EP1173438A1 - Imidazoles substitues, leur preparation et utilisation - Google Patents

Imidazoles substitues, leur preparation et utilisation

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Publication number
EP1173438A1
EP1173438A1 EP00918714A EP00918714A EP1173438A1 EP 1173438 A1 EP1173438 A1 EP 1173438A1 EP 00918714 A EP00918714 A EP 00918714A EP 00918714 A EP00918714 A EP 00918714A EP 1173438 A1 EP1173438 A1 EP 1173438A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
amino
aryl
heteroaryl
aroyl
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Withdrawn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
EP00918714A
Other languages
German (de)
English (en)
Inventor
Florencio Zaragoza DÖRWALD
Knud Erik Andersen
Tine Krogh Jorgensen
Bernd Peschke
Birgitte Schjellerup Wulff
Ingrid Pettersson
Klaus Rudolf
Dirk Stenkamp
Rudolf Hurnaus
Stephan Georg MÜLLER
Bernd Krist
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.)
Boehringer Ingelheim International GmbH
Novo Nordisk AS
Original Assignee
Boehringer Ingelheim International GmbH
Novo Nordisk AS
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Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Novo Nordisk AS filed Critical Boehringer Ingelheim International GmbH
Publication of EP1173438A1 publication Critical patent/EP1173438A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel substituted imidazoles, to the use of these compounds as medicaments, 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 or agonistic activ- ity. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor.
  • histamine H3 receptor has been known for several years and of current interest for the development of new medicaments (see e.g. Stark, H.;
  • the histamine H3 receptor is a presynaptic auto- receptor located in both 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.
  • the histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine.
  • a histamine H3 receptor antagonist would therefore be expected to increase the re- lease 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.
  • WO 98/29119 relates to tetrahydroimidazopyridine farnesyl-protein inhibitors.
  • JP 06312927 discloses tetrahydroimidazopyridine intermediates for preparing angiosin II inhibitors.
  • WO 93/17701 discloses tetrahydroimidazopyridine intermediates for preparing endothelin receptor-binding peptides.
  • Klutchko, S., et al., J. Heterocycl. Chem., 28(1 ), 1991, 97- 108 relates to synthesis methods for the preparation of imidazole derivatives.
  • GB 2158440 relates to antiviral compounds.
  • Arcari, G.; Bernardi, L; Cimaschi, R.; Falconi, G.; Luini, F.; Scarponi, U., Arzneim. Forsch., 34, 11 , 1984, 1467-1471 relates to tetrahydroimidazopyridine intermediates for the preparation of imidazopiperidines with anti-ulcer and antisecretory activity
  • GB 2028798 relates to tetrahydroimidazopyridine intermediates for the preparation of antiulcer and anticholinergic compounds.
  • these references neither disclose nor suggest that the imidazoles may have a histamine H3 receptor antagonistic or agonistic activity.
  • imidazopyridine derivatives which are stated to be useful either as intermediates or as therapeutically active substances such as angiotensin II antagonists effective to treat hypertension, peripheral kappa opioid receptor activating substances effective to treat inflammatory pain and N-myristoyl transferase inhibitors effective as anti-cancer agents.
  • angiotensin II antagonists effective to treat hypertension
  • peripheral kappa opioid receptor activating substances effective to treat inflammatory pain
  • N-myristoyl transferase inhibitors effective as anti-cancer agents.
  • these references neither disclose nor suggest that the imidazoles may have a histamine H3 receptor antagonistic or agonistic activity.
  • 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 specific class of substituted imidazole compounds has a high and specific affinity to the histamine H3 receptor. Some of these substituted imidazole derivatives are novel per se thereby constituting a further as- pect of the invention.
  • the present compounds are useful in the treatment and/or prevention of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial.
  • the com- pounds 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.
  • C,. 6 -alkyl as used herein represent a branched or straight hydrocarbon group having from 1 to 6 carbon atoms.
  • Typical C ⁇ -alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • C 2 - 8 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 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 and the like.
  • C 2.6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
  • C 2.8 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond.
  • Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1 -hexynyl, 2-hexynyl, 1-heptynyl, 2-heptynyl, 1-octynyl, 2-octynyl and the like.
  • C 2 . 6 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • C,_ 6 -alkoxy refers to the radical -O-C ⁇ -alkyl where C ⁇ -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, terf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C ⁇ -alkylthio refers to the radical -S-C ⁇ -alkyl where C ⁇ -alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, propylthio, butylthio, pentylthio and the like.
  • C 3 . 15 -cycloalkyl represents a carbocyclic group having from 3 to 15 carbon atoms such as from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyc- lononyl, cyclodecyl and the like. In the same way the term "C 3 . 8 -cycloalkyl” represents a carbocyclic group having from 3 to 8 carbon atoms
  • C 3 . 15 -cycloalkenyl represents a carbocyclic group having from 3 to 15 carbon atoms such as from 3 to 8 carbon atoms and at least one double bond.
  • Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohepentyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
  • C 3 . 15 -cycloalkynyl represents a carbocyclic group having from 3 to 15 carbon atoms such as from 3 to 8 carbon atoms and at least one triple bond.
  • Representative examples are cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, cyclononynyl, cyclodecynyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl 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-(1 ,2,3,4-tetrahydronaphthyl) and 2-(1 ,2,3,4-tetrahydronaphthyl).
  • aroyl refers to the radical -CO-aryl where aryl is as defined above. Non-limiting examples are benzoyl, naphthoyl, anthracenoyl, phenanthrenoyl, fluorenoyl, indenoyl and the like.
  • aryloxy refers to the radical -O-aryl where aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyl- oxy, fluorenyloxy, indenyloxy and the like.
  • arylthio refers to the radical -S-aryl where aryl is as defined above.
  • Non-limiting examples are phenylthio, naphthylthio, phenanthrenylthio, fluorenylthio, indenylthio and the like.
  • arylamino refers to the radical -NH-aryl where aryl is as defined above.
  • Non-limiting examples are phenylamino, naphthylamino, phenanthrenylamino, fluorenylamino, indenylamino and the like.
  • Non-limiting examples are phenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, fluorenylsulfonyl, indenylsulfonyl 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-triazinyl, 1 ,3,5-triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazol
  • Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydofuranyl.
  • heteroaroyl refers to the radical -CO-heteroaryl where heteroaryl is as defined above.
  • Non-limiting examples are furoyl, thienylcarbonyl, pyridoyl, oxazolylcarbonyl, benzofurylcarbonyl, benzimidazolylcarbonyl, pyrrolinylcarbonyl, azepinylcarbonyl and the like.
  • heteroaryloxy refers to the radical -O-heteroaryl where heteroaryl is as defined above.
  • Non-limiting examples are furyloxy, thienyloxy, pyridyloxy, oxazolyloxy, benzofuryloxy, benzimidazolyloxy, pyrrolinyloxy, azepinyloxy and the like.
  • heteroarylamino refers to the radical -NH-heteroaryl where heteroaryl is as defined above.
  • Non-limiting examples are furylamino, thienylamino, pyridylamino, oxazolylamino, benzofurylamino, benzimidazolylamino, pyrrolinylamino, azepinylamino and the like.
  • heteroarylthio refers to the radical -S-heteroaryl where heteroaryl is as defined above.
  • Non-limiting examples are furylthio, thienylthio, pyridylthio, oxazolylthio, benzofurylthio, benzimidazolylthio, pyrrolinylthio, azepinylthio and the like.
  • Non-limiting examples are furylsulfonyl, thienylsulfonyl, pyridylsulfonyl, oxazolylsulfonyl, benzofurylsulfonyl, benzimidazolylsulfonyl, pyrrolinylsulfonyl, azepinylsulfonyl and the like.
  • G and L independently represent hydrogen, C ⁇ -alkyl, aryl or heteroaryl as defined above.
  • Non-limiting examples are acetylamino, propanoylamino, butyryl- amino, pentanoylamino, benzoylamino, furoylamino, pyridoylamino and the like.
  • G and L independently represent hydrogen, C,. 6 -alkyl, aryl or heteroaryl as defined above.
  • Non-limiting examples are methanesulfonylamino, propanesulfonylamino, benzenesulfonylamino, ⁇ /-methyl- ⁇ /-(benzenesulfonyl)amino, 4-methylbenzenesulfonylamino ⁇ /-butyl- ⁇ /-(4-methylbenzenesulfonyl)amino, 2-thienylsulfonylamino and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • the phrase "3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring” is intended to include carbocyclic rings which are saturated or contain one or more double bonds as well as heterocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen or sulfur which are saturated or contain one or more double bonds.
  • a functional group which can be converted to hydrogen in vivo is intended to include any group which upon administering the present com- pounds to the subjects in need thereof can be converted to hydrogen e.g. enzymati- cally or by the acidic environment in the stomach.
  • Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as C ⁇ -alkanoyl, aroyl, C,_ 6 -alkylcarbamoyl, di-C ⁇ -alkylcarbamoyl, C
  • the phrase "diseases and disorders related to the histamine H3 receptor" is intended to include any disease or disorder in which an effect, either antagonistic or agonistic, on the histamine H3 receptor is beneficial.
  • the present invention relates to novel, substituted imidazoles of the general formula I
  • R 1 is hydrogen or a functional group, which can be converted to hydrogen in vivo;
  • R 2 is hydrogen, C,_ 6 -alkyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy or -NR 7 R 8 ,
  • R 7 and R 8 independently are
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroaryl- amino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • R 7 and R 8 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • R 3 , R 4 , R 5 and R 6 independently are
  • aryl optionally substituted with halogen, cyano, nitro, C ⁇ -alkyl, C.,_ 6 -alkoxy, hydroxy, trifluoromethyl, trifluoro- methoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR 9 R 10 ,
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C,_ 6 -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • R 9 and R 10 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally contain- ing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C ⁇ e-alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, d C ⁇ -alky ⁇ amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 3 and R 4 together with the carbon atom to which they are connected, and/or R 5 and R 6 together with the carbon atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 .
  • C,_ 6 -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • R 11a is C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with hydroxy, amino, C L g-alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • Y is a valence bond, -O- or -N(R 12 )-,
  • C,. 6 -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with C,. 6 -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, d ' ⁇ C ⁇ e-alky ⁇ amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • A is a valence bond, C,. 8 -alkylene, C 2 . 8 -alkenylene, C 2 . 8 -alkynylene, C 3 _ 8 -cyclo- alkylene or phenylene, or
  • Y when Y is -N(R 12 )-, A, together with R 12 and the nitrogen atom to which they are connected, may form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, di(C 1 .
  • R 13 , R 14 and R 15 independently are
  • C ⁇ -alkyl C 2 . 6 -alkenyl or C 2 . 6 -alkynyl, which are optionally substituted with aryl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, C,_ 6 -alkyl- sulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, heteroaryl or C 3 .
  • aryl C 3 . 15 -cycloalkyl, C 3 . 15 -cycloalkenyl, C 3 . 15 -cycloalkynyl, aroyl or heteroaryl, which are optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C,_ 6 -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C ⁇ -alkyl- sulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C,_ 6 -alkyl, C,.
  • -N C 1 ⁇ -alkylene, -O-C ⁇ -alkenylene, -S-C ⁇ -alkenylene or -N(R 16 )-C 2 ⁇ -alke- nylene, to form a mono-, bi- or polycyclic ring system,
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, het- eroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkyl- amino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • R 16 and R 17 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, di(C 1 ⁇ -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • R 5 must not be carboxy, aminocarbonyl or 4-phenyl- piperazin-1 -ylcarbonyl;
  • A is a valence bond, C 2 . 8 -alkenylene or C 2 . 8 -alkynylene.
  • A is a valence bond or such as methylene, ethylene or propylene.
  • Z is -R 13 , -NR 13 R 14 , -CHR 13 R 14 or -CR 13 R 14 R 15 , wherein R 13 , R 14 and R 15 are as defined for formula I above.
  • Z is -R 13 , wherein R 13 is as defined for formula I above.
  • Z is preferably C ⁇ -alkyl, aryl, C 3 . 15 -cycloalkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above. More preferably, Z is C ⁇ -alkyl, phenyl, naphthyl, thienyl, cyclopentyl, cyclohexyl, cyclohexenyl, oxazolyl, indanyl, isoquinolyl, benzoyl or tetrahydronaphthyl, which are optionally substituted for formula I above.
  • Z is phenyl or cyclohexyl, which are optionally substituted as defined for formula I above.
  • Z may be unsubstituted or substituted with one to three substituents selected from C,. 6 -alkyl, C ⁇ -alkoxy, halogen, phenyl, di(C 1 ⁇ -alkyl)amino, C 3 . 8 -cyclopropane- carbonyl, trifluoromethoxy and trifluoromethyl.
  • Z is -NR 13 R 14 , in which R 13 and R 14 are both phenyl, which phenyl groups are joined with a C ⁇ -alkylene group to form a tricyclic ring system, such as 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl.
  • Z is -CHR 13 R 14 , in which R 13 is C ⁇ -alkyl or phenyl and R 14 is phenyl, or R 13 and R 14 are both C ⁇ -alkyl, which are joined with C,. alkylene linkers to form a polycarbocyclic ring system, such as bicyclo[2.2.1]hept-2- yi-
  • Z is -CR 13 R 14 R 15 , in which R 13 , R 14 and R 5 are linkers to form a polycarbocyclic ring system, such as adamantyl.
  • R 3 and R 4 are independently
  • Cs-a-cycloalkyl optionally substituted with C ⁇ -alkyl, C,_ 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, d C ⁇ -alkylamino), halogen, cyano, trifluoromethyl, trifluoro- methoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • aryl optionally substituted with halogen, cyano, nitro, C ⁇ -alkyl, C,_ 6 -alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR 9 R 10 , wherein R 9 and R 10 are as defined in claim 1 , or
  • R 3 and R 4 together with the carbon atom to which they are connected, form a C 3 - 8 -cycloalkyl ring optionally substituted with C,_ 6 -alkyl, C,_ 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, d ⁇ C ⁇ e-alkylamino), halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino.
  • R 3 and R 4 are both hydrogen or are both C ⁇ -alky!, or R 3 and R 4 , together with the carbon atom to which they are connected, form a C 3 . 8 -cycloalkyl ring, or one of R 3 and R 4 is hydrogen while the other is C 3 . 8 -cycloalkyl substituted C 1 6 -alkyl.
  • R 5 and R 6 are both hydrogen.
  • R 3 , R 4 , R 5 and R 6 are hydrogen.
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is -N(R 12 )-, wherein R 2 and A, together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 .
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is -NH-;
  • A is C,. 8 -alkylene;
  • Z is -R 13 , wherein R 13 is C ⁇ -alkyl, aryl, C 3 . 15 - cycloalkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above.
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is a va- lence bond;
  • A is a valence bond or and
  • Z is -R 3 , wherein R 13 is C,_ 6 - alkyl, aryl, C 3 . 15 -cycloalkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above.
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is -N(R 12 )-, wherein R 12 is hydrogen or C ⁇ -alkyl;
  • A is a valence bond or C ⁇ -alkylene;
  • Z is - R 13 , wherein R 13 is C ⁇ -alkyl, aryl, C 3 . 15 -cycloalkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above.
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is -0-;
  • A is a valence bond or C.,_ 8 -alkylene;
  • Z is -R 13 , wherein R 13 is C ⁇ -alkyl, aryl, C 3 . 15 -cyclo- alkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above.
  • R 3 , R 4 , R 5 and R 6 are hydrogen;
  • Y is a valence bond;
  • A is a valence bond or C ⁇ -alkylene;
  • Z is -R 3 , wherein R 13 is C ⁇ -alkyl, aryl, C 3 . 15 -cycloalkyl, C 3 . 15 -cycloalkenyl, aroyl or heteroaryl, which are optionally substituted as defined for formula I above.
  • Z is C,_ 6 -alkyl, phenyl, naphthyl, thienyl, cyclopentyl, cyclohexyl, cyclohexenyl, oxazolyl, indanyl, isoquinolyl, benzoyl or tetrahydronaphthyl, which are optionally substituted as defined for formula I above.
  • Z is phenyl or cyclohexyl which are optionally substituted as defined for formula I above.
  • Z may be unsubstituted or substituted with one to three substituents selected from C,. 6 -alkyl, C-.g-alkoxy, halogen, phenyl, di(C 1 . 6 -alkyl)amino, C ⁇ -cyclopropane- carbonyl, trifluoromethoxy and trifluoromethyl.
  • R 1 is hydrogen or a functional group which can be converted to hydrogen in vivo
  • R 2 is hydrogen, C,_ 6 -alkyl, halogen, cyano, trifluoromethyl, hydroxy or -NR 7 R 8 ,
  • R 7 and R 8 independently are
  • C,. 6 -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C,_ 6 -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C ⁇ -alkylsulfonyl optionally substituted with C 3 . 8 -cycloalkyl, C,_ 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 7 and R 8 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C.,_ 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • R 3 , R 4 , R 5 and R 6 independently are
  • C 3 . 8 -cycloalkyl optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ e-alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • aryl optionally substituted with halogen, cyano, nitro, C ⁇ -alkyl, C,. 6 -alkoxy, hydroxy, trifluoromethyl, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR 9 R 10 ,
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl, which are optionally substituted with
  • R 9 and R 10 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring op- tionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C,_ 6 -alkyl, C, .6 -alkoxy, C,. 6 -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 3 and R 4 together with the carbon atom to which they are connected, and/or R 5 and R 6 together with the carbon atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with C,_ 6 -alkyl, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • n, p and q independently are 0, 1 or 2;
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C ⁇ -alkylsulfonyl optionally substituted with C 3 . 8 -cycloalkyl, C ⁇ -alkoxy, C,. 6 -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • Y is a valence bond, -O- or -N(R 12 )-,
  • A is a valence bond, C ⁇ -alkylene, C 2 . 8 -alkenylene, C 2 . 8 -alkynylene, C 3 . 8 -cyclo- alkylene or phenylene, or
  • Y when Y is -N(R 12 )-, A, together with R 12 and the nitrogen atom to which they are connected, may form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aryl-C ⁇ -alkyl, heteroaryl-C ⁇ -alkyl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; and
  • R 13 , R 14 and R 15 independently are hydrogen
  • C ⁇ -alkyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl which are optionally substituted with aryl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, C ⁇ -alkyl- sulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, heteroaryl or C 3 _ 8 -cycloalkyl, which are optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, aryl-C,_ 6 -alkyl, hetero- aryl-C 1 _ 6 -alkyl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, sulfonylamino
  • aryl C 3 . 15 -cycloalkyl, aroyl or heteroaryl, which are optionally substituted with aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C,_ 6 -alkyl- sulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C,. ⁇ -alkyl, C,. 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano or trifluoromethyl, where
  • C,_ 6 -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 .
  • 8 -cycloalkyl which are optionally substituted with hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with C,_ 6 -alkyl, C ⁇ -alkoxy, C ⁇ e-alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C, .6 -alkylsulfonyl optionally substituted with C 3 . 8 -cycloalkyl, C ⁇ -alkoxy, C,. 6 -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 16 and R 17 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroaryl- amino;
  • R 1 is hydrogen or a functional group which can be converted to hydrogen in vivo
  • R 2 is hydrogen, C ⁇ -alkyl, halogen, cyano, trifluoromethyl, hydroxy or -NR 7 R 8
  • R 7 and R 8 independently are
  • heteroaryl optionally substituted with C ⁇ -alkyl, C,. 6 -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • aroyl optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • heteroaroyl optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • arylsulfonyl optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • heteroarylsulfonyl optionally substituted with C ⁇ -alkyl, C,. 6 -alkoxy, C,. 6 -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; or
  • R 7 and R 8 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally sub- stituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • R 3 , R 4 , R 5 and R 6 independently are
  • C 3 . 8 -cycloalkyl optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • C,. 6 -alkyl optionally substituted with C ⁇ -alkoxy; C ⁇ -alkylthio; hydroxy; cyano; halogen; trifluoromethyl; carboxy; or -CO-NR 7 R 8 wherein R 7 and R 8 are as defined above; or C 3 . 8 -cycloalkyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino which are optionally substituted with C ⁇ -alkyl, C,_ 6 -alkoxy, C,.
  • aryl optionally substituted with halogen, cyano, nitro, C ⁇ -alkyl, C ⁇ -alkoxy, hydroxy, trifluoromethyl, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR 7 R 8 wherein R 7 and R 8 are as defined above; or
  • R 3 and R 4 together with the carbon atom to which they are connected, and/or R 5 and R 6 together with the carbon atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substi- tuted with C.,_ 6 -alkyl, C
  • n, p and q independently are 0, 1 or 2;
  • Y is a valence bond, -O- or -N(R 7 )- wherein R 7 is as defined above;
  • A is a valence bond, C ⁇ -alkylene, C 2 _g-alkenylene, C 2 . 8 -alkynylene, C 3 . 8 -cycloalkylene or phenylene; or
  • A when Y is -N(R 7 )-, A may together with R 7 form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with C,_ 6 -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano, trifluoromethyl, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino; and
  • C ⁇ -alkyl optionally substituted with aryl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, C ⁇ -alkylsulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, heteroaryl or C 3 .
  • C 2.6 -alkynyl optionally substituted with aryl, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, C, ..6 -alkylsu-fonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, heteroaryl or C 3 . 8 -cycloalkyl which are optionally substituted with C,.
  • aryl optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C ⁇ -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C ⁇ -alkylsulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, hydroxy, amino, halogen, cyano or trifluoromethyl;
  • aroyl optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C.,_ 6 -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C g-alkylsulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C,_ 6 -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano or trifluoro- methyl; or
  • heteroaryl optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C ⁇ -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C ⁇ -alkylsulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C 1 _ 6 -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, halogen, cyano or trifluoromethyl; or
  • R 9 or R 10 may together with R 7 form a 3 to 8 membered, saturated or unsaturated, carbocyclic or heterocyclic ring optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C ⁇ -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C.,. 6 -alkylsulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C,. 6 -alkyl, C ⁇ -alkoxy, C.,_ 6 -alky-thio, hydroxy, amino, halogen, cyano or trifluoromethyl;
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
  • geometric isomers may be formed. It is intended that any geo- metric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
  • the compounds of the present invention may exist in different tautomeric 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, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydro- bromic, hydroiodic, phosphoric, sulfuric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric acids and the like.
  • pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, 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 synthe- sis.
  • 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 mo- lecular weight solvents using methods known to the skilled artisan. 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.
  • prodrugs will be functional derivatives of the compounds, which are readily convertible in vivo into the present compounds.
  • 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 may thus be used for the treatment of a wide range of conditions and disorders in which histamine H3 receptor interactions are beneficial.
  • the present invention relates to a compound of the general formula I as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • R 1 is hydrogen or a functional group.which can be converted to hydrogen in vivo;
  • R 2 is hydrogen, C,_ 6 -alkyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy or -NR 7 R 8 ,
  • R 7 and R 8 independently are
  • C 3 - 8 -cycloalkyl C ⁇ -alkoxy, C,. 6 -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 7 and R 8 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally contain- ing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C.,. 6 -alkoxy, C,. 6 -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino;
  • R 3 , R 4 , R 5 and R 6 independently are
  • C 3 . 8 -cycloalkyl optionally substituted with C,. 6 -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C.,_ 6 -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C ⁇ -alkyl C 2 . 6 -alkenyl or C 2 . 6 -alkynyl, which are optionally substituted with C ⁇ -alkoxy, C.,_ 6 -alkylthio, hydroxy, cyano, halogen, trifluoromethyl, trifluoromethoxy, carboxy, C ⁇ -alkoxycarbonyl,
  • aryl optionally substituted with halogen, cyano, nitro, C ⁇ -alkyl, C ⁇ -alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aryloxy, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or -CO-NR 9 R 10 ,
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroarylamino or C 3 . 8 -cycloalkyl, which are optionally substituted with di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with hydroxy, amino, C L e-alkylamino, di(C 1 ⁇ -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C ⁇ -alkylsulfonyl optionally substituted with C 3 . 8 -cycloalkyl, C ⁇ -alkoxy, C,_ 6 -alkylthio, hydroxy, amino, C ⁇ -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • n, p and q independently are 0, 1 or 2;
  • C ⁇ -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroaryl- amino or C 3 . 8 -cycloalkyl, which are optionally substituted with
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with di(C.,_ 6 -alkyl)a ⁇ ino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, C,_ 6 -aIkylsulfonyl optionally substituted with
  • Y is a valence bond, -O- or -N(R 12 )-,
  • C,. 6 -alkyl optionally substituted with aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino, heteroaryl- amino or C 3 . 8 -cycloalkyl, which are optionally substituted with hydroxy, amino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with hydroxy, amino, C,_ 6 -alkylamino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • A is a valence bond, C 2 relieve 8 -alkenylene, C 2 . 8 -alkynylene, C 3 . 8 -cyclo- alkylene or phenylene, or
  • Y when Y is -N(R 12 )-, A, together with R 12 and the nitrogen atom to which they are connected, may form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring system optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, C ⁇ -alkylthio, hydroxy, amino, C 1 _ 6 -alkylamino, di(C 1 .
  • R 13 , R 14 and R 15 independently are hydrogen
  • aryl C 3 . 15 -cycioalkyl, C 3 . 15 -cycloalkynyl, aroyl or heteroaryl, which are optionally substituted with aryl-C ⁇ -alkyl, heteroaryl-C ⁇ -alkyl, aryl, heteroaryl, nitro, arylamino, heteroarylamino, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C ⁇ -alkyl- sulfonyl, sulfonylamino, arylthio, heteroarylthio, aryloxy, acylamino, C,_ 6 -alkyl, C 3 .
  • R 13 and R 14 or R 13 , R 14 and R 15 when they do not represent hydrogen, may be joined by one or more bridging linkers such as a valence bond, C ⁇ -alkylene,
  • R and R 17 independently are hydrogen
  • aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl or heteroarylsulfonyl which are optionally substituted with di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino,
  • C 3 . 8 -cycloalkyl C.,_ 6 -alkoxy, amino, di(C 1 . 6 -alkyl)amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, aroyl, heteroaroyl, arylsulfonyl, arylamino or heteroarylamino, or
  • R 16 and R 17 together with the nitrogen atom to which they are connected, form a 3 to 8 membered, saturated or unsaturated, heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with C,.
  • the invention relates to a method for the treatment of 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' as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the present compounds may possess histamine H3 receptor antagonistic activity and would accordingly be useful in the treatment of a wide range of conditions and disorders in which a histamine H3 receptor blockade 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 and/or prevention 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 atheroscle- rosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
  • disorders and diseases related to overweight or obesity such as atheroscle- rosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially Type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis 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 and/or prevention of IGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the 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. Furthermore, 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 stimulants or as sedatives.
  • the present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypo- thalamo-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 present novel compounds may also interact with the vanilloid receptors, the serotonin receptors, and the adrenergic receptors and may be useful for the treatment of diseases associated with these receptors.
  • the compounds of the present invention may be vanilloid receptor agonists, and thus be useful for the treatment of obesity by enhancement of the metabolic rate and energy expenditure. Further, by virtue of their interaction with the vanilloid receptor the compounds of the present invention may be useful for the treatment of pain or neurogenic inflammation or inflammatory painful conditions.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders related to the vanilloid receptor, such as for the treatment and/or prevention of pain, neurogenic inflammation or obesity.
  • the present compounds may interact with the 5-HT3 receptor (sero- tonin-3-receptor) and may accordingly be useful as antiemetics, in particular the chemotherapy-induced emesis.
  • 5-HT3 antagonists include treatment of central nervous system disorders such as anxiety, schizophre- nia, drug abuse and withdrawal symptoms, and pathological and age-associated amnesia.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or preven- tion of diseases and disorders related to the serotonin-3 receptor (5-HT3), such as for the treatment of emesis.
  • a pharmaceutical composition for the treatment and/or preven- tion of diseases and disorders related to the serotonin-3 receptor (5-HT3) such as for the treatment of emesis.
  • the present compounds may interact with the adrenergic alpha-2 receptor and thus be useful for the treatment of hypertension and of conditions associ- ated with overexpression or hypersensitization of the adrenergic alpha-2 receptor, especially obesity, withdrawal symptoms to an adrenergic alpha-2 agonist, neurological disorders (especially orthostatic hypotension), multiple system atrophy, diabetes mellitus, benign prostatic hyperplasia or drug induced sensitization of the adrenergic alpha-2 receptor.
  • the compounds of the present invention by virtue of their interaction with the alpha-2 receptor, may be useful as sedatives and hypnotics (sleep inducing agents) or as stimulants.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or preven- tion of diseases and disorders related to the alpha-2 adrenergic receptor, such as for use as a sleep inducing agent.
  • the present compounds may be administered in combination with one or more further pharmacologically active substances eg selected from antiobesity agents, antidiabet- ics, antihypertensive agents, agents for the treatment and/or prevention of complica- tions resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • pharmacologically active substances eg selected from antiobesity agents, antidiabet- ics, antihypertensive agents, agents for the treatment and/or prevention of complica- tions resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be adminis- tered 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, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TR
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1 ) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, insulin sensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of glu- coneogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR and RXR agonists and agents
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulphonylurea eg tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea eg tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide eg metformin.
  • the present compounds are administered in combination with a meglitinide eg repaglinide.
  • the present compounds are administered in combination with a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 to Dr. Reddy's Research Foundation.
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 to Dr. Reddy's Research Foundation.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with na- teglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyrox- ine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyrox- ine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and met- formin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ - blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enala- pril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further refer- ence can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro,
  • 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 pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance 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 sublingual), transdermal, intracisternal, intraperitoneal, vaginal and par- enteral (including subcutaneous, intramuscular, intrathecal, intravenous and in- tradermal) route, the oral route being preferred.
  • suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and par- enteral (including subcutaneous, intramuscular, intrathecal, intravenous and in- tradermal) route, the oral route being preferred.
  • 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.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appro- priate, 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 according 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 powders 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.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • 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 adminis- tered 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.
  • a compound according to the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound according to the invention with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
  • 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 present compounds 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 suitable for intravenous, intramuscular, subcutaneous and intraperitoneal admini- stration.
  • 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, phospholipids, 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 compounds according to the invention 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. These 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.
  • 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:
  • 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 sub- stances.
  • the preparation of the compounds of this invention can be realized in many different ways.
  • the preparation of imidazoles of the formula III has been described in the literature (see e.g. F. B. Stocker et al., J. Org. Chem. 1966, 31, 2380; idem, ibid. 1990, 55, 3370; T. Vitali et al., II Farmaco 1967, 22, 821 ; idem, ibid. 1965, 20, 634; S.
  • LG leaving group
  • compounds of the formula lb can be synthesized from 4,5,6,7-tetra- hydroimidazo[4,5-c]pyridines III by treating the latter with suitable activated derivatives of carboxylic acids, such as acyl imidazoles, anhydrides, acid chlorides or active esters, or any of the derivatives commonly used for the preparation of carboxamides, under appropriate conditions.
  • suitable activated derivatives of carboxylic acids such as acyl imidazoles, anhydrides, acid chlorides or active esters, or any of the derivatives commonly used for the preparation of carboxamides, under appropriate conditions.
  • Compounds of the formula Ic can be prepared by treating 4,5,6,7-tetrahydro- imidazo[4,5-c]pyridines III with isocyanates Z-A-NCO or with synthetic equivalents thereof, such as carbamoyl chlorides Z-A-N(R 12 )-CO-CI under suitable conditions.
  • compounds of the formula le can be prepared by treating 4,5,6,7-tetrahydro- imidazo[4,5-c]pyridines III with isothiocyanates Z-A-NCS or with synthetic equivalents thereof, such as thiocarbamoyl chlorides Z-A-N(R 12 )-CS-CI under suitable conditions.
  • the starting materials are either known compounds or compounds, which may be prepared in analogy with the preparation of similar known compounds.
  • HOBt ⁇ /-hydroxybenzotriazole, 1 -hydroxybenzotriazole
  • HPLC-systems from Merck-Hitachi (HibarTM RT 250-4, LichrosorbTM RP 18, 5.0 ⁇ m, 4.0 x 250 mm, gradient elution, 20% to 80% acetonitrile in water within 30 min, 1.0 mL/min, detection at 254 nm) and Waters (SymmetryTM, C- ⁇ 8 , 3.5 ⁇ m, 3.0 x 150 mm, gradient elution, 5% to 90% acetonitrile in water within 15 min, 1.0 mL/min, detection at 214 nm) were used.
  • the reverse phase analysis was performed using UV detections at 214, 254, 276 and 301 nm on a 218TP54 4.6 mm x 150 mm C-18 silica column, which was eluted at 1 mL/min at 42 °C.
  • the column was equilibrated with 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid in water and eluted by a linear gradient from 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid to 90% acetonitrile and 10% of a solution of 0.5% trifluoroacetic acid over 15 min.
  • the purified amine III was then acylated as in general procedure A or by any other, conventional method.
  • reaction mixture is concentrated on a rotavapor at a bath temperature of 35°C.
  • a solution of sodium ethanolate is prepared by dissolving 1.4 g (60 mmol) of sodium in 150 mL of dry ethanol. Then 4.8 g (60 mmol) of formamidine hydrochloride and 7.3 g (20 mmol) of 1-benzyl-5-bromohexahydroazepin-4-one hydrobromide as well as 80 mL chloroform are added successively. After keeping at reflux for about 8 hours the mixture is cooled and treated with a solution of 40 mmol of sodium hydroxide in dry methanol. The reaction mixture is concentrated on a rotavapor and the residue purified by column chromatography on silicagel with chloroform/methanol 9:1 as eluent.
  • Example 1 5-(3-Cyclohexylpropanoyl)-4,4-dimethyl-4,5,6,7-tetrahydroimidazo[4,5-c]- pyridine oxalic acid salt
  • Example 8 5-[3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)propanoyl]-4, 5,6,7- tetrahydroimidazo[4,5-c]pyridine
  • Example 12 4-(2-Cyclohexylethyl)-5-(ethylaminocarbonyl)-4,5,6,7-tetrahydro- imidazo[4,5-c]pyridine
  • Example 13 4-(2-Cyclohexylethyl)-5-(2,4-dichlorobenzylaminocarbonyl)-4, 5,6,7- tetrahydroimidazo[4,5-c]pyridine
  • the compound was prepared from 4,5,6,7-tetrahydro-1/-/-imidazo[4,5-c]pyridine and 4-(te/ ⁇ -butyl)benzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2,3-dimethylbenzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-phenyl-1-butanol oxalate.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-phenyl-1-butanol oxalate.
  • the compound was prepared from 4,5,6, 7-tetrahydro-1 H-imidazo[4,5-c]pyridine and cyclopentylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine and 2-methylbenzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-(2-methoxyphenyl)-1 -ethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine and 2-(3-methylphenyl)-1 -ethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1 -adamantylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 3,4-dimethylbenzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1/-/-imidazo[4,5-c]pyridine and cyclohexen-4-ylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2,4-dimethylbenzylalcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-(2-methylphenyl)ethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1 -naphthylmethanol.
  • the compound was prepared from 4,5,6N-tetrahydro-1H-imidazo[4,5-c]pyridine and 4-isopropylbenzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1/-/-imidazo[4,5-c]pyridine and 2-naphthylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-methylbiphenyl-3-ylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 4-ethylbenzyl alcohol.
  • the compound was prepared from 4,5,6, 7-tetrahydro-1 H-imidazo[4,5-c]pyridine and 2-thienylmethanol.
  • Example 36 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine-5-carboxylic acid 2-thiophen- 2-ylethyl ester oxalate
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-(2-thienyl)-1 -ethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-(3-thienyl)-1 -ethanol.
  • Example 38 4,5,6,7-Tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid 4-methoxy- 2,3-dimethylbenzyl ester oxalate
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2,3-dimethyl-4-methoxybenzyl alcohol.
  • the compound was prepared from 4-trifluoromethyl-4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridine and benzyl alcohol.
  • Example 40 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine-5-carboxylic acid 2-cyclohexylethyl ester oxalate
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-cyclohexyl-1 -ethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and cyclohexylmethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-chlorobenzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 2-(trifluoromethyl)benzyl alcohol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1-phenylethanol.
  • the compound was prepared from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 4-benzylpiperidine according to the following, general procedure for the preparation of ureas:
  • Example 46 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine-5-carboxylic acid ⁇ /-methyl- ⁇ /- benzylamide oxalate
  • the compound was prepared in the same way as disclosed for example 45 from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and benzylmethylamine.
  • the compound was prepared in the same way as disclosed for example 45 from 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and benzylmethylamine .
  • the reaction mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous sodium hydrogen sulfate solution (100 mL). A 1 N solution of sodium hydroxide was added to the aqueous solution until pH 12 was obtained. It was extracted with ethyl acetate (2 x 100 mL). These organic extracts were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloro- methane/methanol/25% aqueous ammonia (100:10:1 ) as eluent to give 125 mg of the title compound.
  • the reaction mixture was stirred for 16 h at room temperature. It was diluted with ethyl acetate (100 mL) and washed with 10% aqueous sodium hydrogensulfate solution (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 60 mL): It was added a 1 N sodium hydroxide solution until pH 12 was obtained. It was extracted with ethyl acetate (3 x 90 mL). These extracts were combined and dried over magne- sium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1 ) as eluent, to give 50 mg of the title compound.
  • the title compound was transferred into its oxalate salt by dissolving in ethyl acetate (20 mL) and addition of a solution of oxalic acid in ethyl acetate (20 mL). The precipitation was collected and washed with ethyl acetate (10 mL). It was dried in vacuo.
  • the title compound was transferred into its oxalate salt: The title compound was dissolved in ethyl acetate (15 mL). A solution of oxalic acid (58 mg, 0.64 mmol) in ethyl acetate (15 mL) was added. The precipitation was collected, washed with ethyl acetate (10 mL) and dried in vacuo.
  • EDC (0.45 g, 2.4 mmol) was added to a solution of 1-hydroxy-7-azabenzo- triazole (0.32 g, 2.4 mmol) and 2-norbornaneacetic acid (0.338 mL, 2.4 mmol) in di- chloromethane (30 mL).
  • the reaction mixture was stirred for 20 min at 0 °C.
  • 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine dihycrochloride (0.50 g, 2.3 mmol) was added.
  • Ethyldiisopropylamine (0.40 mL, 2.3 mmol) was added.
  • the reaction mixture was stirred for 16 h at room temperature.
  • Example 52 4-Pentylphenyl-(1 ,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)methanone hydrochloride
  • the oxalate was dissolved in water (50 mL) and sodium hydroxide (2 mL, 4N in water) was added.
  • the free base was extracted with ethyl acetate (2 x 100 mL), and after drying (MgS04) and concentration it was redissolved in hydrochloric acid (1 N in water). Concentration and precipitation from acetone yielded 0.45 g (36%) of the title compound as colourless solid.
  • the compound was prepared in the same way as example 52 from 4-trifluoro- methoxybenzoic acid and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
  • Example 54 4-Trifluoromethylphenyl-(1 ,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5- yl)methanone oxalate
  • the compound was prepared in the same way as example 52 from 4-trifluoro- methylbenzoic acid and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
  • Example 55 4-lsobutylphenyl-(1 ,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5- yl)methanone oxalate
  • the compound was prepared in the same way as example 52 from 4-isobutylbenzoic acid and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
  • Example 56 4-Chlorophenyl-(1 ,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5- yl)methanone oxalate
  • Rat cerebral cortex was homogenized in ice cold K-Hepes, 5 mM MgCI 2 pH 7.1 buffer. After two differential centrifugations the last pellet was resuspended in fresh Hepes buffer containing 1 mg/mL bacitracin. Aliquots of the membrane suspension (400 mg/mL) were incubated for 60 min at 25°C with 30 pM [ 125 l]-iodoproxifan, a known histamine H3 receptor antagonist, and the test compound at various concentrations. The incubation was stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 h with 0.5% polyethyle- neimine. The radioactivity retained on the filters was counted using a Cobra II auto gamma counter. The radioactivity of the filters was indirectly proportional to the bind- ing affinity of the tested compound. The results were analyzed by nonlinear regression analysis.
  • Binding assay II The H3-receptor agonist ligand R- ⁇ -methyl[ 3 H]histamine was incubated with isolated rat cortex cell-membranes at 25 °C for 1 h, followed by a filtration of the incubate through Whatman GF/B filters. Radioactivity retained on the filters was measured using a beta counter.
  • Rat cerebral cortex was homogenized in 10 volumes (w/w) ice-cold Hepes buffer (20 mM Hepes, 5 mM MgCI 2 pH 7.1 (KOH) + 1 mg/mL bacitracin) using a Ul- tra-Turrax homogenizer for 30 seconds. The homogenate was centrifuged at 140 g in 10 min. The supernatant was transferred to a new test tube and centrifuged for 30 min at 23 000 g.
  • Pellet was resuspended in 5-10 mL Hepes buffer, homogenized and centrifuged for 10 min at 23 000 g. This short centrifugation step is repeated twice. After the last centrifugation the pellet was resuspended in 2-4 mL Hepes buffer and the protein concentration was determined. The membranes were diluted to a protein concentration of 5 mg/mL using Hepes buffer, aliquoted and stored at -80 °C until use
  • test-compound 100 ⁇ L membrane (200 ⁇ g/mL), 300 ⁇ L.
  • Hepes buffer and 50 ⁇ L R- ⁇ -methyl[ 3 H]histamine (1 nM) were mixed in a test tube.
  • the compounds to be tested were dissolved in DMSO and further diluted in H 2 O to the desired concentrations.
  • Radioligand and membranes were diluted in Hepes buffer + 1 mg/mL bacitracin. The mixture was incubated for 60 min at 25 °C. Incubation was terminated by adding 5 mL ice-cold 0.9 % NaCl, followed by rapid filtration through Whatman GF/B filters pre-treated for 1 h with 0.5 % polyethyleneimine.
  • the filters were washed with 2 x 5 mL ice-cold NaCl. To each filter a 3 mL scintillation cocktail was added and the radioactivity retained was measured with a Packard Tri-Carb beta counter. IC 5 o values were calculated by non-linear regression analysis of binding curves (6 points minimum) using the windows program GraphPad Prism, GraphPad software, USA.
  • the present compounds of the formula (I) When tested, the present compounds of the formula (I) generally showed a high binding affinity to the histamine H3 receptor.
  • the compounds according to the invention have an IC 50 value as deter- mined by one or both of the assays of less than 1 ⁇ M, more preferred of less than 500 nM and even more preferred of less than 100 nM.
  • the ability of the present compounds to reduce weight was determined using the in vivo open cage Schedule-fed rat model.
  • Sprague-Dawley (SD) male rats of an age of about V ⁇ to 2 months and a weight of about 250 g were habituated to the presence of food (Altromin pelleted rat chow) in their home cage only during three hours in the morning from 9 to12 a.m. all days a week. Water was present ad libitum. As the consumption of food stabilised after 7 to 9 days, the animals were ready for use.
  • food Altromin pelleted rat chow
  • the animals were tested twice a week. During the test sessions, the test compound was administered intraperitoneally 30 minutes before the start of the sessions. One group of 9 animals was administered the test compound at a dose of 15 mg/kg and another group of 11 animals was administered the test compound at a dose of 30 mg/kg. A control group of 11 animals was administered the vehicle consisting of NaCl 0.9% and Chremophor 5%. Food and water intake were monitored at 1 , 2 and 3 h post administration. 138

Abstract

L'invention concerne une nouvelle classe de composés imidazoles substitués (I), des compositions pharmaceutiques contenant ces composés, ainsi que l'utilisation de ceux-ci dans le traitement et/ou la prévention de maladies et troubles associés au récepteur H3 de l'histamine. Ces composés sont notamment utiles dans le traitement et/ou la prévention de maladies et troubles, dans lesquels une interaction avec le récepteur H3 de l'histamine est bénéfique.
EP00918714A 1999-04-16 2000-04-13 Imidazoles substitues, leur preparation et utilisation Withdrawn EP1173438A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DK50899 1999-04-16
DKPA199900508 1999-04-16
DK134599 1999-09-22
DKPA199901345 1999-09-22
DK200000042 2000-01-12
DKPA200000042 2000-01-12
PCT/DK2000/000179 WO2000063208A1 (fr) 1999-04-16 2000-04-13 Imidazoles substitues, leur preparation et utilisation

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