociclicos sin imidazol como ligandos del receptor de h3 histamina.
US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
US20050256309A1 (en) * 2004-05-12 2005-11-17 Altenbach Robert J Tri-and bi-cyclic heteroaryl histamine-3 receptor ligands
CA2571555A1 (en) * 2004-06-22 2006-01-05 Pfizer Products Inc. Diazabicyclic histamine-3 receptor antagonists
CN101090724A (zh) * 2004-09-20 2007-12-19 泽农医药公司 用于抑制人硬脂酰CoA去饱和酶的吡啶衍生物
CN101084212A (zh) 2004-09-20 2007-12-05 泽农医药公司 杂环衍生物及其作为硬脂酰CoA去饱和酶介导剂的用途
CN101083986A (zh) 2004-09-20 2007-12-05 泽农医药公司 双环杂环衍生物及其作为硬脂酰CoA去饱和酶(SCD)抑制剂的用途
CN101084207A (zh) 2004-09-20 2007-12-05 泽农医药公司 杂环衍生物及其作为硬脂酰CoA去饱和酶抑制剂的用途
WO2006034279A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
CA2580857A1 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
AU2005286793A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
JP5149009B2 (ja) 2004-09-20 2013-02-20 ゼノン・ファーマシューティカルズ・インコーポレイテッド ヒトステアロイル−ＣｏＡデサチュラーゼを阻害するためのピリダジン誘導体
EP1807085B1 (de) 2004-09-20 2013-08-21 Xenon Pharmaceuticals Inc. Heterozyklische Derivate und ihre Verwendung als Stearoyl-Coa-Desaturase-Inhibitoren
EP2592075B1 (de) * 2004-11-02 2015-04-29 Northwestern University Pyridazinverbindungen zur behandlung von entzündlichen erkrankungen
US7700595B2 (en) 2005-03-01 2010-04-20 Wyeth Llc Cinnoline compounds
AU2006343359A1 (en) 2005-06-03 2007-11-15 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors
JP5121707B2 (ja) 2005-07-04 2013-01-16 ハイ ポイント ファーマシューティカルズ，エルエルシー 新規医薬
PT1904455E (pt) * 2005-07-05 2011-10-04 Hoffmann La Roche Derivados de piridazina
EP1917245A1 (de) 2005-08-21 2008-05-07 Abbott GmbH & Co. KG Heterocyclische verbindungen und ihre verwendung als bindungspartner für 5-ht5-rezeptoren
GB0517184D0 (en) * 2005-08-22 2005-09-28 Glaxo Group Ltd Compounds
DE602006013501D1 (de) 2005-09-16 2010-05-20 Janssen Pharmaceutica Nv Cyclopropylamine als modulatoren des histamin-h3-rezeptors
JO2769B1 (en) 2005-10-26 2014-03-15 جانسين فارماسوتيكا ان. في Rapid decomposition of physiologically antagonistic agents of the 2-dopamine receptor
SG170785A1 (en) * 2006-03-28 2011-05-30 Transtech Pharma Benzothiazoles having histamine h3 receptor activity
CN101754762A (zh) * 2006-04-28 2010-06-23 西北大学 用于治疗神经炎症性疾病的包含哒嗪化合物的制剂
JP2009537596A (ja) 2006-05-23 2009-10-29 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー ６−（４−シクロプロピルピペリジン−１−イル）−２’−メチル−［３，４’］−ビピリジン及びその医薬としての使用
SI2079732T1 (sl) * 2006-05-29 2012-03-30 High Point Pharmaceuticals Llc benzodioksol il ciklopropilpiperazin il piridazin njegove soli in solvati in njegova uporaba kot antagonist histaminskega receptorja H
WO2007137955A1 (en) * 2006-05-30 2007-12-06 F. Hoffmann-La Roche Ag Piperidinyl pyrimidine derivatives
MY146506A (en) 2006-05-30 2012-08-15 Janssen Pharmaceutica Nv Substituted pyridyl amide compounds as modulators of the histamine h3 receptor
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
AU2007260836B2 (en) 2006-06-23 2012-11-15 Abbvie Bahamas Ltd. Cyclopropyl amine derivatives as histamin H3 receptor modulators
WO2008003702A2 (en) * 2006-07-03 2008-01-10 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg Fused bicyclic compounds interacting with the histamine h4 receptor
JO2642B1 (en) 2006-12-08 2012-06-17 جانسين فارماسوتيكا ان. في Dopamine 2 receptor antagonists are rapidly hydrolyzed
JO2849B1 (en) * 2007-02-13 2015-03-15 جانسين فارماسوتيكا ان. في Dopamine 2 receptor antagonists are rapidly hydrolyzed
RU2489431C2 (ru) 2007-04-23 2013-08-10 Янссен Фармацевтика Н.В. Тиа(диа)золы как быстро диссоциирующие антагонисты рецептора допамина 2
RS52518B (sr) 2007-04-23 2013-04-30 Janssen Pharmaceutica N.V. Derivati 4-alkoksipiridazina kao brzo disocirajući dopamin 2 receptorski antagonisti
CA2687931C (en) * 2007-05-31 2016-05-24 Boehringer Ingelheim International Gmbh Ccr2 receptor antagonists and uses thereof
EP2014656A3 (de) * 2007-06-11 2011-08-24 High Point Pharmaceuticals, LLC Neue heterocyclische H3-Antagonisten
CA2695071A1 (en) * 2007-08-02 2009-02-05 F. Hoffmann-La Roche Ag The use of benzamide derivatives for the treatment of cns disorders
KR20100059944A (ko) 2007-09-06 2010-06-04 글락소 그룹 리미티드 히스타민 ｈ３ 수용체에 대해 친화성을 갖는 피페라진 유도체
BRPI0820481A2 (pt) 2007-11-20 2015-06-16 Janssen Pharmaceutica Nv Composotos cicloalquilóxi e heterocicloalquilóxi piridina como moduladores do receptor de h3 de histamina
US20120015957A1 (en) * 2007-12-17 2012-01-19 Wenying Chai Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor
WO2009079597A1 (en) * 2007-12-17 2009-06-25 Janssen Pharmaceutica N.V. Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor
JP5417439B2 (ja) 2008-07-03 2014-02-12 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ５−ｈｔ６受容体アンタゴニストとしての置換された６−（１−ピペラジニル）−ピリダジン類
LT2307374T (lt) 2008-07-31 2017-04-25 Janssen Pharmaceutica Nv Piperazin-1-il-trifluormetil-pakeistieji piridinai kaip greitai disocijuojantys dopamino 2 receptoriaus antagonistai
PL2379525T3 (pl) 2008-12-19 2016-01-29 Centrexion Therapeutics Corp Cykliczne pirymidyno-4-karboksamidy jako antagoniści receptora CCR2 do leczenia stanów zapalnych, astmy oraz COPD
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
AU2010332969B2 (en) 2009-12-17 2015-02-12 Centrexion Therapeutics Corporation New CCR2 receptor antagonists and uses thereof
WO2011103091A1 (en) 2010-02-18 2011-08-25 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
WO2011141474A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
JP5646736B2 (ja) 2010-05-12 2014-12-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規ｃｃｒ２受容体アンタゴニスト、これらの製造方法、及び薬物としてのこれらの使用
EP2571870B1 (de) 2010-05-17 2015-01-21 Boehringer Ingelheim International GmbH Ccr2-antagonisten und verwendungen dafür
WO2011147772A1 (en) 2010-05-25 2011-12-01 Boehringer Ingelheim International Gmbh Ccr2 receptor antagonists
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
JP5786258B2 (ja) 2011-07-15 2015-09-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規かつ選択的なｃｃｒ２拮抗薬
WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
PL3177612T3 (pl) 2014-08-04 2022-08-08 Nuevolution A/S Opcjonalnie skondensowane pochodne pirymidyny podstawione heterocyklilem, użyteczne w leczeniu chorób zapalnych, metabolicznych, onkologicznych i autoimmunologicznych
CA2990460C (en) 2015-07-02 2023-10-17 Centrexion Therapeutics Corporation (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
NZ786543A (en) 2019-12-20 2026-01-30 Nuevolution As Compounds active towards nuclear receptors
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
CA3174252A1 (en) 2020-03-31 2021-10-07 Nuevolution A/S Compounds active towards nuclear receptors
CA3174176A1 (en) 2020-03-31 2021-10-07 Sanne Schroder Glad Compounds active towards nuclear receptors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0156433A2 (de) * 1984-03-26 1985-10-02 Janssen Pharmaceutica N.V. Pyridazinamine wirksam gegen Viren
WO2003104235A1 (en) * 2002-06-06 2003-12-18 Novo Nordisk A/S Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]pyrazines and decahydropyrazino[1,2-a]azepines

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB753166A (en) * 1953-05-22 1956-07-18 Miles Lab Improvements in or relating to substituted piperazines
US2993899A (en) * 1958-03-31 1961-07-25 Miles Lab Acetylenically unsaturated piperazine derivatives
US3309370A (en) * 1964-07-16 1967-03-14 Miles Lab Bicycloalkyl piperazine derivatives and process
FR2306694A1 (fr) * 1975-04-07 1976-11-05 Parcor Derives de la piperazine
US4144346A (en) * 1977-01-31 1979-03-13 Janssen Pharmaceutica N.V. Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles
US4163849A (en) * 1978-03-17 1979-08-07 Merck & Co., Inc. Piperazinylpyrazines
JPS56118074A (en) * 1980-02-22 1981-09-16 Tanabe Seiyaku Co Ltd Propane derivative and its preparation
US4339579A (en) * 1980-12-29 1982-07-13 American Home Products Corporation 2,6-Bis-(pyrrolopyrazinyl)pyrazines
FR2573075B1 (fr) * 1984-09-14 1987-03-20 Innothera Lab Sa Nouvelles (pyridyl-2)-1 piperazines, leur procede de preparation et leur application en therapeutique
JP2576862B2 (ja) * 1986-03-05 1997-01-29 大塚製薬 株式会社 カルボスチリル誘導体
DK111387A (da) * 1986-03-05 1987-09-06 Otsuka Pharma Co Ltd Carbostyrilderivater og salte deraf, laegemiddel indeholdende saadanne derivater samt fremgangsmaade til fremstilling af derivaterne
AU639529B2 (en) * 1987-03-04 1993-07-29 Higuchi, Yoshinari Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives
DE3803860A1 (de) * 1988-02-09 1989-08-17 Basf Ag N,n'-disubstituierte piperazine
ATE107922T1 (de) * 1989-03-03 1994-07-15 Dainippon Pharmaceutical Co 2-(1-piperazinyl)-4-phenylcycloalkanpyridin- derivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die sie enthalten.
GB9012316D0 (en) * 1990-06-01 1990-07-18 Wellcome Found Pharmacologically active cns compounds
WO1997002245A1 (en) * 1995-07-06 1997-01-23 Japan Tobacco Inc. Benzamidoxime derivatives and medicinal use thereof
JPH0971564A (ja) * 1995-07-06 1997-03-18 Japan Tobacco Inc ベンズアミドオキシム誘導体及びその医薬用途
DZ2376A1 (fr) * 1996-12-19 2002-12-28 Smithkline Beecham Plc Dérivés de sulfonamides nouveaux procédé pour leurpréparation et compositions pharmaceutiques les c ontenant.
DE69839887D1 (de) * 1997-10-02 2008-09-25 Eisai R&D Man Co Ltd Kondensierte pyridinderivate
JP3989102B2 (ja) * 1997-10-02 2007-10-10 エーザイ・アール・アンド・ディー・マネジメント株式会社 縮合ピリジン誘導体
AU2935200A (en) * 1999-04-30 2000-11-17 Pfizer Products Inc. Compounds for the treatment of obesity
GB9926303D0 (en) * 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
GB9926302D0 (en) * 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
AU2261401A (en) * 1999-12-16 2001-06-25 Schering Corporation Substituted imidazole neuropeptide y y5 receptor antagonists
FI20000480A0 (fi) * 2000-03-01 2000-03-01 Orion Yhtymae Oyj Kinoliini- ja naftaleenijohdannaisia alfa-2 antagonisteina
CN101406469B (zh) * 2001-01-31 2012-06-13 H·隆德贝克有限公司 Gal3受体拮抗剂在治疗抑郁和/或焦虑中的应用及在这种方法中有用的化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0156433A2 (de) * 1984-03-26 1985-10-02 Janssen Pharmaceutica N.V. Pyridazinamine wirksam gegen Viren
WO2003104235A1 (en) * 2002-06-06 2003-12-18 Novo Nordisk A/S Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]pyrazines and decahydropyrazino[1,2-a]azepines

Also Published As

Publication number Publication date
NO328714B1 (no) 2010-05-03
BR0307429A (pt) 2004-12-28
IL162859A0 (en) 2005-11-20
JP4607458B2 (ja) 2011-01-05
NO20043709L (no) 2004-09-03
PL372390A1 (en) 2005-07-25
JP2005533747A (ja) 2005-11-10
MXPA04007612A (es) 2004-11-10
WO2003066604A2 (en) 2003-08-14
AU2003203148A1 (en) 2003-09-02
WO2003066604A3 (en) 2003-12-04
ZA200405694B (en) 2005-09-28
CN1628109A (zh) 2005-06-15
CA2474214A1 (en) 2003-08-14
AU2010200135A1 (en) 2010-02-04

Similar Documents

Publication Publication Date Title
EP1474401A2 (de) Neue aryl- und heteroarylpiperazine
US20090264435A1 (en) Novel Aryl- and Heteroarylpiperazines
CA2532236C (en) Pyridazinyl- piperazines and their use as histamine h3 receptor ligands
EP1611121B1 (de) Pyridazinon-derivate als cdk2-hemmer
US8173682B2 (en) Substituted pyridones as inhibitors of poly(ADP-ribose) polymerase (PARP)
JP6259463B2 (ja) ＩＬ−１２、ＩＬ−２３および／またはＩＦＮα応答のモジュレーターとして有用であるアルキルアミド置換ピリジル化合物
US8501739B2 (en) Medicaments
KR100565439B1 (ko) 신규 피리다진 유도체 및 이를 유효성분으로 하는 의약
US20030130253A1 (en) Novel aminoazetidine,-pyrrolidine and -piperidine derivatives
RU2269519C2 (ru) Соединения фенилпиридазина и содержащие их лекарственные средства
CA2690486A1 (en) New heteocyclic h3 antagonists
EP2121630B1 (de) Schnell dissoziierende antagonisten des dopamin-2-rezeptors
JPS6324996B2 (de)
EP1513842B1 (de) Substituierte hexahydropyrrolo(1,2-a)pyrazine, octahydropyrido(1,2-a)pyrazine und decahydropyrazino(1,2-a)azepine
US7186721B2 (en) Substituted hexahydropyrrolo[1,2-a]pyrazines, octahydropyrido[1,2-a]-pyrazines and decahydropyrazino[1,2-a]azepines
RU2361869C2 (ru) Новые арил- и гетероарилпиперазины
KR20040081177A (ko) 신규 아릴- 및 헤테로아릴피페라진
HK1143364A (en) Novel aryl-and heteroarylpiperazines
US7462613B2 (en) Pyridazinone derivatives as pharmaceuticals and pharmaceutical compositions containing them
ZA200502185B (en) Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors
WO1999042106A1 (fr) Agent anti-hcmv

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040906

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

RIN1 Information on inventor provided before grant (corrected)

Inventor name: PESCHKE, BERND

Inventor name: PETTERSSON, INGRID

Inventor name: STEPHENSEN, HENRIK

Inventor name: DOERWALD, FLORENCIO, ZARAGOZA

Inventor name: HOHLWEG, ROLF

RIN1 Information on inventor provided before grant (corrected)

Inventor name: PESCHKE, BERND

Inventor name: PETTERSSON, INGRID

Inventor name: STEPHENSEN, HENRIK

Inventor name: DOERWALD, FLORENCIO, ZARAGOZA

Inventor name: HOHLWEG, ROLF

17Q First examination report despatched

Effective date: 20080417

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TRANSTECH PHARMA, INC

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: HIGH POINT PHARMACEUTICALS, LLC

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130312