NO328714B1 - Aryl and heteroarylpiperazines, pharmaceutical preparations comprising at least one such compound, and uses of such compounds for the preparation of pharmaceutical preparations - Google Patents

Aryl and heteroarylpiperazines, pharmaceutical preparations comprising at least one such compound, and uses of such compounds for the preparation of pharmaceutical preparations Download PDF

Info

Publication number
NO328714B1
NO328714B1 NO20043709A NO20043709A NO328714B1 NO 328714 B1 NO328714 B1 NO 328714B1 NO 20043709 A NO20043709 A NO 20043709A NO 20043709 A NO20043709 A NO 20043709A NO 328714 B1 NO328714 B1 NO 328714B1
Authority
NO
Norway
Prior art keywords
alkyl
compound
cycloalkyl
alkoxy
halogen
Prior art date
Application number
NO20043709A
Other languages
Norwegian (no)
Other versions
NO20043709L (en
Inventor
Rolf Hohlweg
Bernd Peschke
Florencio Zaragoza Dorwald
Henrik Stephensen
Ingrid Pettersson
Original Assignee
High Point Pharmaceuticals Llc
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 High Point Pharmaceuticals Llc filed Critical High Point Pharmaceuticals Llc
Publication of NO20043709L publication Critical patent/NO20043709L/en
Publication of NO328714B1 publication Critical patent/NO328714B1/en

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

Description

Oppfinnelsens område Field of the invention

Den foreliggende oppfinnelse vedrører nye aryl- og heteroarylpiperaziner, anvendelser av slike forbindelser til fremstilling av farmasøytiske preparater, og farmasøytiske preparater som omfatter forbindelsene. De foreliggende forbindelser oppviser en sterk og selektiv bindingsaffinitet til histamin H3-reseptoren, noe som indikerer histamin H3-reseptor-antagonistisk, -inversagonistisk eller -agonistisk aktivitet. Som et resultat av dette kan forbindelsene anvendes til behandlingen av bestemte sykdommer og forstyrrelser relatert til histamin H3-reseptoren. The present invention relates to new aryl and heteroaryl piperazines, uses of such compounds for the production of pharmaceutical preparations, and pharmaceutical preparations comprising the compounds. The present compounds exhibit a strong and selective binding affinity to the histamine H3 receptor, indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds can be used for the treatment of certain diseases and disorders related to the histamine H3 receptor.

Oppfinnelsens bakgrunn The background of the invention

Eksistensen av histamin H3-reseptoren har vært kjent i flere år, og reseptoren har aktuell interesse for utviklingen av nye medikamenter. Nylig er den humane histamin H3-reseptor blitt klonet. Histamin H3-reseptoren er en presynaptisk autoreseptor lokalisert både i sentralnervesystemet og det perifere nervesystem, huden og i slike organer som lunge, tynntarm, sann-synligvis milten og mage- og tarmkanalen. Nyere bevismateriale tyder på at H3-reseptoren oppviser intrinsisk, konstitutiv aktivitet, in vitro så vel som in vivo (det vil si at den er aktiv i fravær av en agonist). Forbindelser som virker som inversagonister, kan hemme denne aktiviteten. Histamin H3-reseptoren er blitt påvist å regulere frigjørelsen av histamin og også av andre neurotransmittere, slik som serotonin og acetylcholin. En histamin H3-reseptorantagonist eller -inversagonist ville derfor forventes å øke frigjørelsen av disse neurotransmitterne i hjernen. En histamin H3-reseptoragonist fører derimot til en hemming av biosyntesen av histamin og en hemming av frigjørelsen av histamin, og også av andre neurotransmittere, slik som serotonin og acetylcholin. Disse funn tyder på at histamin H3-resep-toragonister, -inversagonister og -antagonister kan være viktige mediatorer for nevronal aktivitet. Følgelig er histamin H3-reseptoren et viktig mål for nye terapeutika. The existence of the histamine H3 receptor has been known for several years, and the receptor has current interest in the development of new drugs. Recently, the human histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autoreceptor located both in the central nervous system and the peripheral nervous system, the skin and in such organs as the lung, small intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor exhibits intrinsic, constitutive activity, in vitro as well as in vivo (that is, it is active in the absence of an agonist). Compounds that act as inverse agonists can inhibit this activity. The histamine H3 receptor has been shown to regulate the release of histamine and also of other neurotransmitters, such as serotonin and acetylcholine. A histamine 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, on the other hand, 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. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists may be important mediators of neuronal activity. Consequently, the histamine H3 receptor is an important target for new therapeutics.

Forbindelser som ligner på forbindelsene ifølge den foreliggende oppfinnelse, er tidligere blitt beskrevet, jf. Compounds similar to the compounds according to the present invention have previously been described, cf.

J. Med. Chem., 1999, 42, 336; J. Med. Chem., 1992, 35, 2369; J. Med. Chem., 1999, 42, 336; J. Med. Chem., 1992, 35, 2369;

DE 2804096; J. Org. Chem., 1996, 61, 3849; Bull. Soc. Chim. Fr., 1969, 319; WO 00/66578; WO 99/21845 og J. Med. Chem., 1968, 11(6), 1144-1150. Disse litteraturreferansene verken åpenbarer eller foreslår imidlertid at disse forbindelsene kan ha en histamin H3-reseptorantagonistisk eller -agonistisk aktivitet. DE 2804096; J. Org. Chem., 1996, 61, 3849; Bull. Soc. Chim. Fr., 1969, 319; WO 00/66578; WO 99/21845 and J. Med. Chem., 1968, 11(6), 1144-1150. However, these literature references neither disclose nor suggest that these compounds may have histamine H3 receptor antagonistic or agonistic activity.

Flere publikasjoner beskriver fremstillingen og anven-delsen av histamin H3-agonister og -antagonister. Flesteparten av disse er imidazolderivater. Nylig er imidlertid noen imid-azolfrie ligander for histamin H3-reseptoren blitt beskrevet (se f.eks. Linney et al., J. Med. Chem., 2000, 43, 2362-2370; Several publications describe the production and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives. Recently, however, some imide-azole-free ligands for the histamine H3 receptor have been described (see, e.g., Linney et al., J. Med. Chem., 2000, 43, 2362-2370;

US 6 316 475; WO 01/66534 og WO 01/74810). Disse forbindelsene atskiller seg imidlertid strukturelt fra de foreliggende forbindelser . US 6,316,475; WO 01/66534 and WO 01/74810). However, these compounds differ structurally from the present compounds.

På bakgrunn av interessen på fagområdet for histamin H3-reseptoragonister, -inversagonister og -antagonister ville nye forbindelser som reagerer med histamin H3-reseptoren, være et svært ønskelig bidrag til teknikkens stand. Den foreliggende oppfinnelse gir et slikt bidrag til teknikkens stand basert på det funn at en ny klasse av aryl- og heteroarylpiperaziner har en sterk og spesifikk affinitet til histamin H3-reseptoren. Based on the interest in the field of histamine H3 receptor agonists, inverse agonists and antagonists, new compounds that react with the histamine H3 receptor would be a highly desirable contribution to the state of the art. The present invention makes such a contribution to the state of the art based on the finding that a new class of aryl and heteroarylpiperazines has a strong and specific affinity for the histamine H3 receptor.

På grunn av deres interaksjon med histamin H3-reseptoren er de foreliggende forbindelser anvendbare ved behandlingen av et bredt spekter av tilstander og forstyrrelser hvor en interaksjon med histamin H3-reseptoren er gunstig. Forbindelsene kan således finne anvendelse f.eks. ved behandlingen av sykdommer i sentralnervesystemet, det perifere nervesystem, det kardiovaskulære system, det pulmonale system, det gastrointesti-nale system og det endokrinologiske system. Because of their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders where an interaction with the histamine H3 receptor is beneficial. The compounds can thus find application, e.g. 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.

Definisjoner Definitions

I strukturformlene som er angitt her og gjennom den foreliggende beskrivelse, har de følgende uttrykk den angitte betydning: Uttrykket "halogen" betyr F, Cl, Br eller I. In the structural formulas set forth herein and throughout the present specification, the following terms have the meanings indicated: The term "halogen" means F, Cl, Br or I.

Uttrykket "alkyl" representerer, slik det her er brukt, en mettet, forgrenet eller rettkjedet hydrokarbongruppe som har det angitte antall karbonatomer. Uttrykkene "Ci-3-alkyl", "Ci-8-alkyl" og "Ci_i0-alkyl" representerer således, slik de her er brukt, mettede, forgrenede eller rettkjedede hydrokarbongrupper som henholdsvis har fra 1 til 3 karbonatomer, 1-8 karbonatomer og fra 1 til 10 karbonatomer. Typiske alkylgrupper omfatter, men er ikke begrenset til, metyl, etyl, n-propyl, isopropyl, butyl, isobutyl, sek.-butyl, tert.-butyl, pentyl, heksyl og lignende. The term "alkyl" as used herein represents a saturated, branched or straight chain hydrocarbon group having the indicated number of carbon atoms. The terms "Ci-3-alkyl", "Ci-8-alkyl" and "Ci-10-alkyl" thus, as used herein, represent saturated, branched or straight-chain hydrocarbon groups which respectively have from 1 to 3 carbon atoms, 1-8 carbon atoms and from 1 to 10 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

Uttrykket "alkenyl" representerer, slik det her er brukt, en forgrenet eller rettkjedet hydrokarbongruppe som har det angitte antall karbonatomer og minst én dobbeltbinding. Uttrykkene "C2-8_alkenyl" og "C2-io-alkenyl" representerer således, slik de her er brukt, en forgrenet eller rettkjedet hydrokarbongruppe som henholdsvis har fra 2 til 8 karbonatomer, fra 2 til 10 karbonatomer og minst én dobbeltbinding. Eksempler på slike grupper omfatter, men er ikke begrenset til, etenyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-heksenyl, 2-heksenyl, 1-heptenyl, 2-heptenyl, 1-oktenyl, 2-oktenyl, 2-nonenyl, 2-decenyl og lignende. The term "alkenyl" as used herein represents a branched or straight chain hydrocarbon group having the indicated number of carbon atoms and at least one double bond. The terms "C2-8_alkenyl" and "C2-io-alkenyl" thus, as used herein, represent a branched or straight-chain hydrocarbon group which respectively has from 2 to 8 carbon atoms, from 2 to 10 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, 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.

Uttrykket "alkynyl" representerer, slik det her er brukt, en forgrenet eller rettkjedet hydrokarbongruppe som har det angitte antall karbonatomer og minst én trippelbinding. Uttrykket "C2-8_alkynyl" representerer således, slik det her er brukt, en forgrenet eller rettkjedet hydrokarbongruppe som har fra 2 til 8 karbonatomer og minst én trippelbinding. Eksempler på slike grupper omfatter, men er ikke begrenset til, etynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-heksynyl, 2-heksynyl, 2-heptynyl, 1-oktynyl, 2-oktynyl og lignende. The term "alkynyl" as used herein represents a branched or straight chain hydrocarbon group having the indicated number of carbon atoms and at least one triple bond. The term "C2-8_alkynyl" thus, as used herein, represents a branched or straight chain 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, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 2-heptynyl, 1-octynyl, 2-octynyl and the like.

Uttrykket "forgrenet C4-6-alkyl" representerer, slik det her er brukt, en mettet, forgrenet hydrokarbongruppe som har fra 4 til 6 karbonatomer. Typiske forgrenede Ci-s-alkylgrupper omfatter, men er ikke begrenset til, 1-metylpropyl, tert.-butyl, 1-etylpropyl, 1,1-(dimetyl)propyl, isopentyl-l-etylbutyl, 1,1-(di-metyl)butyl, 1,1 (dimetyl)pentyl, 1-etylpentyl, 1,1-(dimetyl)-heksyl, 1-etylheksyl og lignende. The term "branched C 4-6 alkyl" as used herein represents a saturated, branched hydrocarbon group having from 4 to 6 carbon atoms. Typical branched C 1-5 alkyl groups include, but are not limited to, 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1-(dimethyl)propyl, isopentyl-1-ethylbutyl, 1,1-(di- methyl)butyl, 1,1 (dimethyl)pentyl, 1-ethylpentyl, 1,1-(dimethyl)hexyl, 1-ethylhexyl and the like.

Uttrykket "forgrenet C4_6-alkenyl" representerer, slik det her er brukt, en forgrenet hydrokarbongruppe som har fra 4 til 6 karbonatomer og minst én dobbeltbinding. Typiske forgrenede C4_6-alkenylgrupper omfatter, men er ikke begrenset til, l-etylprop-2-enyl, 1,1-(dimetyl)prop-2-enyl, l-etylbut-3-enyl, 1,1-(dimetyl)but-2-enyl, 1,1-(dimetyl)pent-3-enyl, l-etylpent-2-enyl, 1,1-(dimetyl)pent-3-enyl, 1,1-(dimetyl)heks-3-enyl, 1-etylheks-4-enyl og lignende. The term "branched C4-6 alkenyl" as used herein represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one double bond. Typical branched C4-6 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.

Uttrykket "forgrenet C4-6-alkynyl" representerer, slik det her er brukt, en forgrenet hydrokarbongruppe som har fra 4 til 6 karbonatomer og minst én trippelbinding. Typiske forgrenede C4_6-alkynylgrupper omfatter, men er ikke begrenset till, l-etylprop-2-ynyl, 1,1-(dimetyl)prop-2-ynyl, l-etylbut-3-ynyl, 1,1-(dimetyl)but-2-ynyl, 1,1-(dimetyl)pent-3-ynyl, l-etylpent-2-ynyl, 1,1-(dimetyl)pent-3-ynyl, 1,1-(dimetyl)heks-3-ynyl, 1-etylheks-4-ynyl og lignende. The term "branched C 4-6 alkynyl" as used herein represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one triple bond. Typical branched C4-6 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, l-ethylpent-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1,1-(dimethyl)hex-3- ynyl, 1-ethylhex-4-ynyl and the like.

Uttrykket "Ci-6-alkoksy" henviser, slik det her er brukt, til radikalet -0-Ci_6-alkyl, hvor Ci-6-alkyl er som definert ovenfor. Representative eksempler er metoksy, etoksy, n-propoksy, isopropoksy, butoksy, sek.-butoksy, tert.-butoksy, pentoksy, isopentoksy, heksoksy, isoheksoksy og lignende. The term "C 1-6 -Alkoxy" refers, as used here, to the radical -O-C 1-6 -alkyl, where C 1-6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

Uttrykket "C2-io-alkanoyl" henviser, slik det her er brukt, til radikalet -C (=0) Ci_9-alkyl, hvor Ci-g-alkyl er en mettet, forgrenet eller rettkjedet hydrokarbongruppe som har fra 1 til 9 karbonatomer. Representative eksempler er acetyl, propionyl, butanoyl, pentanoyl, heksanoyl, heptanoyl, oktanoyl, nonanoyl, dekanoyl og lignende. The term "C2-10-alkanoyl" as used herein refers to the radical -C (=O)C1-9-alkyl, where C1-8-alkyl is a saturated, branched or straight chain hydrocarbon group having from 1 to 9 carbon atoms. Representative examples are acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like.

Uttrykket "Ci-6-alkylamino" henviser, slik det her er brukt, til radikalet -NH-Ci-6-alkyl, hvor Ci-6-alkyl er som definert ovenfor. Representative eksempler er metylamino, etylamino, isopropylamino, n-propylamino, butylamino, pentylamino, heksyl-amino og lignende. The term "Ci-6-alkylamino" refers, as used here, to the radical -NH-Ci-6-alkyl, where Ci-6-alkyl is as defined above. Representative examples are methylamino, ethylamino, isopropylamino, n-propylamino, butylamino, pentylamino, hexylamino and the like.

Uttrykket "di-Ci-6-alkylamino" henviser, slik det her er brukt, til radikalet -N (Ci-6-alkyl) 2, hvor Ci-6-alkyl er som definert ovenfor. Det skal forstås at Ci-6-alkylgruppene kan være like eller forskjellige. Representative eksempler er dimetyl-amino, metyletylamino, dietylamino, diisopropylamino, di-n-propylamino, dibutylamino, dipentylamino, diheksylamino og lignende. The term "di-Ci-6-alkylamino" refers, as used herein, to the radical -N (Ci-6-alkyl) 2 , where Ci-6-alkyl is as defined above. It should be understood that the C 1-6 alkyl groups may be the same or different. Representative examples are dimethylamino, methylethylamino, diethylamino, diisopropylamino, di-n-propylamino, dibutylamino, dipentylamino, dihexylamino and the like.

Uttrykket "C3-5-sykloalkyl" representerer, slik det her er brukt, en monosyklisk, karbosyklisk gruppe som har fra 3 til 8 karbonatomer. Representative eksempler er syklopropyl, syklobutyl, syklopentyl og lignende. The term "C 3-5 cycloalkyl" as used herein represents a monocyclic carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like.

På samme måte representerer uttrykkene "C3_6-sykloalkyl" og "C3-8-sykloalkyl", slik de her er brukt, monosykliske, karbosykliske grupper som henholdsvis har fra 3 til 6 karbonatomer og fra 3 til 8 karbonatomer. Similarly, the terms "C3-6-cycloalkyl" and "C3-8-cycloalkyl" as used herein represent monocyclic carbocyclic groups having from 3 to 6 carbon atoms and from 3 to 8 carbon atoms, respectively.

Uttrykket "C3-7-sykloalkenyl" representerer, slik det her er brukt, en monosyklisk, karbosyklisk, ikke-aromatisk gruppe som har fra 3 til 7 karbonatomer og minst én dobbeltbinding. Representative eksempler er syklopropenyl, syklobutenyl, syklopentenyl og lignende. The term "C3-7-cycloalkenyl" as used herein 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.

På samme måte representerer uttrykket "C3_6-sykloalken-yl" en monosyklisk, karbosyklisk, ikke-aromatisk gruppe som har fra 3 til 6 karbonatomer og minst én dobbeltbinding. Similarly, the term "C3-6-cycloalken-yl" represents a monocyclic, carbocyclic, non-aromatic group having from 3 to 6 carbon atoms and at least one double bond.

Uttrykket "C3-6-sykloalkyl-Ci-3-alkyl" henviser, slik det her er brukt, til radikalet -Ci-3-alkyl-C3_6-sykloalkyl, hvor C3_6-sykloalkyl og Ci_3-alkyl er som definert ovenfor. The term "C3-6-cycloalkyl-C1-3-alkyl" refers, as used here, to the radical -C1-3-alkyl-C3-6-cycloalkyl, where C3-6-cycloalkyl and C1-3-alkyl are as defined above.

Uttrykket "C3-6-sykloalkenyl-Ci-3-alkyl" henviser, slik det her er brukt, til radikalet -Ci-3-alkyl-C3-6-sykloalkenyl, hvor C3-6-sykloalkenyl og Ci-3-alkyl er som definert ovenfor. The term "C3-6-cycloalkenyl-C1-3-alkyl" refers, as used herein, to the radical -C1-3-alkyl-C3-6-cycloalkenyl, where C3-6-cycloalkenyl and C1-3-alkyl are as defined above.

Uttrykket "C3-8-sykloalkyloksy" henviser, slik det her er brukt, til radikalet -0-C3-8-sykloalkyl, hvor C3_8-sykloalkyl er som definert ovenfor. Representative eksempler er syklo-propyloksy, syklobutyloksy, syklopentyloksy, sykloheksyloksy, sykloheptyloksy, syklooktyloksy og lignende. The term "C3-8-cycloalkyloxy" refers, as used herein, to the radical -O-C3-8-cycloalkyl, where C3-8-cycloalkyl is as defined above. Representative examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.

Uttrykket "C4-9-sykloalkanoyl" henviser, slik det her er brukt, til radikalet -C (=0)-C3_8-sykloalkyl, hvor C3-8-sykloalkyl er som definert ovenfor. Representative eksempler er syklo-propylkarbonyl, syklobutylkarbonyl, syklopentylkarbonyl, syklo-heksylkarbonyl, sykloheptylkarbonyl, syklooktylkarbonyl og lignende. The term "C4-9-cycloalkanoyl" refers, as used here, to the radical -C (=0)-C3-8-cycloalkyl, where C3-8-cycloalkyl is as defined above. Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like.

Uttrykket "Ci-6-alkylsulfonyl" henviser, slik det her er brukt, til radikalet -S (=0) 2-Ci-6-alkyl, hvor Ca-6-alkyl er som definert ovenfor. Representative eksempler er metylsulfonyl, etylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfo-nyl, pentylsulfonyl og lignende. The term "Ci-6-alkylsulfonyl" refers, as used here, to the radical -S (=O) 2-Ci-6-alkyl, where C-6-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like.

Uttrykket "Ci-6-alkylsulfanyl" henviser, slik det her er brukt, til radikalet -S-Ci_6-alkyl, hvor Ci-6-alkyl er som definert ovenfor. Representative eksempler er metylsulfanyl, etyl-sulfanyl, isopropylsulfanyl, n-propylsulfanyl, butylsulfanyl, pentylsulfonyl og lignende. The term "Ci-6-alkylsulfanyl", as used herein, refers to the radical -S-Ci-6-alkyl, where Ci-6-alkyl is as defined above. Representative examples are methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, n-propylsulfanyl, butylsulfanyl, pentylsulfonyl and the like.

Uttrykket "C3_8-heterosyklyl" henviser, slik det her er brukt, til en mettet monosyklisk 3-8-ring som inneholder ett eller flere heteroatomer valgt fra nitrogen, oksygen og svovel. Representative eksempler er aziridinyl, pyrrolidinyl, piperidin-yl, morfolinyl, piperazinyl, tetrahydrofuranyl og lignende. The term "C3-8-heterocyclyl" as used herein refers to a saturated monocyclic 3-8 ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl and the like.

Uttrykket "C4_9-heterosykloalkanoyl" henviser, slik det her er brukt, til radikalet -C (=0)-C3_8-heterosyklyl, hvor C3-8-heterosyklyl er som definert ovenfor. Representative eksempler er aziridinylkarbonyl, pyrrolidinylkarbonyl, piperidinylkarbo-nyl, morfolinylkarbonyl, piperazinylkarbonyl, tetrahydrofuranyl-karbonyl og lignende. The term "C4-9-heterocycloalkanoyl", as used herein, refers to the radical -C (=0)-C3-8-heterocyclyl, where C3-8-heterocyclyl is as defined above. Representative examples are aziridinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl and the like.

Uttrykket "aryl" er, slik det her er brukt, ment å omfatte karbosykliske, aromatiske ringsystemer, slik som fenyl, bifenylyl, naftyl, antracenyl, fenantrenyl, fluorenyl, indenyl, pentalenyl, azulenyl og lignende. Aryl er også ment å omfatte de delvis hydrogenerte derivatene av de karbosykliske systemene som er angitt ovenfor. Ikke-begrensende eksempler på slike delvis hydrogenerte derivater er 1,2,3,4-tetrahydronaftyl, 1,4-dihydro-naftyl og lignende. The term "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 listed above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydro-naphthyl and the like.

Uttrykket "aryloksy" henviser, slik det her er brukt, til radikalet -0-aryl, hvor aryl er som definert ovenfor. Ikke-begrensende eksempler er fenoksy, naftoksy, antracenyloksy, fenantrenyloksy, fluorenyloksy, indenyloksy og lignende. The term "aryloxy" as used herein refers to the radical -O-aryl, where aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenanthrenyloxy, fluorenyloxy, indenyloxy and the like.

Uttrykket "aroyl" henviser, slik det her er brukt, til radikalet -C(=0)-aryl, hvor aryl er som definert ovenfor. Ikke-begrensende eksempler er benzoyl, naftoyl, antracenylkarbonyl, fenantrenylkarbonyl, fluorenylkarbonyl, indenylkarbonyl og lignende. The term "aroyl", as used herein, refers to the radical -C(=O)-aryl, where aryl is as defined above. Non-limiting examples are benzoyl, naphthoyl, anthracenylcarbonyl, phenanthrenylcarbonyl, fluorenylcarbonyl, indenylcarbonyl and the like.

Uttrykket "arylamino" henviser, slik det her er brukt, til radikalet -NH-aryl, hvor aryl er som definert ovenfor. Ikke-begrensende eksempler er fenylamino, naftylamino, antracenyl-amino, fenantrenylamino, fluorenylamino, indenylamino og lignende. The term "arylamino", as used herein, refers to the radical -NH-aryl, where aryl is as defined above. Non-limiting examples are phenylamino, naphthylamino, anthracenylamino, phenanthrenylamino, fluorenylamino, indenylamino and the like.

Uttrykket "heteroaryl" er, slik det her er brukt, ment å omfatte heterosykliske, aromatiske ringsystemer som inneholder ett eller flere heteroatomer valgt fra nitrogen, oksygen og svovel slik som furyl, tienyl, pyrrolyl, oksazolyl, tiazolyl, imidazolyl, isoksazolyl, isotiazolyl, 1,2,3-tiazolyl, 1,2,4-tiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oksadiazolyl, 1,2,4-oksadiazolyl, 1,2,5-oksadiazolyl, 1,3,4-oksadiazolyl, 1,2,3-tiadiazolyl, 1,2,4-tiadiazolyl, 1,2,5-tiadiazolyl, 1,3,4-tiadiazolyl, tetrazolyl, tiadiazinyl, indolyl, isoindolyl, benzofuryl, benzotienyl, indazolyl, benzimidazolyl, benzotiazolyl, benzoisotiazolyl, benzoksazolyl, benzisoksazolyl, purinyl, kinazolinyl, kinolizinyl, kinolinyl, isokinolinyl, kinoksalinyl, naftyridinyl, pteridinyl, karbazolyl, azepinyl, diazepinyl, akridinyl og lignende. Heteroaryl er også ment å omfatte de delvis hydrogenerte derivatene av de heterosykliske systemene som er angitt ovenfor. Ikke-begrensende eksempler på slike delvis hydrogenerte derivater er 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oksazolidinyl, oksazolinyl, oksazepinyl og lignende. The term "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-thiazolyl, 1,2,4-thiazolyl, 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-thiadiazolyl, 1, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

Uttrykket "heteroaryloksy" henviser, slik det her er brukt, til radikalet -O-heteroaryl, hvor heteroaryl er som definert ovenfor. The term "heteroaryloxy" as used herein refers to the radical -O-heteroaryl, where heteroaryl is as defined above.

Uttrykket "heteroaroyl" henviser, slik det her er brukt, til radikalet -C(=0)-heteroaryl, hvor heteroaryl er som definert ovenfor. The term "heteroaroyl", as used herein, refers to the radical -C(=O)-heteroaryl, where heteroaryl is as defined above.

Uttrykket "heteroarylamino" henviser, slik det her er brukt, til radikalet -NH-heteroaryl, hvor heteroaryl er som definert ovenfor. The term "heteroarylamino", as used herein, refers to the radical -NH-heteroaryl, where heteroaryl is as defined above.

Noen av de ovenfor definerte uttrykk kan opptre mer enn én gang i strukturformlene, og i slike tilfeller skal hvert uttrykk være definert uavhengig av de øvrige. Some of the expressions defined above may appear more than once in the structural formulas, and in such cases each expression must be defined independently of the others.

"Aryl-Ci-e-alkyl", "aryl-Cx_6-alkoksy" etc. betyr Ci-6-alkyl eller Ci_6-alkoksy som definert ovenfor, substituert med aryl som definert ovenfor, f.eks.: "Aryl-C 1-6 -alkyl", "aryl-C 1-6 -Alkoxy" etc. means C 1-6 -Alkyl or C 1-6 -Alkoxy as defined above, substituted with aryl as defined above, e.g.:

Uttrykket "eventuelt substituert" betyr, slik det her er brukt, at de aktuelle gruppene enten er usubstituert eller substituert med én eller flere av substituentene som er angitt. Når de aktuelle gruppene er substituert med mer enn én substi-tuent, kan substituentene være like eller forskjellige. The term "optionally substituted" means, as used here, that the relevant groups are either unsubstituted or substituted with one or more of the substituents indicated. When the relevant groups are substituted with more than one substituent, the substituents may be the same or different.

Uttrykket "behandling" betyr, slik det her er brukt, behandlingen og pleien av en pasient for det formål å bekjempe en sykdom, forstyrrelse eller tilstand. Uttrykket er ment å omfatte forsinkelsen av utviklingen av sykdommen, forstyrrelsen eller tilstanden, lindringen av eller befrielsen fra symptomer og komplikasjoner og/eller helbredelsen eller elimineringen av sykdommen, forstyrrelsen eller tilstanden. Pasienten som skal behandles, er fortrinnsvis et pattedyr, særlig et menneske. The term "treatment" as used herein means the treatment and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delay of the development of the disease, disorder or condition, the alleviation of or relief from symptoms and complications and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, especially a human.

Beskrivelse av oppfinnelsen Description of the invention

Den foreliggende oppfinnelse vedrører en forbindelse med den generelle formel (II) : The present invention relates to a compound with the general formula (II):

hvor where

R2 er hydrogen eller Ci_4-alkyl, R 2 is hydrogen or C 1-4 alkyl,

(i) R<1> er: (i) R<1> is:

• forgrenet C4_6-alkyl, forgrenet C4-6-alkenyl eller forgrenet C4.6-alkynyl, med det forbehold at R<1 >ikke er isobutyl, eller C3_5-sykloalkyl, C3_7-sykloalkenyl, C3-6-sykloalkyl-Ci_3-alkyl eller C3_6-sykloalkenyl-Ci-3-alkyl, og A er: • branched C4_6-alkyl, branched C4-6-alkenyl or branched C4.6-alkynyl, with the proviso that R<1 >is not isobutyl, or C3_5-cycloalkyl, C3_7-cycloalkenyl, C3-6-cycloalkyl-Ci_3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, and A is:

eller or

(ii) R<1> er: (ii) R<1> is:

• etyl, n-propyl eller isopropyl, og A er: • ethyl, n-propyl or isopropyl, and A is:

R<3> er hydrogen, R<3> is hydrogen,

Z og X er uavhengig av hverandre -N= eller -C(H)=, Z and X are independently -N= or -C(H)=,

W er -C(R<10>)=, W is -C(R<10>)=,

Y er -N= eller -C(R<n>)=, Y is -N= or -C(R<n>)=,

R<4>, R10 og R1<1>, er uavhengig av hverandre: R<4>, R10 and R1<1>, are independent of each other:

hydrogen, halogen, hydroksy, trifluormetyl, tri fluormetoksy, -SCF3, amino, cyan, nitro eller -C-(=0)NR<14>R15, hydrogen, halogen, hydroxy, trifluoromethyl, tri fluoromethoxy, -SCF3, amino, cyan, nitro or -C-(=0)NR<14>R15,

Ci-io-alkyl, C2-io-alkenyl, C3-8-sykloalkyl, Ci_6-alkoksy, C3-8-sykloalkyl-Ci_6-alkoksy, Ci-6-alkyl-amino, di-Ci_6-alkylamino, C3_8-sykloalkyloksy, Ci_6-alkylsulfanyl, Ci-6-alkylsulfonyl, C2-io-alkanoyl, C4-9-sykloalkanoyl, C3-8-heterosyklyl eller C4_9-heterosykloalkanoyl, C4_9-heterosykloalkoksy, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<16>, C1-10-alkyl, C2-10-alkenyl, C3-8-cycloalkyl, C1-6-alkyloxy, C3-8-cycloalkyl-C1-6-alkyloxy, C1-6-alkylamino, di-C1-6-alkylamino, C3-8-cycloalkyloxy, C1-6-alkylsulfanyl, C1-6-alkylsulfonyl, C2-io-alkanoyl, C4-9-cycloalkanoyl, C3-8-heterocyclyl or C4-9-heterocycloalkanoyl, C4-9-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R< 16>,

fenyl, f enyl-Ci_6-alkyl eller fenyl-Ci-6-alkoksy, phenyl, phenyl-C 1-6 -alkyl or phenyl-C 1-6 -alkoxy,

som eventuelt kan være substituert med én eller flere substituenter valgt fra R<17>, which may optionally be substituted with one or more substituents selected from R<17>,

fenoyl, fenoyloksy eller fenylamino, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<18>, phenol, phenoyloxy or phenylamino, which may optionally be substituted with one or more substituents selected from R<18>,

eller R<1>0 og R1<1> i nabostillinger danner til sammen en Ci-6-alkylenbro eller en -0-Ci-6-alkylen-0-bro, or R<1>0 and R1<1> in neighboring positions together form a C1-6-alkylene bridge or a -0-C1-6-alkylene-0-bridge,

R14 og R1<5> er uavhengig av hverandre hydrogen, Ci-6-alkyl eller fenyl-Ci_6-alkyl, eller R<14> og R15 kan til sammen danne en C3_6-alkylenbro, R14 and R1<5> are independently hydrogen, C1-6-alkyl or phenyl-C1-6-alkyl, or R<14> and R15 can together form a C3-6-alkylene bridge,

R1<6> er uavhengig av hverandre valgt fra fenyl, C3-8~ sykloalkyl, halogen, trif luormetyl, trif luormetoksy, NR19R2<0> og Ci-6-alkoksy, R1<6> is independently selected from phenyl, C3-8~ cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR19R2<0> and C1-6-alkoxy,

R<11> er uavhengig av hverandre valgt fra halogen, hydroksy, trif luormetyl, trif luormetoksy, Ci-6-alkoksy, Ci-6-alkyl, amino, Ci-6-alkylsulfonyl, Ci-6-alkylamino, di-Ci-6-alkyl-amino, cyan, fenyl og C3-8-sykloalkyl, R<11> is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1- 6-alkyl-amino, cyan, phenyl and C3-8-cycloalkyl,

R<18> er uavhengig av hverandre valgt fra fenyl, Ci-io-alkyl, C3_8-sykloalkyl, halogen, trifluormetyl, trifluormetoksy, Ci-6-alkoksy, cyan, amino, Ci-6-alkylamino, di-Ci-6-alkylamino og hydroksy, R<18> is independently selected from phenyl, C1-10-alkyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyan, amino, C1-6-alkylamino, di-C1-6- alkylamino and hydroxy,

R19 og R2<0> er uavhengig av hverandre hydrogen eller Ci_6-alkyl, eller R19 og R20 kan til sammen danne en C3-6-alkylenbro, med det forbehold at forbindelsen ikke er: R19 and R2<0> are independently hydrogen or C1_6 alkyl, or R19 and R20 can together form a C3-6 alkylene bridge, with the proviso that the compound is not:

eller or

samt enhver diastereomer eller enantiomer eller tautomer form derav, inkludert blandinger av disse, eller et farmasøytisk akseptabelt salt derav. as well as any diastereomer or enantiomeric or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof.

Ved en foretrukket utførelsesform av oppfinnelsen er R<1> forgrenet C4_6-alkyl, C3_5-sykloalkyl eller C3_6-sykloalkyl-Ci_3-alkyl, med det forbehold at R<1> ikke er isobutyl. In a preferred embodiment of the invention, R<1> is branched C4-6-alkyl, C3-5-cycloalkyl or C3-6-cycloalkyl-C1-3-alkyl, with the proviso that R<1> is not isobutyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<1> 1,1-(dimetyl)propyl, 1-etylpropyl, syklopropylmetyl, syklopropyl, syklobutyl, syklopentyl eller 1-syklopropyl-l-metyletyl. In another preferred embodiment of the invention, R<1> is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<1> 1-etylpropyl, syklopropylmetyl, syklopropyl eller syklopentyl . In another preferred embodiment of the invention, R<1> is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<1> forgrenet C4-6-alkyl eller C3_5-sykloalkyl, med det forbehold at R<1> ikke er isobutyl. In another preferred embodiment of the invention, R<1> is branched C4-6-alkyl or C3-5-cycloalkyl, with the proviso that R<1> is not isobutyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<1> 1-etylpropyl, syklopropyl eller syklopentyl. In another preferred embodiment of the invention, R<1> is 1-ethylpropyl, cyclopropyl or cyclopentyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Z -C(H)=. In another preferred embodiment of the invention, Z is -C(H)=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Z -N=. In another preferred embodiment of the invention, Z is -N=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Z -C(H)=. In another preferred embodiment of the invention, Z is -C(H)=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Z -N=. In another preferred embodiment of the invention, Z is -N=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Y -N=. In another preferred embodiment of the invention, Y is -N=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er Y -C(R<n>)=. In another preferred embodiment of the invention, Y is -C(R<n>)=.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<2> hydrogen. In another preferred embodiment of the invention, R<2> is hydrogen.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<2> Ci-4-alkyl. In another preferred embodiment of the invention, R<2> is C1-4 alkyl.

Ved en annen foretrukket utførelsesform av oppfinnelsen er R<2> metyl eller etyl. In another preferred embodiment of the invention, R<2> is methyl or ethyl.

Ved et annet aspekt tilveiebringer oppfinnelsen et farmasøytisk preparat. Det farmasøytiske preparat kan i et annet aspekt av oppfinnelsen omfatte som en aktiv bestanddel minst én forbindelse ifølge formel (II), sammen med én eller flere farma-søytisk akseptable bærere eller eksipienser. Ved en foretrukket utførelsesform tilveiebringer oppfinnelsen et slikt farmasøytisk preparat i enhetsdoseringsform som omfatter fra ca. 0,05 mg til ca. 1000 mg, fortrinnsvis fra ca. 0,1 mg til ca. 500 mg, og spesielt foretrukket fra ca. 0,5 mg til ca. 200 mg av forbindelsen ifølge formel (II). In another aspect, the invention provides a pharmaceutical preparation. In another aspect of the invention, the pharmaceutical preparation can comprise as an active ingredient at least one compound according to formula (II), together with one or more pharmaceutically acceptable carriers or excipients. In a preferred embodiment, the invention provides such a pharmaceutical preparation in unit dosage form comprising from approx. 0.05 mg to approx. 1000 mg, preferably from approx. 0.1 mg to approx. 500 mg, and particularly preferred from approx. 0.5 mg to approx. 200 mg of the compound according to formula (II).

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'): In another aspect, the invention provides the use of a compound of the general formula (II'):

hvor where

R<2> er hydrogen eller Ci_4-alkyl, R<2> is hydrogen or C1_4-alkyl,

R<1> er: R<1> is:

Ci-e-alkyl, C2-8-alkenyl eller C2-8_alkynyl, som eventuelt kan være substituert med én eller flere halogensubstituenter, C 1-6 -alkyl, C 2-8 -alkenyl or C 2-8 -alkynyl, which may optionally be substituted with one or more halogen substituents,

C3_5-sykloalkyl, C3_7-sykloalkenyl, C3_6-sykloalkyl-Ci-3-alkyl eller C3_6-sykloalkenyl-Ci-3-alkyl, som eventuelt kan være substituert med én eller flere halogensubstituenter, C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl-Ci-3-alkyl or C3-6-cycloalkenyl-Ci-3-alkyl, which may optionally be substituted with one or more halogen substituents,

R<1> og R<2> danner til sammen en C3-6-alkylenbro, A er: eller R<1> and R<2> together form a C3-6 alkylene bridge, A is: or

R<3> er hydrogen, halogen, hydroksy, trifluormetyl, trifluormetoksy, Ci_i0-alkyl, C2-io-alkenyl, C3_8-sykloalkyl, Ci-6~ alkoksy, aryl, aryl-Ci_6-alkyl, amino, Ci_6-alkylamino, di-Ci-6-alkylamino, C3_8-sykloalkyl, C3_8-sykloalkyloksy, cyan, nitro, Ci-6-alkylsulfanyl eller Ci-6-alkylsulfonyl, R<3> is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10-alkyl, C2-10-alkenyl, C3-8-cycloalkyl, C1-6~ alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di -Ci-6-alkylamino, C3-8-cycloalkyl, C3-8-cycloalkyloxy, cyan, nitro, C1-6-alkylsulfanyl or C1-6-alkylsulfonyl,

Z og X er uavhengig av hverandre -N=, -C(H)=, -C(F)=, Z and X are independent of each other -N=, -C(H)=, -C(F)=,

-C(C1)=, -C(CN)= eller -C(CF3)=, -C(C1)=, -C(CN)= or -C(CF3)=,

W er -N= eller -C(R<10>)=, W is -N= or -C(R<10>)=,

Y er -N= eller -C(R<n>)=, Y is -N= or -C(R<n>)=,

R<4>, R5, R<6>, R<7>, R<8>, R<9>, R<10>, R<11>, R12 og R1<3> er uavhengig av hverandre: hydrogen, halogen, hydroksy, trifluormetyl, tri fluormetoksy, -SCF3, amino, cyan, nitro eller -C-(=0)NR<14>R15, R<4>, R5, R<6>, R<7>, R<8>, R<9>, R<10>, R<11>, R12 and R1<3> are independent of each other: hydrogen, halogen, hydroxy, trifluoromethyl, tri fluoromethoxy, -SCF3, amino, cyan, nitro or -C-(=0)NR<14>R15,

Ci-io-alkyl, C2-io-alkenyl, C3-8-sykloalkyl, Ci-6-alkoksy, C3-8-sykloalkyl-Ci-6-alkoksy, Ci_6-alkyl-amino, di-Ci-6-alkylamino, C3-8-sykloalkyloksy, Ci-6~ alkylsulfanyl, Ci_6-alkylsulfonyl, C2-io-alkanoyl, C4-9-sykloalkanoyl, C3_8-heterosyklyl eller C4_9-heterosykloalkanoyl, C4-9-heterosykloalkoksy, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<16>, C1-10-alkyl, C2-10-alkenyl, C3-8-cycloalkyl, C1-6-alkyloxy, C3-8-cycloalkyl-C1-6-alkoxy, C1-6-alkyl-amino, di-C1-6-alkylamino, C3-8-cycloalkyloxy, C1-6~ alkylsulfanyl, C1-6-alkylsulfonyl, C2-io-alkanoyl, C4-9-cycloalkanoyl, C3-8-heterocyclyl or C4-9-heterocycloalkanoyl, C4-9-heterocycloalkoxy, which may optionally be substituted with one or several substituents selected from R<16>,

aryl, aryl-Ci_6-alkyl, aryl-Ci_6-alkoksy eller heteroaryl, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<17>, aryl, aryl-Ci-6-alkyl, aryl-Ci-6-alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from R<17>,

aroyl, heteroaroyl, aryloksy, heteroaryloksy, aroyl, heteroaroyl, aryloxy, heteroaryloxy,

arylamino eller heteroarylamino, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<18>, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from R<18>,

eller to av R<5>, R<6>, R7, R8, R9, R<1>0, Ru, R<12> og R<13> i nabostillinger danner til sammen en Ci_6-alkylenbro eller en -0-Ci-6-alkylen-0-bro, or two of R<5>, R<6>, R7, R8, R9, R<1>0, Ru, R<12> and R<13> in adjacent positions together form a C1_6-alkylene bridge or a -0- C1-6-alkylene-O-bro,

R<1>4 og R1<5> er uavhengig av hverandre hydrogen, Ci-6-alkyl eller aryl-Ci-6-alkyl, eller R14 og R15 kan til sammen danne en C3_6-alkylenbro, R<1>4 and R1<5> are independently hydrogen, C1-6-alkyl or aryl-C1-6-alkyl, or R14 and R15 can together form a C3-6-alkylene bridge,

R1<6> er uavhengig av hverandre valgt fra aryl, heteroaryl, Ca-g-sykloalkyl, halogen, trif luormetyl, trif luormetoksy, NR<19>R<20> og Ci-e-alkoksy, R 1<6> is independently selected from aryl, heteroaryl, C 1-6 cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR<19>R<20> and C 1-6 alkoxy,

R1<7> er uavhengig av hverandre valgt fra halogen, hydroksy, trif luormetyl, trif luormetoksy, d-6-alkoksy, Ci_6-alkyl, amino, Ci-6-alkylsulfonyl, Ci-6-alkylamino, di-Ci-6-alkyl-amino, cyan, aryl, heteroaryl og C3-s-sykloalkyl, R1<7> is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, 1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1-6- alkyl-amino, cyan, aryl, heteroaryl and C3-s-cycloalkyl,

R1<8> er uavhengig av hverandre valgt fra aryl, heteroaryl, Ci-io-alkyl, C3_e-sykloalkyl, halogen, trif luormetyl, trifluormetoksy, Ci-6-alkoksy, cyan, amino, Ci-6-alkylamino, di-Ci-6-alkylamino og hydroksy, R 1<8 > is independently selected from aryl, heteroaryl, C 1-10 alkyl, C 3-e cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkoxy, cyan, amino, C 1-6 alkylamino, di-C 1 -6-alkylamino and hydroxy,

R19 og R2<0> er uavhengig av hverandre hydrogen eller C1-6-alkyl, eller R<19> og R20 kan til sammen danne en C3-6-alkylenbro, samt enhver diastereomer eller enantiomer eller tautomer form derav, inkludert blandinger av disse, eller et farmasøytisk akseptabelt salt derav, til fremstillingen av et farmasøytisk preparat for profylakse og/eller behandling av overvekt eller fedme, forstyrrelser og sykdommer relatert til overvekt eller fedme, spiseforstyrrelser, IGT, sukkersyke av type 2, sykdommer forbundet med regulering av søvn og våkenhet, narkolepsi, forstyrrelser med oppmerksomhetssvikt, demens og Alzheimers sykdom, allergisk rhinitt, magesår, migrene, tilstander forbundet med epilepsi, bevegelsessykelighet og svimmelhet, depresjon og irritabel tarm-syndrom. R19 and R2<0> are independently hydrogen or C1-6-alkyl, or R<19> and R20 can together form a C3-6-alkylene bridge, as well as any diastereomer or enantiomeric or tautomeric form thereof, including mixtures of these , or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation for the prophylaxis and/or treatment of overweight or obesity, disorders and diseases related to overweight or obesity, eating disorders, IGT, diabetes type 2, diseases associated with the regulation of sleep and alertness, narcolepsy, attention deficit disorders, dementia and Alzheimer's disease, allergic rhinitis, peptic ulcer, migraine, conditions associated with epilepsy, motion sickness and vertigo, depression and irritable bowel syndrome.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for reduksjon av vekt. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for reducing weight.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for behandling av overvekt eller fedme. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the treatment of overweight or obesity.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for undertrykkelse av appetitt eller for metthetsinduksjon. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the suppression of appetite or for the induction of satiety.

Ved en annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for profylakse og/eller behandling av forstyrrelser og sykdommer relatert til overvekt eller fedme. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the prophylaxis and/or treatment of disorders and diseases related to overweight or obesity.

Ved et annet aspekt tilveiebringer oppfinnelsen anvendelse^ av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for profylakse og/eller behandling av spiseforstyrrelser, slik som bulimi og overdreven spising. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the prophylaxis and/or treatment of eating disorders, such as bulimia and binge eating.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II<1>), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for behandling av IGT. In another aspect, the invention provides the use of a compound of the general formula (II<1>), as defined above, for the preparation of a pharmaceutical preparation for the treatment of IGT.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for behandling av sukkersyke av type 2. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the treatment of type 2 diabetes.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II<1>), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for forsinkelse eller forhindring av utviklingen fra IGT til sukkersyke av type 2. In another aspect, the invention provides the use of a compound of the general formula (II<1>), as defined above, for the preparation of a pharmaceutical preparation for delaying or preventing the progression from IGT to type 2 diabetes.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for forsinkelse eller forhindring av utviklingen fra ikke-insulinkrevende sukkersyke av type 2 til insulinkrevende sukkersyke av type 2. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for delaying or preventing the progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes 2.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for behandling av allergisk rhinitt, magesår eller anoreksi. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the treatment of allergic rhinitis, peptic ulcer or anorexia.

Ved et annet aspekt tilveiebringer oppfinnelsen anven-delsen av en forbindelse med den generelle formel (II'), som definert ovenfor, til fremstillingen av et farmasøytisk preparat for behandling av Alzheimers sykdom, narkolepsi eller forstyrrelser med oppmerksomhetssvikt. In another aspect, the invention provides the use of a compound of the general formula (II'), as defined above, for the preparation of a pharmaceutical preparation for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.

Forbindelsene ifølge den foreliggende oppfinnelse kan være kirale, og det er ment at hvilke som helst enantiomerer, som fraskilte, rene eller delvis rensede enantiomerer, eller racemiske blandinger derav, er inkludert innenfor omfanget av oppfinnelsen. The compounds of the present invention may be chiral, and it is intended that any enantiomers, such as separated, pure or partially purified enantiomers, or racemic mixtures thereof, are included within the scope of the invention.

Dessuten kan det, når en dobbeltbinding eller et helt eller delvis mettet ringsystem eller mer enn ett asymmetri-sentrum eller en binding med begrenset roterbarhet er til stede i molekylet, dannes diastereomerer. Det er ment at eventuelle diastereomerer, som fraskilte, rene eller delvis rensede diastereomerer, eller blandinger derav, er inkludert innenfor omfanget av oppfinnelsen. Also, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with limited rotatability is present in the molecule, diastereomers may be formed. It is intended that any diastereomers, such as separated, pure or partially purified diastereomers, or mixtures thereof, are included within the scope of the invention.

Dessuten kan noen av forbindelsene ifølge den foreliggende oppfinnelse foreligge i forskjellige tautomere former, og det er ment at hvilke som helst tautomere former som forbindelsene er i stand til å danne, er inkludert innenfor omfanget av den foreliggende oppfinnelse. Moreover, some of the compounds of the present invention may exist in various tautomeric forms, and it is intended that any tautomeric forms that the compounds are capable of forming are included within the scope of the present invention.

Den foreliggende oppfinnelse omfatter også farmasøytisk akseptable salter av de foreliggende forbindelser. Slike salter omfatter farmasøytisk akseptable syreaddisjonssalter, farmasøyt-isk akseptable metallsalter, ammonium- og alkylerte ammoniumsalter. Syreaddisjonssalter omfatter salter av uorganiske syrer samt organiske syrer. Representative eksempler på egnede uorganiske syrer omfatter saltsyre, hydrobromsyre, hydrojodsyre, fosforsyre, svovelsyre, salpetersyrer og lignende. Representative eksempler på egnede organiske syrer omfatter maursyre, eddiksyre, trikloreddiksyre, trifluoreddiksyre, propionsyre, benzosyre, kanelsyre, sitronsyre, fumarsyre, glykolsyre, melke-syre, maleinsyre, eplesyre, malonsyre, mandelsyre, oksalsyre, pikrinsyre, pyrodruesyre, salisylsyre, ravsyre, metansulfonsyre, etansulfonsyre, vinsyre, askorbinsyre, embonsyre, bismetylen-salisylsyre, etandisulfonsyre, glukonsyre, citraconsyre, asparaginsyre, stearinsyre, palmitinsyre, EDTA, glykolsyre, p-aminobenzosyre, glutaminsyre, benzensulfonsyre, p-toluensulfon-syrer og lignende. Ytterligere eksempler på farmasøytisk akseptable uorganiske eller organiske syreaddisjonssalter omfatter de farmasøytisk akseptable saltene angitt i J. Pharm. Sei., 1977, 66, 2. Eksempler på metallsalter omfatter litium-, natrium-, kalium-, magnesiumsalter og lignende. Eksempler på ammonium- og alkylerte ammoniumsalter omfatter ammonium-, metylammonium-, dimetylammonium-, trimetylammonium-, etylammonium-, hydroksy-etylammonium-, dietylammonium-, butylammonium-, tetrametyl-ammoniumsalter og lignende. The present invention also includes 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 acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acids and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid , ethanesulfonic acid, tartaric acid, ascorbic acid, embonic acid, bismethylene-salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acids and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts set forth in J. Pharm. Sei., 1977, 66, 2. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

Også ment som farmasøytisk akseptable syreaddisjonssalter er hydratene som de foreliggende forbindelser er i stand til å danne. Syreaddisjonssaltene kan fås som de direkte produk-tene av forbindelsessyntese. Alternativt kan den frie base opp-løses i et egnet oppløsningsmiddel som inneholder den passende syre, og saltet isoleres ved fordampning av oppløsningsmidlet eller på annen måte skille saltet og oppløsningsmidlet. Also intended as pharmaceutically acceptable acid addition salts are the hydrates that the present compounds are capable of forming. The acid addition salts can be obtained as the direct products of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and the solvent.

Forbindelsene ifølge den foreliggende oppfinnelse kan danne solvater med standardoppløsningsmidler med lav molekylvekt under anvendelse av metoder som er godt kjent for fagfolk innen teknikken. Slike solvater anses for å være innenfor omfanget av den foreliggende oppfinnelse. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods well known to those skilled in the art. Such solvates are considered to be within the scope of the present invention.

Forbindelsene ifølge den foreliggende oppfinnelse reagerer med histamin H3-reseptoren, og er følgelig anvendbare for behandlingen av et bredt spekter av til stander og forstyr-reiser hvor histamin H3-reseptorinteraksjoner er gunstig. The compounds according to the present invention react with the histamine H3 receptor, and are consequently applicable for the treatment of a wide range of conditions and disorders where histamine H3 receptor interactions are beneficial.

Farmasøytiske preparater Pharmaceutical preparations

Forbindelsene ifølge oppfinnelsen kan administreres alene eller i kombinasjon med farmasøytisk akseptable bærere eller eksipienser, enten i enkelt- eller flerdoser. De farma-søytiske preparatene ifølge oppfinnelsen kan formuleres med farmasøytisk akseptable bærere eller fortynnere, samt hvilke som helst andre kjente adjuvanser og eksipienser, i overensstemmelse med vanlige teknikker, slik som dem beskrevet i Remington: The Science and Practice of Pharmacy, 19. utg., Gennaro, red., Mack Publishing Co., Easton, PA, 1995. De farmasøytiske preparatene kan formuleres spesifikt for administrering ved hjelp av hvilken som helst egnet vei, slik som den orale, rektale, nasale, pulmonale, topiske (inkludert bukkale og sublinguale), transdermale, intracisternale, intraperitoneale, vaginale og parenterale (inkludert subkutane, intramuskulære, intratekale, intravenøse og intradermale) vei, idet den orale vei er foretrukket. Det vil forstås at den foretrukne vei vil avhenge av den generelle tilstand og alderen til individet som skal behandles, typen tilstand som skal behandles og den aktive bestanddel som velges. The compounds according to the invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either in single or multiple doses. The pharmaceutical preparations according to the invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, in accordance with common techniques, such as those described in Remington: The Science and Practice of Pharmacy, 19th ed. , Gennaro, eds., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical 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 parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be understood that the preferred route will depend on the general condition and age of the subject to be treated, the type of condition to be treated and the active ingredient selected.

Farmasøytiske preparater for oral administrering omfatter faste doseringsformer, slik som kapsler, tabletter, drasjeer, piller, sugetabletter, pulvere og granulater. Når det er passende, kan de fremstilles med belegg, slik som enteriske belegg, eller de kan formuleres slik at de gir kontrollert frigivelse av den aktive bestanddel, slik som forsinket eller for-lenget frigivelse, i henhold til metoder som er godt kjent innenfor teknikken. Pharmaceutical preparations for oral administration include fixed dosage forms, such as capsules, tablets, dragees, pills, lozenges, powders and granules. When appropriate, they may be prepared with coatings, such as enteric coatings, or they may be formulated to provide controlled release of the active ingredient, such as delayed or sustained release, according to methods well known in the art .

Flytende doseringsformer for oral administrering omfatter oppløsninger, emulsjoner, suspensjoner, siruper og eliksirer. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Farmasøytiske preparater for parenteral administrering omfatter sterile, vandige og ikke-vandige, injiserbare oppløs-ninger, dispersjoner, suspensjoner eller emulsjoner, samt sterile pulvere som skal rekondisjoneres i sterile, injiserbare oppløsninger eller dispersjoner før bruk. Injiserbare depot-formuleringer er også omfattet innenfor omfanget av den foreliggende oppfinnelse. Pharmaceutical preparations for parenteral administration include sterile, aqueous and non-aqueous, injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders that must be reconstituted in sterile, injectable solutions or dispersions before use. Injectable depot formulations are also included within the scope of the present invention.

Andre egnede administreringsformer omfatter supposi-torier, sprayer, salver, kremer, geler, inhalasjonsmidler, hud-plastre, implantater etc. Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc.

En typisk oral dosering er i området fra ca. 0,001 til ca. 100 mg/kg kroppsvekt pr. dag, fortrinnsvis fra ca. 0,01 til ca. 50 mg/kg kroppsvekt pr. dag, og mer foretrukket fra ca. 0,05 til ca. 10 mg/kg kroppsvekt pr. dag, administrert i én eller flere doseringer, slik som 1-3 doseringer. Den nøyaktige dosering vil avhenge av hyppigheten og måten for administrering, kjønnet, alderen, vekten og den generelle tilstanden til individet som skal behandles, typen og alvorligheten av tilstanden som behandles og eventuelle ledsagende sykdommer som skal behandles, og andre faktorer som er åpenbare for fagfolk innen teknikken. A typical oral dosage is in the range from approx. 0.001 to approx. 100 mg/kg body weight per day, preferably from approx. 0.01 to approx. 50 mg/kg body weight per day, and more preferably from approx. 0.05 to approx. 10 mg/kg body weight per day, administered in one or more doses, such as 1-3 doses. The exact dosage will depend on the frequency and manner of administration, the sex, age, weight, and general condition of the subject to be treated, the type and severity of the condition being treated and any concomitant diseases to be treated, and other factors apparent to those skilled in the art. in the field of technology.

Formuleringene kan passende presenteres i enhetsdoseringsform ved hjelp av metoder som er kjent for fagfolk innen teknikken. En typisk enhetsdoseringsform for oral administrering én eller flere ganger pr. dag, slik som 1-3 ganger pr. dag, kan inneholde fra 0,05 til ca. 1000 mg, fortrinnsvis fra ca. 0,1 til ca. 500 mg, og mer foretrukket fra ca. 0,5 mg til ca. 200 mg. For parenterale veier, slik som intravenøs, intra-tekal, intramuskulær og lignende administrering, er typiske doser i størrelsesorden ca. halvparten av dosen anvendt for oral administrering. The formulations may conveniently be presented in unit dosage form using methods known to those skilled in the art. A typical unit dosage form for oral administration once or more per day, such as 1-3 times per day, can contain from 0.05 to approx. 1000 mg, preferably from approx. 0.1 to approx. 500 mg, and more preferably from approx. 0.5 mg to approx. 200 mg. For parenteral routes, such as intravenous, intra-thecal, intramuscular and similar administration, typical doses are in the order of approx. half the dose used for oral administration.

Forbindelsene ifølge denne oppfinnelsen anvendes generelt som det frie stoff eller som et farmasøytisk akseptabelt salt derav. Ett eksempel er et syreaddisjonssalt av en forbindelse som har utnyttbarheten til en fri base. Når en forbindelse med formel (I) inneholder en fri base, fremstilles slike salter på en vanlig måte ved å behandle en oppløsning eller suspensjon av en fri base med formel (I) med en kjemisk ekvivalent av en farmasøytisk akseptabel syre, f.eks. uorganiske og organiske syrer. Representative eksempler er nevnt ovenfor. Fysiologisk akseptable salter av en forbindelse med en hydroksygruppe omfatter anionet av forbindelsen i kombinasjon med et egnet kation, slik som natrium- eller ammoniumion. The compounds according to this invention are generally used 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. When a compound of formula (I) contains a free base, such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, e.g. inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group comprise the anion of the compound in combination with a suitable cation, such as sodium or ammonium ion.

For parenteral administrering kan det anvendes oppløs-ninger av de nye forbindelsene med formel (I) i steril, vandig oppløsning, vandig propylenglykol eller sesam- eller peanøtt-olje. Slike vandige oppløsninger bør være passende bufret om nødvendig, og væskefortynneren først gjort isotonisk med til-strekkelig saltoppløsning eller glukose. De vandige oppløs-ningene er særlig egnet for intravenøs, intramuskulær, subkutan og intraperitoneal administrering. De sterile, vandige medier som anvendes, er lett tilgjengelige ved standardteknikker som er kjent for fagfolk på området. For parenteral administration, solutions of the new compounds of formula (I) in sterile, aqueous solution, aqueous propylene glycol or sesame or peanut oil can be used. Such aqueous solutions should be suitably buffered if necessary, and the fluid diluent first made isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile, aqueous media used are readily available by standard techniques known to those skilled in the art.

Egnede farmasøytiske bærere omfatter inerte, faste for-tynningsmidler eller fyllstoffer, steril, vandig oppløsning og forskjellige organiske oppløsningsmidler. Eksempler på faste bærere er laktose, terra alba, sukrose, syklodekstrin, talkum, gelatin, agar, pektin, akasie, magnesiumstearat, stearinsyre eller lavere alkyleter av cellulose. Eksempler på flytende bærere er sirup, peanøttolje, olivenolje, fosfolipider, fett-syrer, fettsyreaminer, polyoksyetylen eller vann. Likeledes omfatter bæreren eller fortynneren hvilket som helst materiale for forsinket frigivelse som er kjent innenfor teknikken, slik som glyserylmonostearat eller glyseryldistearat, alene eller blandet med en voks. De farmasøytiske preparatene som dannes ved å kombinere de nye forbindelsene med formel (I) og de farma-søytisk akseptable bærerne, administreres så lett i mange forskjellige doseringsformer som er egnet for de beskrevne admini-streringsveier. Formuleringene kan passende presenteres i enhetsdoseringsform ved hjelp av metoder som er kjent innenfor farmasien. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Likewise, the carrier or diluent includes any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical preparations formed by combining the novel compounds of formula (I) and the pharmaceutically acceptable carriers are thus readily administered in many different dosage forms suitable for the described routes of administration. The formulations may conveniently be presented in unit dosage form using methods known in pharmacy.

Formuleringer ifølge den foreliggende oppfinnelse som er egnet for oral administrering, kan presenteres som enkelt-stående enheter, slik som kapsler eller tabletter, som hver inneholder en forutbestemt mengde av den aktive bestanddel, og som kan omfatte en egnet eksipiens. Disse formuleringene kan være i form av pulver eller granulater, eller som en oppløsning eller suspensjon i en vandig eller ikke-vandig væske, eller som en flytende olje-i-vann- eller vann-i-oljeemulsjon. Formulations according to the present invention which are suitable for oral administration can be presented as individual units, such as capsules or tablets, each of which contains a predetermined amount of the active ingredient, and which can include a suitable excipient. These formulations may be in the form of powders or granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid oil-in-water or water-in-oil emulsion.

Dersom det anvendes en fast bærer til oral administrering, kan preparatet være tablettert, plassert i en hard gelatinkapsel i pulver- eller pelletform, eller det kan være i form av en pastill eller sugetablett. Mengden av fast bærer vil variere bredt, men vil vanligvis være fra ca. 25 mg til ca. lg. Dersom det anvendes en flytende bærer, kan preparatet være i form av en sirup, emulsjon, myk gelatinkapsel eller steril, injiserbar væske, slik som en vandig eller ikke-vandig væskesuspensjon eller oppløsning. If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or it can be in the form of a lozenge or lozenge. The amount of solid carrier will vary widely, but will usually be from approx. 25 mg to approx. lg. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile, injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

En typisk tablett som kan fremstilles ved hjelp av vanlige tabletteringsteknikker, kan inneholde: A typical tablet that can be prepared using conventional tableting techniques may contain:

Kjerne: Core:

Eksempler Examples

I eksemplene er de følgende uttrykk ment å ha de følgende generelle betydninger: In the examples, the following expressions are intended to have the following general meanings:

DIPEA: diisopropylamin DIPEA: diisopropylamine

DMSO: dimetylsulfoksid DMSO: dimethyl sulfoxide

THF: tetrahydrofuran. THF: tetrahydrofuran.

HPLC ( metode A) HPLC (method A)

NMR-spektra ble tatt opp på Bruker 300 MHz og 400 MHz instrumenter. HPLC-MS ble utført på et Perkin Elmer-instrument (API 100). Den anvendte kolonne var X-Terra C18, 5 um, 50 x 3 mm, og eluering ble gjort ved 1,5 ml/minutt ved romtemperatur med en gradient på 5 % til 90 % acetonitril i vann, med 0,01 % trifluoreddiksyre i løpet av 7,5 minutter. NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. HPLC-MS was performed on a Perkin Elmer instrument (API 100). The column used was X-Terra C18, 5 µm, 50 x 3 mm, and elution was done at 1.5 ml/minute at room temperature with a gradient of 5% to 90% acetonitrile in water, with 0.01% trifluoroacetic acid in within 7.5 minutes.

HPLC ( metode B) HPLC (method B)

Reversfaseanalysen ble utført ved å anvende UV-påvis-ninger ved 214 og 254 nm på en 218TP54, 4,6 mm x 150 mm C-18-silikakolonne som ble eluert ved 1 ml/minutt ved 42 °C. Kolonnen ble ekvilibrert med 5 % acetonitril, 85 % vann og 10 % av en oppløsning av 0,5 % trifluoreddiksyre i vann, og eluert ved hjelp av en lineær gradient fra 5 % acetonitril, 85 % vann og 10 % av en oppløsning av 0,5 % trifluoreddiksyre til 90 % acetonitril og 10 % av en oppløsning av 0,5 % trifluoreddiksyre i løpet av 15 minutter. The reverse phase analysis was performed using UV detections at 214 and 254 nm on a 218TP54, 4.6 mm x 150 mm C-18 silica column eluting at 1 ml/minute 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 using 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 0.5% trifluoroacetic acid solution over 15 minutes.

HPLC ( metode C) HPLC (method C)

RP-analysene ble utført ved å anvende et Alliance Waters 2695-system utstyrt med en Waters 2487-dobbeltbånd-detektor. UV-deteksjoner ble tatt opp ved å anvende en Symmetry C18, 3,5 um, 3,0 mm x 100 mm kolonne. Elueringen gjøres med en lineær gradient på 5-90 % acetonitril, 90-0 % vann og 5 % trifluoreddiksyre (1,0 %) i vann i løpet av 8 minutter ved en strømningshastighet på 1,0 minutt/minutt. The RP analyzes were performed using an Alliance Waters 2695 system equipped with a Waters 2487 dual-band detector. UV detections were recorded using a Symmetry C18, 3.5 µm, 3.0 mm x 100 mm column. The elution is done with a linear gradient of 5-90% acetonitrile, 90-0% water and 5% trifluoroacetic acid (1.0%) in water over 8 minutes at a flow rate of 1.0 minute/minute.

Generell fremgangsmåte ( A) General procedure (A)

Generell fremgangsmåte (A) kan anvendes til fremstillingen av forbindelsene med den generelle formel (Ia): General method (A) can be used for the preparation of the compounds with the general formula (Ia):

hvor -CH(R<20>R<21>) er etyl, isopropyl, forgrenet C4-6-alkyl, forgrenet C4-6-alkenyl, forgrenet C4_6-alkynyl, C3_5-sykloalkyl, C3-7-sykloalkenyl, C3_6-sykloalkyl-Ci_3-alkyl eller C3-6-sykloalkenyl-Ci-3-alkyl, som eventuelt kan være substituert med én eller flere halogensubstituenter. where -CH(R<20>R<21>) is ethyl, isopropyl, branched C4-6 alkyl, branched C4-6 alkenyl, branched C4_6 alkynyl, C3_5 cycloalkyl, C3-7 cycloalkenyl, C3_6 cycloalkyl -Ci_3-alkyl or C3-6-cycloalkenyl-Ci-3-alkyl, which may optionally be substituted with one or more halogen substituents.

Til en blanding av et monosubstituert piperazin To a mixture of a monosubstituted piperazine

(15,2 mmol) i et passende oppløsningsmiddel, slik som THF, tilsettes et keton eller et aldehyd (22,6 mmol), vann, eddiksyre (45,0 mmol) og så NaCNBH3 (18 mmol). Blandingen omrøres ved 55 °C i 5,5 timer (ketoner) eller ved romtemperatur over natten (alde-hyder) , og konsentreres så under redusert trykk. Mettet, vandig NaHC03-oppløsning (100 ml) tilsettes, og blandingen ekstraheres med et slikt oppløsningsmiddel som etylacetat (3 x 40 ml). De kombinerte ekstrakter vaskes med saltoppløsning, tørkes over magnesiumsulfat og konsentreres under redusert trykk. Resten kan omdannes til et passende salt, slik som hydrokloridsaltet, ved hjelp av saminndamping med en syre, slik som 1 molar vandig saltsyre, etanol og toluen, og resten renses så ved hjelp av rekrystallisasjon. (15.2 mmol) in a suitable solvent, such as THF, is added a ketone or an aldehyde (22.6 mmol), water, acetic acid (45.0 mmol) and then NaCNBH3 (18 mmol). The mixture is stirred at 55 °C for 5.5 hours (ketones) or at room temperature overnight (aldehyder), and then concentrated under reduced pressure. Saturated aqueous NaHCO 3 solution (100 mL) is added and the mixture is extracted with a solvent such as ethyl acetate (3 x 40 mL). The combined extracts are washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue can be converted to a suitable 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 then purified by recrystallization.

Generell fremgangsmåte ( B) General procedure ( B)

Forbindelsene med den generelle formel (I) kan fremstilles ved hjelp av den generelle fremgangsmåte (B): The compounds with the general formula (I) can be prepared using the general method (B):

En blanding av et monosubstituert piperazin A mixture of a monosubstituted piperazine

(2,00 mmol), DMSO (1,0 ml), et passende aryl- eller heteroaryl-halogenid (2,00 mmol) og en slik base som DIPEA (0,20 ml) om-røres i 1 time ved 100 °C og så i 18 timer ved 120 °C. Vann og kaliumkarbonat tilsettes, og blandingen ekstraheres med et slikt oppløsningsmiddel som etylacetat (3 x 20 ml). Isolering og rensing gjøres som i generell fremgangsmåte (A). (2.00 mmol), DMSO (1.0 mL), an appropriate aryl or heteroaryl halide (2.00 mmol) and a base such as DIPEA (0.20 mL) are stirred for 1 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 cleaning are done as in general procedure (A).

Ikke-kommersielt tilgjengelige, substituerte 2-klor-kinoliner fremstilles som beskrevet i litteraturen: F. Effen-berger, W. Hartmann, Chemische Berichte, 1969, 102, 3260-3267. Non-commercially available substituted 2-chloroquinolines are prepared as described in the literature: F. Effenberger, W. Hartmann, Chemische Berichte, 1969, 102, 3260-3267.

Generell fremgangsmåte ( C) General procedure ( C)

Forbindelsene med den generelle formel (I) kan fremstilles ved hjelp av den generelle fremgangsmåte (C): The compounds with the general formula (I) can be prepared using the general method (C):

En forbindelse med formel I kan fremstilles fra et passende monosubstituert piperazin og et passende arylbromid i nærvær av en passende katalysator, slik som f.eks. tris(di-benzylidenaceton)dipalladium, i et passende oppløsningsmiddel, slik som toluen, ved en passende temperatur mellom 0 og 150 °C. A compound of formula I can be prepared from a suitable monosubstituted piperazine and a suitable aryl bromide in the presence of a suitable catalyst, such as e.g. tris(di-benzylideneacetone)dipalladium, in a suitable solvent, such as toluene, at a suitable temperature between 0 and 150 °C.

Eksempel 1 Example 1

4-( 4- syklopentylpiperazin- l- yl) fenol 4-(4-cyclopentylpiperazin-1-yl)phenol

Til en suspensjon av 1-(4-hydroksyfenyl)piperazin (2,70 g, 15,2 mmol) i THF (28 ml) ble tilsatt syklopentanon (1,90 ml, 22,6 mmol), vann (0,15 ml), eddiksyre (2,70 ml, To a suspension of 1-(4-hydroxyphenyl)piperazine (2.70 g, 15.2 mmol) in THF (28 mL) was added cyclopentanone (1.90 mL, 22.6 mmol), water (0.15 mL ), acetic acid (2.70 ml,

45,0 mmol) og så NaCNBH3 (18 ml, 1 molar i THF, 18 mmol). Blandingen ble omrørt ved 55 °C i 5,5 timer og så konsentrert under redusert trykk. Mettet, vandig NaHCC>3-oppløsning (100 ml) og etylacetat (40 ml) ble tilsatt, og blandingen ble filtrert. Det resulterende faste stoff ble på nytt oppslemmet i metanol (30 ral), det ble varmet opp til refluks, og suspensjonen fikk stå ved romtemperatur over natten. Filtrering og tørking under redusert trykk ga tittelforbindelsen (1,82 g, 49 %) som et fast stoff. 45.0 mmol) and then NaCNBH 3 (18 mL, 1 molar in THF, 18 mmol). The mixture was stirred at 55°C for 5.5 hours and then concentrated under reduced pressure. Saturated aqueous NaHCO 3 solution (100 mL) and ethyl acetate (40 mL) were added and the mixture was filtered. The resulting solid was reslurried in methanol (30 ral), heated to reflux, and the suspension allowed to stand at room temperature overnight. Filtration and drying under reduced pressure afforded the title compound (1.82 g, 49%) as a solid.

<1>H-NMR (DMSO-d6) 8 1,34 (m, 2 H) , 1,49 (m, 2 H) , 1,60 (m, 2 H), 1,79 (m, 2 H), 2,43 (m, 1 H), 2,51 (m, 4 H), 2,92 (m, 4 H), 6,62 (d, J = 8 Hz, 2 H), 6,77 (d, J = 8 Hz, 2 H), 8,78 (s, <1>H-NMR (DMSO-d6) 8 1.34 (m, 2H) , 1.49 (m, 2H) , 1.60 (m, 2H), 1.79 (m, 2H ), 2.43 (m, 1 H), 2.51 (m, 4 H), 2.92 (m, 4 H), 6.62 (d, J = 8 Hz, 2 H), 6.77 (d, J = 8 Hz, 2 H), 8.78 (s,

1 H); HPLC-MS: m/z 247 (MH+) ; Rf: 2,70 minutter. 1H); HPLC-MS: m/z 247 (MH + ); Rf: 2.70 minutes.

Eksempel 2 Example 2

l- syklopentyl- 4-[ 4-( 4- fluorbenzyloksy) fenyl] piperazin 1-cyclopentyl-4-[4-(4-fluorobenzyloxy)phenyl]piperazine

Til en suspensjon av kaliumhydroksid (0,165 g, To a suspension of potassium hydroxide (0.165 g,

2,95 mmol) i etanol (4 ml) ble tilsatt 4-(4-syklopentylpiperazin-l-yl)fenol (0,25 g, 1,02 mmol). Etter 10 minutter ble 4-fluorbenzylklorid (0,18 ml, 0,22 g, 1,51 mmol) tilsatt, og blandingen ble omrørt ved 7 0 °C i 5 timer. Mettet, vandig NaHC03~ oppløsning (20 ml) ble tilsatt, og blandingen ble ekstrahert med etylacetat (3 x 20 ml). De kombinerte ekstrakter ble vasket med saltoppløsning, tørket over magnesiumsulfat og konsentrert. Re-krystallisering fra metanol (4 ml) ga 0,125 g (35 %) av tittelforbindelsen. 2.95 mmol) in ethanol (4 mL) was added 4-(4-cyclopentylpiperazin-1-yl)phenol (0.25 g, 1.02 mmol). After 10 min, 4-fluorobenzyl chloride (0.18 mL, 0.22 g, 1.51 mmol) was added and the mixture was stirred at 70 °C for 5 h. Saturated aqueous NaHCO 3 - solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. Recrystallization from methanol (4 mL) gave 0.125 g (35%) of the title compound.

<1>H-NMR (DMSO-de) 5 1,34 (m, 2 H) , 1,50 (m, 2 H) , 1,62 (m, 2 H), 1,81 (m, 2 H), 2,45 (m, 1 H), 2,51 (m, 4 H), 2,99 (m, 4 H) , 5,00 (s, 2 H) , 6,87 (m, 4 H) , 7,19 (t, J = 8 Hz, 2 H) , 7,46 (m, 2 H); HPLC-MS: m/z 355 (MH+) ; Rf: 4,73 minutter. <1>H-NMR (DMSO-de) δ 1.34 (m, 2H) , 1.50 (m, 2H) , 1.62 (m, 2H), 1.81 (m, 2H ), 2.45 (m, 1 H), 2.51 (m, 4 H), 2.99 (m, 4 H) , 5.00 (s, 2 H) , 6.87 (m, 4 H ) , 7.19 (t, J = 8 Hz, 2 H) , 7.46 (m, 2 H); HPLC-MS: m/z 355 (MH + ); Rf: 4.73 minutes.

Eksempel 3 Example 3

( 3- klorfenyl)- 4- syklopentylpiperazin (3-chlorophenyl)-4-cyclopentylpiperazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 1, ved å starte fra 1-(3-klorfenyl)piperazin. This compound was prepared as described in Example 1, starting from 1-(3-chlorophenyl)piperazine.

<X>H-NMR (DMSO-d6) 8 1,34 (m, 2 H) , 1,50 (m, 2 H) , 1,60 (m, 2 H), 1,80 (m, 2 H), 2,45 (m, 1 H), 2,51 (m, 4 H), 3,14 (m, 4 H), 6,78 (d, J = 8 Hz, 1 H), 6,88 (m, 2 H), 7,19 (t, J = 8 Hz, <X>H-NMR (DMSO-d6) 8 1.34 (m, 2H) , 1.50 (m, 2H) , 1.60 (m, 2H), 1.80 (m, 2H ), 2.45 (m, 1 H), 2.51 (m, 4 H), 3.14 (m, 4 H), 6.78 (d, J = 8 Hz, 1 H), 6.88 (m, 2 H), 7.19 (t, J = 8 Hz,

1 H); HPLC-MS: m/z 265 (MH+) ; Rf: 3,88 minutter. 1H); HPLC-MS: m/z 265 (MH + ); Rf: 3.88 minutes.

Eksempel 4 Example 4

1-[ 4-( 4- syklopentylpiperazin- l- yl) fenyl] etanon 1-[4-(4-Cyclopentylpiperazin-1-yl)phenyl]ethanone

Denne forbindelsen ble fremstilt som beskrevet i eksempel 1, ved å starte fra 1-(4-acetylfenyl)piperazin. This compound was prepared as described in Example 1, starting from 1-(4-acetylphenyl)piperazine.

<1>H-NMR (DMSO-de) 8 1, 30-1,88 (m, 8 H) , 2,45 (s, 3 H) , 2,45 (m, 1 H), 2,51 (m, 4 H) , 3,31 (m, 4 H) , 6,95 (d, J = 8 Hz, 2 H), 7,79 (d, J = 8 Hz, 2 H); HPLC-MS: m/z 273 (MH+) ; Rf: <1>H-NMR (DMSO-de) 8 1, 30-1.88 (m, 8 H) , 2.45 (s, 3 H) , 2.45 (m, 1 H), 2.51 ( m, 4 H) , 3.31 (m, 4 H), 6.95 (d, J = 8 Hz, 2 H), 7.79 (d, J = 8 Hz, 2 H); HPLC-MS: m/z 273 (MH + ); RF:

3,25 minutter. 3.25 minutes.

Eksempel 5 Example 5

1-( 3, 4- diklorfenyl)- 4-( l- etylpropyl) piperazin 1-(3,4-dichlorophenyl)-4-(1-ethylpropyl)piperazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 1, ved å starte fra 1-(3,4-diklorfenyl)piperazin og 3-pentanon. This compound was prepared as described in Example 1, starting from 1-(3,4-dichlorophenyl)piperazine and 3-pentanone.

<1>H-NMR (DMSO-de) 5 0,88 (t, J = 7 Hz, 6 H) , 1,28 (m, <1>H-NMR (DMSO-de) δ 0.88 (t, J = 7 Hz, 6 H) , 1.28 (m,

2 H) , 1,45 (m, 2 H) , 2,19 (m, 1 H) , 2,56 (br s, 4 H) , 3,12 (br s, 4 H), 6,91 (m, 1 H), 7,09 (br s, 1 H), 7,36 (d, J = 8 Hz, 2 H) , 1.45 (m, 2 H) , 2.19 (m, 1 H) , 2.56 (br s, 4 H) , 3.12 (br s, 4 H), 6.91 ( m, 1 H), 7.09 (br s, 1 H), 7.36 (d, J = 8 Hz,

1 H); HPLC-MS: m/z 301 (MH+) ; Rf: 4,25 minutter. 1H); HPLC-MS: m/z 301 (MH + ); Rf: 4.25 minutes.

Eksempel 6 Example 6

( 4-[ 4-( 1- etylpropyl) piperazin- l- yl] fenyl} fenylmetanon- hydroklorid ( 4-[ 4-( 1- ethylpropyl) piperazin-1- yl] phenyl} phenylmethanone hydrochloride

En blanding av 1-(3-pentyl)piperazin (0,31 g, A mixture of 1-(3-pentyl)piperazine (0.31 g,

2,00 mmol), DMSO (1,0 ml), 4-fluorbenzofenon (0,40 g, 2,00 mmol) og DIPEA (0,20 ml) ble omrørt i 1 time ved 100 °C og så i 18 timer ved 120 °C. Vann (50 ml) og kaliumkarbonat (2 g) ble tilsatt, og blandingen ble ekstrahert med etylacetat (3 x 2.00 mmol), DMSO (1.0 mL), 4-fluorobenzophenone (0.40 g, 2.00 mmol) and DIPEA (0.20 mL) were stirred for 1 h at 100 °C and then for 18 h at 120 °C. Water (50 mL) and potassium carbonate (2 g) were added and the mixture was extracted with ethyl acetate (3 x

20 ml). De kombinerte ekstrakter ble vasket med saltoppløsning, tørket med magnesiumsulfat og konsentrert under redusert trykk. Råproduktet ble på nytt oppløst i etanol (10 ml) og 1 molar vandig HC1 (4 ml), og oppløsningen ble konsentrert under redusert trykk. Etter saminndamping med etanol og toluen størknet resten og ble rekrystallisert fra acetonitril (100 ml). 0,20 g (27 %) av tittelforbindelsen ble erholdt. <1>H-NMR (DMSO-d6) 8 0, 95 (m, 6 H) , 1,62 (m, 2 H) , 1,89 (m, 2 H), 3,04-3,27 (m, 3 H), 3,48 (m, 4 H), 4,05 (m, 2 H), 7,08 (m, 2 H), 7,51 (m, 2 H), 7,65 (m, 5 H), 10,75 (br s, 1 H); HPLC-MS: m/z 337 (MH+) ; Rf: 4,27 minutter. Eksempel 7 1-( 4- benzylfenyl)- 4-( 1- etylpropyl) piperazin- hydroklorid 20 ml). The combined extracts were washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The crude product was redissolved in ethanol (10 mL) and 1 M aqueous HCl (4 mL), and the solution was concentrated under reduced pressure. After coevaporation with ethanol and toluene, the residue solidified and was recrystallized from acetonitrile (100 mL). 0.20 g (27%) of the title compound was obtained. <1>H-NMR (DMSO-d6) 8 0.95 (m, 6H) , 1.62 (m, 2H) , 1.89 (m, 2H), 3.04-3.27 ( m, 3 H), 3.48 (m, 4 H), 4.05 (m, 2 H), 7.08 (m, 2 H), 7.51 (m, 2 H), 7.65 ( m, 5H), 10.75 (br s, 1H); HPLC-MS: m/z 337 (MH + ); Rf: 4.27 minutes. Example 7 1-(4-benzylphenyl)-4-(1-ethylpropyl)piperazine hydrochloride

En blanding av {4-[4-(1-etylpropyl)piperazin-l-yl]-fenyl}fenylmetanon-hydroklorid (77 mg, 0,21 mmol), trifluoreddiksyre (2,0 ml) og trietylsilan (0,5 ml) ble omrørt ved 60 °C 1 20 timer. Blandingen ble konsentrert under redusert trykk og blandet med vann og kaliumkarbonat. Blandingen ble ekstrahert med etylacetat (3 x 20 ml). De kombinerte ekstrakter ble vasket med saltoppløsning, tørket over magnesiumsulfat og konsentrert under redusert trykk. Råproduktet ble på nytt oppløst i etanol og 1 molar vandig HC1, og oppløsningen ble konsentrert under redusert trykk. Etter saminndamping med etanol og toluen størknet resten. 4 5 mg (61 %) av tittelforbindelsen ble erholdt. A mixture of {4-[4-(1-ethylpropyl)piperazin-1-yl]-phenyl}phenylmethanone hydrochloride (77 mg, 0.21 mmol), trifluoroacetic acid (2.0 mL) and triethylsilane (0.5 mL ) was stirred at 60 °C for 120 h. The mixture was concentrated under reduced pressure and mixed with water and potassium carbonate. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was redissolved in ethanol and 1 molar aqueous HCl, and the solution was concentrated under reduced pressure. After coevaporation with ethanol and toluene, the residue solidified. 45 mg (61%) of the title compound was obtained.

<X>H-NMR (DMSO-d6) 8 0, 98 (t, J = 7 Hz, 6 H) , 1,64 (m, <X>H-NMR (DMSO-d6) 8 0.98 (t, J = 7 Hz, 6 H) , 1.64 (m,

2 H), 1,89 (m, 2 H), 3,04-3,23 (m, 5 H), 3,48 (m, 2 H), 3,72 (m, 2 H), 3,85 (s, 2 H), 6,93 (d, J = 8 Hz, 2 H), 7,10-7,30 (m, 7 H), 10,05 (br s, 1 H); HPLC-MS: m/z 323 (MH+) ; Rf: 4,93 minutter . Eksempel 8 Syklopropyl-{ 4-[ 4-( 1- etylpropyl) piperazin- l- yl] fenyl} metanon-hydroklorid 2H), 1.89 (m, 2H), 3.04-3.23 (m, 5H), 3.48 (m, 2H), 3.72 (m, 2H), 3, 85 (s, 2 H), 6.93 (d, J = 8 Hz, 2 H), 7.10-7.30 (m, 7 H), 10.05 (br s, 1 H); HPLC-MS: m/z 323 (MH + ); Rf: 4.93 minutes. Example 8 Cyclopropyl-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone hydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 4-fluorfenyl(syklopropyl)keton. This compound was prepared as described in Example 6, starting from 4-fluorophenyl(cyclopropyl)ketone.

<1>H-NMR (DMSO-de) 6 0, 98 (m, 10 H) , 1,64 (m, 2 H) , 1,89 (m, 2 H), 2,82 (br s, 1 H), 3,04-3,23 (m, 3 H), 3,49 (m, 4 H), 4,04 (m, 2 H), 7,07 (d, J = 8 Hz, 2 H), 7,96 (d, J = 8 Hz, 2 H), 10,95 (br s, 1 H); HPLC-MS: m/z 301 (MH+) ; Rf: 4,03 minutter. <1>H-NMR (DMSO-de) 6 0.98 (m, 10 H) , 1.64 (m, 2 H) , 1.89 (m, 2 H), 2.82 (br s, 1 H), 3.04-3.23 (m, 3 H), 3.49 (m, 4 H), 4.04 (m, 2 H), 7.07 (d, J = 8 Hz, 2 H ), 7.96 (d, J = 8 Hz, 2 H), 10.95 (br s, 1 H); HPLC-MS: m/z 301 (MH + ); Rf: 4.03 minutes.

Eksempel 9 Example 9

( 2- klorfenyl)-{ 4-[ 4-( 1- etylpropyl) piperazin- l- yl] fenyl} metanon-hydroklorid (2-chlorophenyl)-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone hydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 4-fluorfenyl-(2-klorfenyl)keton. This compound was prepared as described in Example 6, starting from 4-fluorophenyl-(2-chlorophenyl)ketone.

<X>H-NMR (DMS0-d6) 8 0, 98 (t, J = 7 Hz, 6 H) , 1,64 (m, <X>H-NMR (DMS0-d6) 8 0.98 (t, J = 7 Hz, 6 H) , 1.64 (m,

2 H), 1,88 (m, 2 H), 3,08-3,23 (m, 3 H), 3,50 (m, 4 H), 4,06 (m, 2 H), 7,08. (d, J = 8 Hz, 2 H), 7,31 (m, 1 H), 7,48 (m, 1 H), 7,50-7,61 (m, 4 H), 10,85 (br s, 1 H); HPLC-MS: m/z 371 (MH+) ; Rf: 4,43 minutter. Eksempel 10 { 4 - [ 4-( 1- etylpropyl) piperazin- l- yl] fenyl}-( 4- fluorfenyl) metanon-hydroklorid 2H), 1.88 (m, 2H), 3.08-3.23 (m, 3H), 3.50 (m, 4H), 4.06 (m, 2H), 7, 08. (d, J = 8 Hz, 2 H), 7.31 (m, 1 H), 7.48 (m, 1 H), 7.50-7.61 (m, 4 H), 10.85 ( br s, 1 H); HPLC-MS: m/z 371 (MH + ); Rf: 4.43 minutes. Example 10 {4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}(4-fluorophenyl)methanone hydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 4,4<1->difluorbenzofenon. This compound was prepared as described in Example 6, starting from 4,4<1->difluorobenzophenone.

<1>H-NMR (DMSO-d5) 8 0, 98 (t, J = 7 Hz, 6 H) , 1,66 (m, <1>H-NMR (DMSO-d5) 8 0.98 (t, J = 7 Hz, 6 H), 1.66 (m,

2 H), 1,89 (m, 2 H), 3,08-3,25 (m, 3 H), 3,41-3,53 (m, 4 H), 4,05 (m, 2 H), 7,09 (d, J = 8 Hz, 2 H), 7,38 (m, 2 H), 7,69 (d, J = 8 Hz, 2 H), 7,76 (m, 2 H), 10,80 (br s, 1 H); HPLC-MS: m/z 355 (MH+) ; Rf: 4,37 minutter. Eksempel 11 l- syklopentyl- 4-( 6- trifluormetylpyridin- 2- yl) piperazin 2 H), 1.89 (m, 2 H), 3.08-3.25 (m, 3 H), 3.41-3.53 (m, 4 H), 4.05 (m, 2 H ), 7.09 (d, J = 8 Hz, 2 H), 7.38 (m, 2 H), 7.69 (d, J = 8 Hz, 2 H), 7.76 (m, 2 H ), 10.80 (br s, 1 H); HPLC-MS: m/z 355 (MH + ); Rf: 4.37 minutes. Example 11 1-cyclopentyl-4-(6-trifluoromethylpyridin-2-yl)piperazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 1, ved å starte fra 1-(6-trifluormetylpyridin-2-yl)-piperazin. This compound was prepared as described in Example 1, starting from 1-(6-trifluoromethylpyridin-2-yl)-piperazine.

<1>H-NMR (DMSO-d6) 8 1,34 (m, 2 H) , 1,50 (m, 2 H) , 1,60 (m, 2 H), 1,80 (m, 2 H), 2,45-2,51 (m, 5 H), 3,52 (m, 4 H), 7,02 (d, J = 8 Hz, 1 H), 7,11 (d, J = 8 Hz, 1 H), 7,71 (t, J = 8 Hz, 1 H); HPLC-MS: m/z 300 (MH+) ; Rf: 4,10 minutter. <1>H-NMR (DMSO-d6) 8 1.34 (m, 2H) , 1.50 (m, 2H) , 1.60 (m, 2H), 1.80 (m, 2H ), 2.45-2.51 (m, 5 H), 3.52 (m, 4 H), 7.02 (d, J = 8 Hz, 1 H), 7.11 (d, J = 8 Hz, 1 H), 7.71 (t, J = 8 Hz, 1 H); HPLC-MS: m/z 300 (MH + ); Rf: 4.10 minutes.

Eksempel 12 Example 12

1- syklopentyl- 4-( 5- trifluormetylpyridin- 2- yl) piperazin 1-cyclopentyl-4-(5-trifluoromethylpyridin-2-yl)piperazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 1, ved å starte fra 1-(5-trifluormetylpyridin-2-yl)-piperazin. This compound was prepared as described in Example 1, starting from 1-(5-trifluoromethylpyridin-2-yl)-piperazine.

<1>H-NMR (DMSO-d6) 8 1,36 (m, 2 H) , 1,50 (m, 2 H) , 1,60 (m, 2 H), 1,80 (m, 2 H), 2,45-2,52 (m, 5 H), 3,58 (m, 4 H), 6,92 (d, J = 8 Hz, 1 H), 7,78 (br d, J = 8 Hz, 1 H), 8,39 (s, 1 H); HPLC-MS: m/z 300 (MH+) ; Rf. 3,87 minutter. <1>H-NMR (DMSO-d6) 8 1.36 (m, 2H) , 1.50 (m, 2H) , 1.60 (m, 2H), 1.80 (m, 2H ), 2.45-2.52 (m, 5 H), 3.58 (m, 4 H), 6.92 (d, J = 8 Hz, 1 H), 7.78 (br d, J = 8 Hz, 1 H), 8.39 (s, 1 H); HPLC-MS: m/z 300 (MH + ); Rf. 3.87 minutes.

Eksempel 13 Example 13

[ 4-( 4- syklopentylpiperazin- l- yl) fenyl]-( 3, 4- dimetoksyfenyl)-metanon- hydroklorid [ 4-( 4- cyclopentylpiperazin-1- yl) phenyl]-( 3, 4- dimethoxyphenyl)-methanone hydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 4'-fluor-3,4-dimetoksybenzofenon. This compound was prepared as described in Example 6, starting from 4'-fluoro-3,4-dimethoxybenzophenone.

<:>H-NMR (DMSO-d6) 8 1,55 (m, 2 H) , 1, 65-1, 90 (m, 4 H) , 2,02 (m, 2 H), 3,05-3,40 (m, 4 H), 3,55 (m, 3 H), 3,81 (s, 3 H), 3,88 (s, 3 H), 4,08 (m, 2 H), 7,10 (m, 3 H), 7,29 (m, 2 H), 7,69 (d, J = 8 Hz, 2 H), 10,78 (br s, 1 H); HPLC-MS: m/z 395 (MH+) ; Rf: 3,03 minutter. <:>H-NMR (DMSO-d6) δ 1.55 (m, 2H) , 1.65-1.90 (m, 4H) , 2.02 (m, 2H), 3.05- 3.40 (m, 4 H), 3.55 (m, 3 H), 3.81 (s, 3 H), 3.88 (s, 3 H), 4.08 (m, 2 H), 7.10 (m, 3 H), 7.29 (m, 2 H), 7.69 (d, J = 8 Hz, 2 H), 10.78 (br s, 1 H); HPLC-MS: m/z 395 (MH + ); Rf: 3.03 minutes.

Eksempel 14 Example 14

[ 6-( 4- syklopentylpiperazin- l- yl) pyridin- 3- yl] piperidin- l- yl-metanon- hydroklorid [ 6-( 4-cyclopentylpiperazin-1-yl)pyridin-3-yl] piperidin-1-yl-methanone hydrochloride

<1>H-NMR (DMSO-de) 8 1, 45-2, 08 (m, 14 H), 3,06 (m, 2 H) , 3,38-3,61 (m, 9 H), 4,44 (m, 2 H) , 7,02 (d, J = 8 Hz, 1 H), 7,70 (dd, J = 8 Hz, 1 Hz, 1 H), 8,19 (d, J = 1 Hz, 1 H); HPLC-MS: m/z <1>H-NMR (DMSO-de) δ 1.45-2.08 (m, 14 H), 3.06 (m, 2 H), 3.38-3.61 (m, 9 H), 4.44 (m, 2 H), 7.02 (d, J = 8 Hz, 1 H), 7.70 (dd, J = 8 Hz, 1 Hz, 1 H), 8.19 (d, J = 1Hz, 1H); HPLC-MS: m/z

(MH<+>) . (MH<+>) .

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6 (generell fremgangsmåte B), ved å anvende l-(6-klor-nikotinoyl)piperidin (Thunus, Ann. Pharm. Fr., 1977, 35, 197). This compound was prepared as described in Example 6 (general procedure B), using 1-(6-chloro-nicotinoyl)piperidine (Thunus, Ann. Pharm. Fr., 1977, 35, 197).

Eksempel 15 Example 15

{ 6-[ 4-( 1- syklopropyl- l- metyletyl) piperazin- l- yl] pyridin- 3- yl)-fenylmetanon- hydroklorid { 6-[ 4-( 1- cyclopropyl- 1- methylethyl) piperazin- 1- yl] pyridin- 3- yl)-phenylmethanone hydrochloride

<X>H-NMR (DMSO-d6) 8 0, 48-0, 62 (m, 4 H) , 1,22-1, 39 (m, 7 H), 3,14 (m, 2 H), 3,69 (m, 4 H), 4,64 (m, 2 H), 7,08 (d, J = 8 Hz, 1 H), 7,55 (m, 2 H), 7,61-7,72 (m, 3 H) , 8,00 (dd, J = 8 Hz, 1 Hz, 1 H), 8,52 (d, J = 1 Hz, 1 H), 11,27 (br s, 1 H); HPLC-MS: m/z 350 (MH+) ; Rf: 3,03 minutter. <X>H-NMR (DMSO-d6) δ 0.48-0.62 (m, 4H), 1.22-1.39 (m, 7H), 3.14 (m, 2H), 3.69 (m, 4 H), 4.64 (m, 2 H), 7.08 (d, J = 8 Hz, 1 H), 7.55 (m, 2 H), 7.61-7 .72 (m, 3 H) , 8.00 (dd, J = 8 Hz, 1 Hz, 1 H), 8.52 (d, J = 1 Hz, 1 H), 11.27 (br s, 1 H); HPLC-MS: m/z 350 (MH + ); Rf: 3.03 minutes.

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 2-klor-5-benzoylpyridin (T.D. Penning et al., J. Med. Chem., 2000, 43, 721-735). This compound was prepared as described in Example 6, starting from 2-chloro-5-benzoylpyridine (T.D. Penning et al., J. Med. Chem., 2000, 43, 721-735).

Eksempel 16 Example 16

{ 6-[ 4-( 1- etylpropyl) piperazin- l- yl] pyridin- 3- yl} fenylmetanon-hydroklorid {6-[4-(1-ethylpropyl)piperazin-1-yl]pyridin-3-yl}phenylmethanone hydrochloride

<1>H-NMR (DMSO-de) 8 0, 97 (t, J = 7 Hz, 6 H) , 1,65 (m, <1>H-NMR (DMSO-de) 8 0.97 (t, J = 7 Hz, 6 H) , 1.65 (m,

2 H), 1,90 (m, 2 H), 3,02-3,22 (m, 3 H), 3,49-3,69 (m, 4 H), 4,60 (m, 2 H), 7,08 (d, J = 8 Hz, 1 H), 7,56 (m, 2 H), 7,68 (m, 3 H), 7,99 (dd, J = 8 Hz, 1 Hz, 1 H), 8,50 (d, J = 1 Hz, 1 H), 10,90 (br s, 1 H); HPLC-MS: m/z 338 (MH+) ; Rf: 3,00 minutter. Eksempel 17 { 2-[ 4-( 1- etylpropyl) piperazin- l- yl] pyridin- 4- yl} fenylmetanon-hydroklorid 2 H), 1.90 (m, 2 H), 3.02-3.22 (m, 3 H), 3.49-3.69 (m, 4 H), 4.60 (m, 2 H ), 7.08 (d, J = 8 Hz, 1 H), 7.56 (m, 2 H), 7.68 (m, 3 H), 7.99 (dd, J = 8 Hz, 1 Hz , 1 H), 8.50 (d, J = 1 Hz, 1 H), 10.90 (br s, 1 H); HPLC-MS: m/z 338 (MH + ); Rf: 3.00 minutes. Example 17 {2-[4-(1-ethylpropyl)piperazin-1-yl]pyridin-4-yl}phenylmethanone hydrochloride

<1>H-NMR (DMSO-de) 8 0, 97 (t, J = 7 Hz, 6 H) , 1,63 (m, <1>H-NMR (DMSO-de) 8 0.97 (t, J = 7 Hz, 6 H) , 1.63 (m,

2 H), 1,85 (m, 2 H), 3,12 (m, 3 H), 3,47 (m, 4 H), 4,43 (m, 2 H), 6,91 (d, J = 6 Hz, 1 H), 7,14 (s, 1 H), 7,58 (t, J = 8 Hz, 2 H), 7,70-7,84 (m, 3 H), 8,33 (d, J = 6 Hz, 1 H), 10,43 (br s, 2 H), 1.85 (m, 2 H), 3.12 (m, 3 H), 3.47 (m, 4 H), 4.43 (m, 2 H), 6.91 (d, J = 6 Hz, 1 H), 7.14 (s, 1 H), 7.58 (t, J = 8 Hz, 2 H), 7.70-7.84 (m, 3 H), 8, 33 (d, J = 6 Hz, 1 H), 10.43 (br s,

1 H); HPLC-MS: m/z 338 (MH+) ; RF: 2,97 minutter. 1H); HPLC-MS: m/z 338 (MH + ); RF: 2.97 minutes.

Denne forbindelsen ble fremstilt fra 2-klor-4-benzoyl-pyridin, som ble fremstilt ved hjelp av Friedel-Crafts-acylering av benzen med 2-klor-4-klorkarbonylpyridin. This compound was prepared from 2-chloro-4-benzoyl-pyridine, which was prepared by Friedel-Crafts acylation of benzene with 2-chloro-4-chlorocarbonylpyridine.

Eksempel 18 Example 18

{ 4-[ 4-( 1- etylpropyl) piperazin- l- yl] fenyl}-( 4- hydroksyfenyl)-metanon- hydroklorid { 4-[ 4-( 1- ethylpropyl) piperazin- 1- yl] phenyl }- ( 4- hydroxyphenyl) methanone hydrochloride

<1>H-NMR (DMSO-d6) 8 0, 97 (t, J = 7 Hz, 6 H) , 1,65 (m, <1>H-NMR (DMSO-d6) 8 0.97 (t, J = 7 Hz, 6 H) , 1.65 (m,

2 H), 1,92 (m, 2 H), 3,05-3,25 (m, 3 H), 3,35-3,55 (m, 4 H), 4,02 (m, 2 H), 6,89 (d, J = 8 Hz, 2 H), 7,08 (d, J = 8 Hz, 2 H), 7,59 (d, J = 8 Hz, 2 H) , 7,63 (d, J = 8 Hz, 2 H), 10,36 (s, 1 H), 10,60 (br s, 1 H); HPLC-MS: m/z 353 (MH+) ; Rf: 2,13 minutter . Eksempel 19 { 6-[ 4-( 1- etylpropyl) piperazin- l- yl] pyridin- 3- yl} piperidin- l- yl-metanon- hydroklorid 2 H), 1.92 (m, 2 H), 3.05-3.25 (m, 3 H), 3.35-3.55 (m, 4 H), 4.02 (m, 2 H ), 6.89 (d, J = 8 Hz, 2 H), 7.08 (d, J = 8 Hz, 2 H), 7.59 (d, J = 8 Hz, 2 H), 7.63 (d, J = 8 Hz, 2 H), 10.36 (s, 1 H), 10.60 (br s, 1 H); HPLC-MS: m/z 353 (MH + ); Rf: 2.13 minutes. Example 19 {6-[4-(1-ethylpropyl)piperazin-1-yl]pyridin-3-yl}piperidin-1-yl-methanone hydrochloride

<X>H-NMR (DMS0-d6) 8 0, 97 (t, J = 7 Hz, 6 H) , 1,50 (m, <X>H-NMR (DMS0-d6) 8 0.97 (t, J = 7 Hz, 6 H) , 1.50 (m,

4 H), 1,63 (m, 4 H), 1,89 (m, 2 H), 3,05-3,20 (m, 3 H), 3,50 (m, 8 H), 4,46 (m, 2 H), 7,04 (m, 1 H), 7,70 (m, 1 H), 8,18 (br s, 1 H), 10,90 (br s, 1 H); HPLC-MS: m/z 345 (MH+) ; Rf: 2,27 minutter . Eksempel 20 { 6-[ 4-( 1- etylpropyl) piperazin- l- yl] pyridin- 3- yl)-( 4- fluorfenyl)-metanon- hydroklorid 4 H), 1.63 (m, 4 H), 1.89 (m, 2 H), 3.05-3.20 (m, 3 H), 3.50 (m, 8 H), 4, 46 (m, 2 H), 7.04 (m, 1 H), 7.70 (m, 1 H), 8.18 (br s, 1 H), 10.90 (br s, 1 H); HPLC-MS: m/z 345 (MH + ); Rf: 2.27 minutes. Example 20 {6-[4-(1-ethylpropyl)piperazin-1-yl]pyridin-3-yl)-(4-fluorophenyl)-methanone hydrochloride

<1>H-NMR (DMSO-d6) 8 0, 95 (t, J = 7 Hz, 6 H) , 1,62 (m, <1>H-NMR (DMSO-d6) 8 0.95 (t, J = 7 Hz, 6 H) , 1.62 (m,

2 H), 1,83 (m, 2 H), 3,10 (m, 3 H), 3,45-3,65 (m, 4 H), 4,55 (m, 2 H), 7,05 (d, J = 8 Hz, 1 H), 7,38 (d, J = 8 Hz, 2 H), 7,78 (dd, J = 8 Hz, 4 Hz, 2 H), 7,96 (dd, J = 8 Hz, 1 Hz, 1 H), 8,48 (d, J = 1 Hz, 1 H), 10,85 (br s, 1 H); HPLC-MS: m/z 356 (MH+) ; Rf: 2,40 minutter. Eksempel 21 ( generell fremgangsmåte ( B)) 3-( 4- isopropylpiperazin- l- yl)- 6- fenylpyridazin- hydroklorid 2 H), 1.83 (m, 2 H), 3.10 (m, 3 H), 3.45-3.65 (m, 4 H), 4.55 (m, 2 H), 7, 05 (d, J = 8 Hz, 1 H), 7.38 (d, J = 8 Hz, 2 H), 7.78 (dd, J = 8 Hz, 4 Hz, 2 H), 7.96 ( dd, J = 8 Hz, 1 Hz, 1 H), 8.48 (d, J = 1 Hz, 1 H), 10.85 (br s, 1 H); HPLC-MS: m/z 356 (MH + ); Rf: 2.40 minutes. Example 21 (general procedure (B)) 3-(4-isopropylpiperazin-1-yl)-6-phenylpyridazine hydrochloride

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-isopropylpiperazin og 3-klor-6-fenylpyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 25, 881 (1978). 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., 25, 881 (1978).

<:>H-NMR (D20): 8 1,46 (d, 6 H), 3,28 (m, 2 H), 3,48 (m, 2 H), 3,64-3,84 (m, 3 H), 4,57 (m, 2 H), 7,63-7,72 (m, 4 H), 7,90 (m, 2 H), 8,12 (d, 1 H); HPLC-MS: m/z = 283,2 (M + 1); Rt = 1,52 minutter. <:>H-NMR (D2O): δ 1.46 (d, 6 H), 3.28 (m, 2 H), 3.48 (m, 2 H), 3.64-3.84 (m , 3H), 4.57 (m, 2H), 7.63-7.72 (m, 4H), 7.90 (m, 2H), 8.12 (d, 1H); HPLC-MS: m/z = 283.2 (M + 1); Rt = 1.52 minutes.

Eksempel 22 ( generell fremgangsmåte ( B)) Example 22 (general method (B))

3-( 4- syklopentylpiperazin- l- yl)- 6-( 4- metansulfonylfenyl) pyridazin 3-(4-cyclopentylpiperazin-1-yl)-6-(4-methanesulfonylphenyl)pyridazine

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(4-metansulfonylfenyl)pyridazin, fremstilt som beskrevet 1 J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared according to general procedure (B), starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonylphenyl)pyridazine, prepared as described 1 J. Heterocycl. Chem., 15, 881 (1978).

<1>H-NMR (CDC13) : 8 1, 38-1, 80 (m, 6 H) , 1,92 (m, 2 H) , 2,56 (kvint., 1 H), 2,66 (dd, 4 H), 3,10 (s, 3 H), 3,97 (dd, 4 H), 6,99 (d, 1 H), 7,69 (d, 1 H), 8,03 (d, 2 H), 8,20 (d, <1>H-NMR (CDCl 3 ) : δ 1.38-1.80 (m, 6 H), 1.92 (m, 2 H), 2.56 (quint., 1 H), 2.66 ( dd, 4 H), 3.10 (s, 3 H), 3.97 (dd, 4 H), 6.99 (d, 1 H), 7.69 (d, 1 H), 8.03 ( d, 2H), 8.20 (d,

2 H); HPLC-MS: m/z = 387,0 (M + 1); Rt = 2,20 minutter. 2H); HPLC-MS: m/z = 387.0 (M + 1); Rt = 2.20 minutes.

Eksempel 23 ( generell fremgangsmåte ( B)) Example 23 (general method (B))

3-( 4- syklopropylmetylpiperazin- l- yl)- 6-( 4- metansulfonylfenyl)-pyridazin 3-(4-Cyclopropylmethylpiperazin-1-yl)-6-(4- Methanesulfonylphenyl)-pyridazine

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(4-metansulfonylfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared according to general procedure (B), starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonylphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).

<1>H-NMR (CDCI3) : 8 0,15 (q, 2 H) , 0,57 (m, 2 H) , 0,92 (m, 1 H), 2,34 (d, 2 H), 2,69 (dd, 4 H), 3,10 (s, 3 H), 3,80 (dd, <1>H-NMR (CDCl 3 ) : δ 0.15 (q, 2 H), 0.57 (m, 2 H), 0.92 (m, 1 H), 2.34 (d, 2 H) , 2.69 (dd, 4 H), 3.10 (s, 3 H), 3.80 (dd,

4 H), 7,01 (d, 1 H), 7,70 (d, 1 H), 8,03 (d, 2 H), 8,21 (d, 2 H); HPLC-MS: m/z = 373,4 (M + 1); Rt= 2,04 minutter. Eksempel 24 ( generell fremgangsmåte ( B)) 3-( 4- isopropylpiperazin- l- yl)- 6-( 4- metansulfonylfenyl) pyridazin 4H), 7.01 (d, 1H), 7.70 (d, 1H), 8.03 (d, 2H), 8.21 (d, 2H); HPLC-MS: m/z = 373.4 (M + 1); Rt= 2.04 minutes. Example 24 (general method (B)) 3-(4-isopropylpiperazin-1-yl)-6-(4-methanesulfonylphenyl)pyridazine

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-isopropylpiperazin og 3-klor-6-(4-metansulfonylfenyl)pyridazin, fremstilt som beskrevet 1 J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared according to general procedure (B), starting from 1-isopropylpiperazine and 3-chloro-6-(4-methanesulfonylphenyl)pyridazine, prepared as described 1 J. Heterocycl. Chem., 15, 881 (1978).

<X>H-NMR (DMSO-d6) 8 1,01 (d, 6 H) , 2,57 (m, 4 H) , 2,71 (m, 1 H), 3,26 (s, 3 H), 3,67 (m, 4 H), 7,39 (d, 1 H), 8,02 (d, 2 H), 8,06 (d, 1 H), 8,30,(d, 2 H); HPLC-MS: m/z = 360,8 <X>H-NMR (DMSO-d6) δ 1.01 (d, 6 H) , 2.57 (m, 4 H) , 2.71 (m, 1 H), 3.26 (s, 3 H ), 3.67 (m, 4 H), 7.39 (d, 1 H), 8.02 (d, 2 H), 8.06 (d, 1 H), 8.30,(d, 2 H); HPLC-MS: m/z = 360.8

(M + 1); Rt = 1,43 minutter. (M + 1); Rt = 1.43 minutes.

Eksempel 25 ( generell fremgangsmåte ( B)) Example 25 (general method (B))

3-( 4- klorfenyl)- 6-( 4- isopropylpiperazin- l- yl)- 4- metylpyridazin-dihydroklorid 3-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1-yl)-4- methylpyridazine dihydrochloride

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-isopropylpiperazin og 6-klor-3-(4-klorfenyl)-4-metylpyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared according to general procedure (B), starting from 1-isopropylpiperazine and 6-chloro-3-(4-chlorophenyl)-4-methylpyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).

<X>H-NMR (D20): 8 1, 08 (d, 6 H) , 2,10 (s, 1 H) , 3,01 (m, 2 H), 3,23 (m, 2 H), 3,28-3,44 (m, 3 H), 4,31 (bred d, 2 H), 7,27 (d, 2 H), 7,34 (d, 2 H), 7,58 (s, 1 H); HPLC-MS: m/z = 331,1 (M + 1); Rt= 3,1 minutter. <X>H-NMR (D 2 O): δ 1.08 (d, 6 H), 2.10 (s, 1 H), 3.01 (m, 2 H), 3.23 (m, 2 H) , 3.28-3.44 (m, 3 H), 4.31 (broad d, 2 H), 7.27 (d, 2 H), 7.34 (d, 2 H), 7.58 ( s, 1H); HPLC-MS: m/z = 331.1 (M + 1); Rt= 3.1 minutes.

C18 H23 N4 Cl, 2 HC1. C18 H23 N4 Cl, 2 HCl.

Beregnet: C 53,54 H 6,24 N 13,88. Calculated: C 53.54 H 6.24 N 13.88.

Funnet: C 53,34 H 6,31 N 13,70. Found: C 53.34 H 6.31 N 13.70.

Eksempel 26 ( generell fremgangsmåte ( B)) Example 26 (general method (B))

3-( 4- klorfenyl)- 6-( 4- syklopentylpiperazin- l- yl)- 4- metylpyrid-azin- hydroklorid 3-( 4- Chlorophenyl)- 6-( 4- Cyclopentylpiperazin-1- yl)- 4- Methylpyridazine Hydrochloride

Denne forbindelsen ble fremstilt i henhold til generell fremgangsmåte (B), ved å starte fra 1-syklopentylpiperazin og 6-klor-3-(4-klorfenyl)-4-metylpyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared according to general procedure (B), starting from 1-cyclopentylpiperazine and 6-chloro-3-(4-chlorophenyl)-4-methylpyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).

<1>H-NMR (D20) : 8 1,29-1,60 (m, 6 H) , 1,91 (m, 2 H) , 2,12 (s, 3 H), 3,00 (m, 2 H), 3,24 (m, 2 H), 3,36 (m, 1 H), 3,51 (bred d, 2 H), 4,29 (bred d, 2 H), 7,29 (d, 2 H), 7,36 (d, 2 H), 7,60 (s, 1 H); HPLC-MS: m/z = 357,1 (M + 1); Rt= 3,25 minutter. <1>H-NMR (D2O) : δ 1.29-1.60 (m, 6 H), 1.91 (m, 2 H), 2.12 (s, 3 H), 3.00 (m , 2 H), 3.24 (m, 2 H), 3.36 (m, 1 H), 3.51 (wide d, 2 H), 4.29 (wide d, 2 H), 7.29 (d, 2H), 7.36 (d, 2H), 7.60 (s, 1H); HPLC-MS: m/z = 357.1 (M + 1); Rt= 3.25 minutes.

C20, H25 N4 Cl, 2 HC1. C20, H25 N4 Cl, 2 HCl.

Beregnet: C 55,89 H 6,33 N 13,04. Calculated: C 55.89 H 6.33 N 13.04.

Funnet: C 55,83 H 6,47 N 12,93. Found: C 55.83 H 6.47 N 12.93.

Eksempel 27 ( generell fremgangsmåte ( B)) Example 27 (general procedure (B))

3-( 4- klorfenyl)- 6-( 4- syklopentylpiperazin- l- yl) pyridazin 3-(4-chlorophenyl)-6-(4-cyclopentylpiperazin-1-yl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(4-klorfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-chlorophenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<X>H-NMR (CDCI3) : 8 1,39-1,81 (m, 6 H) , 1,91 (m, 2 H) , 2,56 (q, 1 H), 2,66 (dd, 4 H), 3,74 (dd, 4 H), 6,96 (d, J = <X>H-NMR (CDCl 3 ) : δ 1.39-1.81 (m, 6 H), 1.91 (m, 2 H), 2.56 (q, 1 H), 2.66 (dd , 4 H), 3.74 (dd, 4 H), 6.96 (d, J =

9,5 Hz, 1 H), 7,43 (d, J = 8,7 Hz, 2 H), 7,61 (d, J = 9,5 Hz, 9.5 Hz, 1 H), 7.43 (d, J = 8.7 Hz, 2 H), 7.61 (d, J = 9.5 Hz,

1 H), 7,93 (d, J = 8,7 Hz, 2 H); HPLC-MS (metode #): m/z = 343 (M + 1); Rt = 2,93 minutter. Eksempel 28 ( generell fremgangsmåte ( B)) 3-( 4- syklopentylpiperazin- l- yl)- 6-( 3- fluor- 4- metoksyfenyl) pyridazin- dihydroklorid 1 H), 7.93 (d, J = 8.7 Hz, 2 H); HPLC-MS (Method #): m/z = 343 (M + 1); Rt = 2.93 minutes. Example 28 (general procedure (B)) 3-(4-cyclopentylpiperazin-1-yl)-6-(3-fluoro-4-methoxyphenyl)pyridazine dihydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(3-fluor-4-metoksyfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared as described in Example 6, starting from 1-cyclopentylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).

<X>H-NMR (DMSO-d6) 8 1,45-2,15 (m, 8 H) , 3,17 (m, 2 H) , 3,40-3,77 (m, 5 H), 3,92 (s, 3 H), 7,34 (t, J = 8,7 Hz, 1 H), 7,80 (d, J = 9,8 Hz, 1 H), 7,85-8,05 (m, 2 H), 8,29 (d, J = <X>H-NMR (DMSO-d6) δ 1.45-2.15 (m, 8H) , 3.17 (m, 2H) , 3.40-3.77 (m, 5H), 3.92 (s, 3 H), 7.34 (t, J = 8.7 Hz, 1 H), 7.80 (d, J = 9.8 Hz, 1 H), 7.85-8, 05 (m, 2 H), 8.29 (d, J =

9,8 Hz, 1 H), 11,75 (bs, 1 H); HPLC-MS: m/z = 357 (M + 1); Rt= 2,47 minutter. 9.8 Hz, 1 H), 11.75 (bs, 1 H); HPLC-MS: m/z = 357 (M + 1); Rt= 2.47 minutes.

Eksempel 29 ( generell fremgangsmåte ( B)) Example 29 (general procedure (B))

3-( 4- syklopentylpiperazin- l- yl)- 6-( 3, 4- dimetoksyfenyl) pyridazin 3-(4-cyclopentylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(3,4-dimetoksyfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopentylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (CDCI3) : 8 1,40-1, 65 (m, 4 H) , 1,73 (m, 2 H) , 1,91 (m, 2 H), 2,55 (q, 1 H), 2,66 (t, 4 H), 3,72 (t, 4 H), 3,93 (s, 3 H), 3,98 (s, 3 H), 6,93 (d, 1 H), 6,97 (d, 1 H) , 7,36 (dd, <1>H-NMR (CDCl 3 ) : δ 1.40-1.65 (m, 4 H), 1.73 (m, 2 H), 1.91 (m, 2 H), 2.55 (q , 1 H), 2.66 (t, 4 H), 3.72 (t, 4 H), 3.93 (s, 3 H), 3.98 (s, 3 H), 6.93 (d , 1H), 6.97 (d, 1H) , 7.36 (dd,

1 H), 7,64 (d, 1 H), 7,86 (d, 1 H); HPLC-MS: m/z = 370 (M + 1); Rt = 1,90 minutter. Eksempel 30 ( generell fremgangsmåte ( B)) 3-( 4klorfenyl)- 6-( 4- syklopropylmetylpiperazin- l- yl) pyridazin 1H), 7.64 (d, 1H), 7.86 (d, 1H); HPLC-MS: m/z = 370 (M + 1); Rt = 1.90 minutes. Example 30 (general procedure (B)) 3-(4chlorophenyl)-6-(4-cyclopropylmethylpiperazin-1-yl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopropylmetylpiperazin og 3-klor-6-(4-klorfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopropylmethylpiperazine and 3-chloro-6-(4-chlorophenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<X>H-NMR (CDC13) : 8 0, 46 (m, 2 H) , 0,88 (m, 2 H) , 1,33 (m, 1 H), 2,90 (d, 2 H), 3,1-3,5 (m, 4 H), 4,1-4,35 (m, 4 H) , 7,05 (d, 1 H), 7,46 (d, 2 H), 7,72 (d, 1 H), 7,95 (d, 2 H); HPLC-MS: m/z - 329 (M + 1); Rt= 2,11 minutter. <X>H-NMR (CDCl 3 ) : δ 0.46 (m, 2H), 0.88 (m, 2H), 1.33 (m, 1H), 2.90 (d, 2H) , 3.1-3.5 (m, 4 H), 4.1-4.35 (m, 4 H), 7.05 (d, 1 H), 7.46 (d, 2 H), 7 .72 (d, 1H), 7.95 (d, 2H); HPLC-MS: m/z - 329 (M + 1); Rt= 2.11 minutes.

Eksempel 31 ( generell fremgangsmåte ( B)) Example 31 (general procedure (B))

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopentylpiperazin og 3-klor-6-(4-trifluormetylfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopentylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (CDCI3) : 8 1, 40-1, 65 (m, 4 H) , 1, 65-1,80 (m, <1>H-NMR (CDCl 3 ) : 8 1.40-1.65 (m, 4 H), 1.65-1.80 (m,

2 H), 1,92 (m, 2 H), 2,55 (q, 1 H), 2,65 (t, 4 H), 3,76 (t, 4 H), 6,99 (d, 1 H), 7,67 (d, 1 H), 7,72 (d, 2 H), 8,12 (d, 2 H); HPLC-MS): m/z = 377 (M + 1); Rt= 2,68 minutter. Eksempel 32 ( generell fremgangsmåte ( B)) 3-( 4- isopropylpiperazin- l- yl)- 6-( 4- trifluormetylfenyl) pyridazin 2 H), 1.92 (m, 2 H), 2.55 (q, 1 H), 2.65 (t, 4 H), 3.76 (t, 4 H), 6.99 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H), 8.12 (d, 2H); HPLC-MS): m/z = 377 (M + 1); Rt= 2.68 minutes. Example 32 (general procedure (B)) 3-(4-isopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-isopropylpiperazin og 3-klor-6-(4-trifluormetylfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (DMSO-d6) 8 1,20 (d, 6 H) , 2,8-4,2 (m, 9 H) , 7,47 (d, 1 H), 7,85 (d, 2 H), 8,12 (d, 1 H), 8,28 (d, 2 H); HPLC-MS: m/z = 351 (M + 1); Rt = 2,51 minutter. <1>H-NMR (DMSO-d6) δ 1.20 (d, 6 H) , 2.8-4.2 (m, 9 H) , 7.47 (d, 1 H), 7.85 ( d, 2H), 8.12 (d, 1H), 8.28 (d, 2H); HPLC-MS: m/z = 351 (M + 1); Rt = 2.51 minutes.

Eksempel 33 ( generell fremgangsmåte ( B)) Example 33 (general procedure (B))

3-( 4- syklopropylmetylpiperazin- l- yl)- 6-( 4- trifluormetylfenyl)-pyridazin 3-(4-cyclopropylmethylpiperazin-1-yl)-6-(4- trifluoromethylphenyl)-pyridazine

^4 ^4

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopropylmetylpiperazin og 3-klor-6-(4-trifluormetylfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopropylmethylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (CDC13) : 8 0,15 (m, 2 H) , 0,57 (m, 2 H) , 0,92 (m, 1 H), 2,33 (d, 2 H), 2,69 (t, 4 H), 3,79 (t, 4 H), 7,00 (d, 1 H), 7,67 (d, 1 H), 7,72 (d, 2 H), 8,12 (d, 2 H); HPLC-MS: m/z = 363 (M + 1); Rt= 2,65 minutter. <1>H-NMR (CDCl 3 ) : δ 0.15 (m, 2 H), 0.57 (m, 2 H), 0.92 (m, 1 H), 2.33 (d, 2 H) , 2.69 (t, 4H), 3.79 (t, 4H), 7.00 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H) , 8.12 (d, 2H); HPLC-MS: m/z = 363 (M + 1); Rt= 2.65 minutes.

Eksempel 34 ( generell fremgangsmåte ( B)) Example 34 (general procedure (B))

3-( 4- klorfenyl)- 6-( 4- isopropylpiperazin- l- yl) pyridazin 3-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1-yl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-isopropylpiperazin og 3-klor-6-(4-klorfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 25, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(4-chlorophenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 25, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (CDC13) : 1,10 (d, 6 H) , 2,68 (t, 4 H) , 2,75 (q, 1 H), 3,73 (t, 4 H), 6,97 (d, 1 H), 7,43 (d, 2 H), 7,61 (d, <1>H-NMR (CDCl 3 ) : 1.10 (d, 6 H), 2.68 (t, 4 H), 2.75 (q, 1 H), 3.73 (t, 4 H), 6.97 (d, 1 H), 7.43 (d, 2 H), 7.61 (d,

1 H), 7,94 (d, 2 H); HPLC-MS: m/z = 317 (M + 1); Rt = 2,03 minutter . Eksempel 35 ( generell fremgangsmåte ( B)) 3-( 4- syklopropylmetylpiperazin- l- yl)- 6-( 3- fluor- 4- metoksyfenyl)-pyridazin 1H), 7.94 (d, 2H); HPLC-MS: m/z = 317 (M + 1); Rt = 2.03 minutes. Example 35 (general procedure (B)) 3-(4-cyclopropylmethylpiperazin-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-syklopropylmetylpiperazin og 3-klor-6-(3-fluor-4-metoksyfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 25, 881 (1978). Tittelforbindelsen ble-erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-cyclopropylmethylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 25, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (DMSO-d6) 8 0, 40 (m, 2 H) , 0,65 (m, 2 H) , 1,15 (m, 1 H), 2,8-3,7 (m, 10 H), 3,90 (s, 3 H), 7,29 (t, 1 H), 7,47 (d, 1 H), 7,88 (d, 1 H), 7,93 (d, 1 H), 8,06 (d, 1 H); HPLC-MS: m/z = 343 (M + 1); Rt = 1,90 minutter. <1>H-NMR (DMSO-d6) 8 0.40 (m, 2H) , 0.65 (m, 2H) , 1.15 (m, 1H), 2.8-3.7 ( m, 10 H), 3.90 (s, 3 H), 7.29 (t, 1 H), 7.47 (d, 1 H), 7.88 (d, 1 H), 7.93 ( d, 1H), 8.06 (d, 1H); HPLC-MS: m/z = 343 (M + 1); Rt = 1.90 minutes.

Eksempel 36 ( generell fremgangsmåte ( B)) Example 36 (general procedure (B))

3-( 3- fluor- 4- metoksyfenyl)- 6-( 4- isopropylpiperazin- l- yl) pyridazin 3-(3-fluoro-4-methoxyphenyl)-6-(4-isopropylpiperazin-1-yl)pyridazine

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-isopropylpiperazin og 3-klor-6-(3-fluor-4-metoksyfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). Tittelforbindelsen ble erholdt som den frie base. This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base.

<1>H-NMR (CDC13) : 8 1,11 (d, 6 H) , 2,70 (m, 4 H) , 2,80 (q, 1 H), 3,74 (m, 4 H) , 3,94 (s, 3 H) , 6,96 (d, 1 H) , 7,04 (t, <1>H-NMR (CDCl 3 ) : δ 1.11 (d, 6 H), 2.70 (m, 4 H), 2.80 (q, 1 H), 3.74 (m, 4 H) , 3.94 (s, 3 H) , 6.96 (d, 1 H) , 7.04 (t,

1 H), 7,57 (d, 1 H), 7,72 (d, 1 H), 7,78 (m, 1 H); HPLC-MS: m/z = 331 (M + 1); Rt= 1,57 minutter. Eksempel 37 ( generell fremgangsmåte ( B)) 3-( 3, 4- dimetoksyfenyl)- 6-( 4- isopropylpiperazin- l- yl) pyridazin-dihydroklorid 1H), 7.57 (d, 1H), 7.72 (d, 1H), 7.78 (m, 1H); HPLC-MS: m/z = 331 (M + 1); Rt= 1.57 minutes. Example 37 (general procedure (B)) 3-(3,4-dimethoxyphenyl)-6-(4-isopropylpiperazin-1-yl)pyridazine dihydrochloride

Denne forbindelsen ble fremstilt som beskrevet i eksempel 6, ved å starte fra 1-isopropylpiperazin og 3-klor-6-(3,4-dimetoksyfenyl)pyridazin, fremstilt som beskrevet i J. Heterocycl. Chem., 15, 881 (1978). This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).

<1>H-NMR (DMSO-d6) 8 1,32 (d, 6 H) , 3,17 (q, 1 H) , 3,3-4,1 (m, 6 H), 3,84 (s, 3 H), 3,87 (s, 3 H), 4,56 (d, 2 H), 7,09 (d, 1 H), 7,62 (d, 1 H), 7,68-7,73 (m, 2 H), 8,23 (d, 1 H), 11,35 (s, 1 H); HPLC-MS: m/z = 343 (M + 1); Rt= 1,50 minutter. <1>H-NMR (DMSO-d6) δ 1.32 (d, 6 H) , 3.17 (q, 1 H) , 3.3-4.1 (m, 6 H), 3.84 ( s, 3H), 3.87 (s, 3H), 4.56 (d, 2H), 7.09 (d, 1H), 7.62 (d, 1H), 7.68- 7.73 (m, 2H), 8.23 (d, 1H), 11.35 (s, 1H); HPLC-MS: m/z = 343 (M + 1); Rt= 1.50 minutes.

Eksempel 38 ( generell fremgangsmåte ( B)) Example 38 (general procedure (B))

[ 4-( 4- syklopropylpiperazin- l- yl) fenyl] fenylmetanon- hydroklorid [ 4-( 4- cyclopropylpiperazin-1- yl) phenyl] phenylmethanone hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 4-fluorbenzofenon. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 4-fluorobenzophenone.

<X>H-NMR (DMSO-d6) 8 0, 82 (m, 2 H) , 1,16 (m, 2 H) , 2,92 (br s, 1 H), 3,30-3,40 (m, 4 H), 3,56 (br s, 2 H), 4,09 (m, 2 H), 7,12 (d, J = 8 Hz, 2 H), 7,54 (m, 2 H), 7,60-7,75 (m, <X>H-NMR (DMSO-d6) δ 0.82 (m, 2H) , 1.16 (m, 2H) , 2.92 (br s, 1H), 3.30-3.40 (m, 4 H), 3.56 (br s, 2 H), 4.09 (m, 2 H), 7.12 (d, J = 8 Hz, 2 H), 7.54 (m, 2 H), 7.60-7.75 (m,

5 H) , 10,82 (br s, 1 H); HPLC-MS: m/z 307 (MH+) / Rt = 2,00 minutter. Eksempel 39 ( generell fremgangsmåte ( B)) l- syklopropyl- 4-[ 5-( 4- trifluormetylfenyl) pyridin- 2- yl] piperazin- hydroklorid 5H), 10.82 (br s, 1H); HPLC-MS: m/z 307 (MH + ) / Rt = 2.00 minutes. Example 39 (general procedure (B)) 1-cyclopropyl-4-[5-(4-trifluoromethylphenyl)pyridin-2-yl]piperazin- hydrochloride

Det nødvendige 2-klor-5-(4-trifluorfenyl)pyridin ble fremstilt som beskrevet av R. Church, R. Trust, J.D. Albright og D. Powell, J. Org. Chem., 1995, 60, 3750-3758, på den følgende måte: Til en oppløsning av Vilsmeier-reagens fremstilt fra dimetylformamid (5,98 g, 0,082 mol) og fosforoksyklorid (22,5 g, 0,146 mol) ved 10 °C ble 4-(trifluormetyl) fenyleddiksyre (6,64 g, 0,033 mol) tilsatt. Blandingen ble omrørt ved 70 °C i 8 timer. Etter avkjøling til omgivelsestemperatur ble blandingen sakte tilsatt til en blanding av is og vann (temperaturen var < 10 °C) , og så ble oppløsningen av Na2C03 sakte tilsatt inntil pH 11 ble nådd. Toluen (125 ml) ble tilsatt til den alkaliske blanding, og den resulterende blanding ble kokt under tilbakeløpskjøling i 1,5 timer. Etter avkjøling til omgivelsestemperatur ble det fraskilte vannlag ekstrahert med toluen (100 ml). De kombinerte organiske lag ble vasket med vann, tørket (Na2S04) og konsentrert under redusert trykk. Det resulterende faste stoff ble rekrystallisert fra en blanding av diklormetan og heptan, hvorved man fikk 6,98 g (87 %) 3-dimetylamino-2-(4-trifluormetylfenyl)-propenal som gule krystaller, smp. 97 °C. The required 2-chloro-5-(4-trifluorophenyl)pyridine was prepared as described by R. Church, R. Trust, J.D. Albright and D. Powell, J. Org. Chem., 1995, 60, 3750-3758, as follows: To a solution of Vilsmeier reagent prepared from dimethylformamide (5.98 g, 0.082 mol) and phosphorus oxychloride (22.5 g, 0.146 mol) at 10 °C 4-(trifluoromethyl)phenylacetic acid (6.64 g, 0.033 mol) was added. The mixture was stirred at 70 °C for 8 hours. After cooling to ambient temperature, the mixture was slowly added to a mixture of ice and water (the temperature was < 10 °C), and then the solution of Na 2 CO 3 was slowly added until pH 11 was reached. Toluene (125 mL) was added to the alkaline mixture and the resulting mixture was refluxed for 1.5 hours. After cooling to ambient temperature, the separated aqueous layer was extracted with toluene (100 ml). The combined organic layers were washed with water, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting solid was recrystallized from a mixture of dichloromethane and heptane to give 6.98 g (87%) of 3-dimethylamino-2-(4-trifluoromethylphenyl)-propenal as yellow crystals, m.p. 97 °C.

^-NMR-spektrum (CDC13) 8 9,10 (s, 1 H) , 7,57 (m, 2 H) , 7,32 (m, 2 H) , 6,95 (s, 1 H) , 2,85 (s, 6 H) ; RF (Si02, kloro-form/metanol 95:5) 0,34. 3-NMR spectrum (CDCl 3 ) δ 9.10 (s, 1 H) , 7.57 (m, 2 H) , 7.32 (m, 2 H) , 6.95 (s, 1 H) , 2 .85 (p, 6 H) ; RH (SiO 2 , chloroform/methanol 95:5) 0.34.

Til en oppløsning av natriummetoksid (3,64 g, To a solution of sodium methoxide (3.64 g,

0,068 mol) i metanol (68 ml) ble cyanoacetamid (6,95 g, 0.068 mol) in methanol (68 mL) became cyanoacetamide (6.95 g,

0,082 mol) og produktet ovenfor (6,98 g, 0,029 mol) tilsatt. Blandingen ble omrørt ved omgivelsestemperatur i 1,5 timer og så kokt under tilbakeløpskjøling i 8 timer. I løpet av denne tiden utfeltes et gult, fast stoff. Reaksjonsblandingen ble fortynnet med vann (75 ml) og surgjort med 10 % vandig saltsyre. Det gule, faste stoff ble frafiltrert, vasket med vann, etanol, dietyleter og så med heksan. Dette ga 2-hydroksy-5-(4-trifluormetylfenyl)-nikotinonitril (6,66 g, 87 %) som et gult, fast stoff, smp. 235-242 °C. 0.082 mol) and the above product (6.98 g, 0.029 mol) added. The mixture was stirred at ambient temperature for 1.5 hours and then refluxed for 8 hours. During this time, a yellow solid is precipitated. The reaction mixture was diluted with water (75 mL) and acidified with 10% aqueous hydrochloric acid. The yellow solid was filtered off, washed with water, ethanol, diethyl ether and then with hexane. This gave 2-hydroxy-5-(4-trifluoromethylphenyl)-nicotinonitrile (6.66 g, 87%) as a yellow solid, m.p. 235-242 °C.

<1>H-NMR (DMSO-d6) 8 8, 42 (m, 1 H) , 7,91 (m, 1 H) , 7,66 (m, 4 H) ; RF (Si02, kloroform/metanol 95:5) 0,18. <1>H-NMR (DMSO-d6) δ 8.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); RH (SiO 2 , chloroform/methanol 95:5) 0.18.

Produktet ovenfor (6,66 g, 0,025 mol) ble tilsatt til en blanding av eddiksyre (100 ml) og konsentrert saltsyre The above product (6.66 g, 0.025 mol) was added to a mixture of acetic acid (100 mL) and concentrated hydrochloric acid

(70 ml). Reaksjonsblandingen ble kokt under tilbakeløpskjøling i 18 timer, fortynnet med vann (200 ml) og fikk avkjøles til romtemperatur mens det ble omrørt. Det faste stoff ble frafiltrert, vasket med vann og så med 50 % vandig etanol, hvorved man fikk 5,42 g (77 %) 2-hydroksy-5-(4-trif luormetylf eny.l ) ni kotinsyre som et lysegrått, fast stoff, smp. 305-315 °C. (70ml). The reaction mixture was refluxed for 18 h, diluted with water (200 mL) and allowed to cool to room temperature while stirring. The solid was filtered off, washed with water and then with 50% aqueous ethanol, whereby 5.42 g (77%) of 2-hydroxy-5-(4-trifluoromethylphenyl)nicotinic acid was obtained as a light gray solid substance, m.p. 305-315 °C.

<1>H-NMR (DMSO-d6) 8 8,71 (d, 1 H) , 8,43 (d, 1 H) , 7,96 (m, 2 H), 7,81 (m, 2 H); RF (Si02, kloroform/metanol 95:5): 0,13. <1>H-NMR (DMSO-d6) 8 8.71 (d, 1 H) , 8.43 (d, 1 H) , 7.96 (m, 2 H), 7.81 (m, 2 H ); RH (SiO 2 , chloroform/methanol 95:5): 0.13.

En blanding av produktet ovenfor (5,42 g, 0,019 mol) og nydestillert kinolin (50 ml) ble omrørt ved 215 °C i 12 timer. Reaksjonsblandingen ble avkjølt til omgivelsestemperatur, og heptan (250 ml) ble tilsatt. Det faste stoff ble frafiltrert, vasket med heptan og rekrystallisert fra en blanding av diklormetan og heptan, hvorved man fikk 3,92 g (86 %) 2-hydroksy-5-(4-trifluormetylfenyl)pyridin, smp. 178-182 °C. A mixture of the above product (5.42 g, 0.019 mol) and freshly distilled quinoline (50 mL) was stirred at 215 °C for 12 h. The reaction mixture was cooled to ambient temperature and heptane (250 mL) was added. The solid was filtered off, washed with heptane and recrystallized from a mixture of dichloromethane and heptane, whereby 3.92 g (86%) of 2-hydroxy-5-(4-trifluoromethylphenyl)pyridine were obtained, m.p. 178-182 °C.

<1>H-NMR (CDC13) 8 7, 79 (dd, 2 H) , 7,68 (d, 3 H) , 7,52 (d, 2 H), 6,73 (d, 1 H); RF (Si02, kloroform/metanol 95:5) 0,23. <1>H-NMR (CDCl 3 ) δ 7.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); RH (SiO 2 , chloroform/methanol 95:5) 0.23.

En blanding av fosforoksyklorid (27,6 g, 0,18 mol) og produktet ovenfor (3,92 g, 0,016 mol) ble omrørt ved 105 °C i 10 timer. Overskuddet fosforoksyklorid ble avdampet under redusert trykk, og resten ble strippet én gang med toluen (75 ml). Vann (75 ml) og diklormetan (75 ml) ble tilsatt til resten, diklormetanlaget ble fraskilt, og vannfasen ble ekstrahert med diklormetan (75 ml). De kombinerte ekstrakter ble vasket med vann, så med oppløsning av natriumhydrogenkarbonat, tørket (MgS04) og konsentrert under redusert trykk, hvorved man fikk 2,95 g (72 %) 2-klor-5-(4-trifluormetylfenyl)pyridin som lyse-brune krystaller, smp 98-101 °C. A mixture of phosphorus oxychloride (27.6 g, 0.18 mol) and the above product (3.92 g, 0.016 mol) was stirred at 105 °C for 10 hours. The excess phosphorus oxychloride was evaporated under reduced pressure and the residue was stripped once with toluene (75 mL). Water (75 mL) and dichloromethane (75 mL) were added to the residue, the dichloromethane layer was separated, and the aqueous phase was extracted with dichloromethane (75 mL). The combined extracts were washed with water, then with sodium hydrogencarbonate solution, dried (MgSO 4 ) and concentrated under reduced pressure to give 2.95 g (72%) of 2-chloro-5-(4-trifluoromethylphenyl)pyridine as lys- brown crystals, mp 98-101 °C.

<1>H-NMR (CDCI3) 8 8,62 (dd, 1 H) , 7,86 (dd, 1 H) , 7,44 (dd, 1 H) , 7,66 (m, 2 H), 7,75 (m, 2 H) ; RF (Si02, kloro-form/metanol 95:5) 0, 94. <1>H-NMR (CDCl 3 ) δ 8.62 (dd, 1 H) , 7.86 (dd, 1 H) , 7.44 (dd, 1 H) , 7.66 (m, 2 H), 7.75 (m, 2H); RH (SiO 2 , chloroform/methanol 95:5) 0.94.

Dette produktet ble behandlet med 1-syklopropylpiperazin, som beskrevet i generell fremgangsmåte (B), hvorved man fikk tittelforbindelsen. This product was treated with 1-cyclopropylpiperazine, as described in general procedure (B), whereby the title compound was obtained.

<1>H-NMR (DMSO-dg) 8 0, 83 (m, 2 H) , 1,13 (m, 2 H) , 2,85 (m, 1 H), 3,25-3,75 (m, 6 H), 4,51 (m, 2 H), 7,12 (d, J = 8 Hz, 1 H), 7,79 (d, J = 8 Hz, 2 H), 7,89 (d, J = 8 Hz, 2 H), 8,05 (m, <1>H-NMR (DMSO-dg) δ 0.83 (m, 2H) , 1.13 (m, 2H) , 2.85 (m, 1H), 3.25-3.75 ( m, 6 H), 4.51 (m, 2 H), 7.12 (d, J = 8 Hz, 1 H), 7.79 (d, J = 8 Hz, 2 H), 7.89 ( d, J = 8 Hz, 2 H), 8.05 (m,

1 H), 8,59 (m, 1 H), 10,56 (br s, 1 H); HPLC-MS: m/z 348 (MH+) ; Rt = 2,77 minutter. Eksempel 40 ( generell fremgangsmåte ( B)) 3-( 4- syklopropylpiperazin- l- yl)- 6-( 4- trifluormetylfenyl) pyridazin- hydroklorid 1 H), 8.59 (m, 1 H), 10.56 (br s, 1 H); HPLC-MS: m/z 348 (MH + ); Rt = 2.77 minutes. Example 40 (general method (B)) 3-(4-cyclopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)pyridazine hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 3-klor-6-(4-trifluormetylfenyl)pyridazin. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine.

<1>H-NMR (DMSO-d6) 8 0, 83 (m, 2 H) , 1,19 (m, 2 H) , 2,89 (m, 1 H), 3,30-3,70 (m, 6 H), 4,61 (m, 2 H), 7,61 (d, J = 8 Hz, 1 H), 7,88 (d, J = 8 Hz, 2 H), 8,22 (d, J = 8 Hz, 1 H), 8,29 (d, J = 8 Hz, 2 H), 11,11 (br s, 1 H) ; HPLC-MS: m/z 349 (MH+) ; Rt = 2,40 minutter. <1>H-NMR (DMSO-d6) δ 0.83 (m, 2H) , 1.19 (m, 2H) , 2.89 (m, 1H), 3.30-3.70 ( m, 6 H), 4.61 (m, 2 H), 7.61 (d, J = 8 Hz, 1 H), 7.88 (d, J = 8 Hz, 2 H), 8.22 ( d, J = 8 Hz, 1 H), 8.29 (d, J = 8 Hz, 2 H), 11.11 (br s, 1 H); HPLC-MS: m/z 349 (MH + ); Rt = 2.40 minutes.

Eksempel 41 ( generell fremgangsmåte ( B)) Example 41 (general procedure (B))

[ 6-( 4- syklopropylpiperazin- l- yl) piperidin- 3- yl] piperidin- 1- yl-metanon- hydroklorid [ 6-( 4-cyclopropylpiperazin-1-yl)piperidin-3-yl]piperidin-1-yl-methanone hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 6-klornikotinsyrepiperidid. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 6-chloronicotinic acid piperidide.

<1>H-NMR (DMSO-de) 8 0,81 (m, 2 H) , 1,17 (m, 2 H) , 1,51 (m, 4 H), 1,60 (m, 2 H), 2,87 (m, 1 H), 3,20-3,60 (m, 10 H), 4,47 (m, 2 H), 7,01 (d, J = 7 Hz, 1 H) , 7,67 (d, J = 7 Hz, 1 H), 8.21 (s, 1 H) , 11,04 (br s, 1 H); HPLC-MS: m/z 315 (MH+) ; Rt = 1.22 minutter. <1>H-NMR (DMSO-de) 8 0.81 (m, 2 H) , 1.17 (m, 2 H) , 1.51 (m, 4 H), 1.60 (m, 2 H ), 2.87 (m, 1 H), 3.20-3.60 (m, 10 H), 4.47 (m, 2 H), 7.01 (d, J = 7 Hz, 1 H) , 7.67 (d, J = 7 Hz, 1 H), 8.21 (s, 1 H), 11.04 (br s, 1 H); HPLC-MS: m/z 315 (MH + ); Rt = 1.22 minutes.

Eksempel 42 ( generell fremgangsmåte ( B)) Example 42 (general procedure (B))

[ 6-( 4- syklopropylpiperazin- l- yl) pyridin- 3- yl] pyrrolidin- l- yl-metanon- hydroklorid [ 6-( 4-cyclopropylpiperazin-1-yl)pyridin-3-yl]pyrrolidin-1-yl-methanone hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 6-klornikotinsyrepyrrolidid. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 6-chloronicotinic acid pyrrolidide.

<1>H-NMR (DMSO-d6) 8 0,81 (m, 2 H) , 1,15 (m, 2 H) , 1,84 (m, 4 H), 2,88 (m, 1 H), 3,15-3,60 (m, 10 H), 4,49 (m, 2 H), 7,00 (d, J = 7 Hz, 1 H), 7,83 (d, J = 7 Hz, 1 H), 8,38 (s, 1 H), 10,91 (br s, 1 H); HPLC-MS: m/z 301 (MH+) ; Rt = 1,22 minutter. <1>H-NMR (DMSO-d6) 8 0.81 (m, 2H) , 1.15 (m, 2H) , 1.84 (m, 4H), 2.88 (m, 1H ), 3.15-3.60 (m, 10 H), 4.49 (m, 2 H), 7.00 (d, J = 7 Hz, 1 H), 7.83 (d, J = 7 Hz, 1 H), 8.38 (s, 1 H), 10.91 (br s, 1 H); HPLC-MS: m/z 301 (MH + ); Rt = 1.22 minutes.

Eksempel 43 ( generell fremgangsmåte ( B)) Example 43 (general procedure (B))

3-( 4- syklopropylpiperazin- l- yl)- 6- fenylpyridazin- hydroklorid 3-(4-cyclopropylpiperazin-1-yl)-6-phenylpyridazine hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 3-klor-6-fenylpyridazin. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-phenylpyridazine.

<1>H-NMR (DMSO-d6) 8 0, 82 (m, 2 H) , 1,22 (m, 2 H) , 2,88 (br s, 1 H), 3,37 (m, 2 H), 3,59 (m, 4 H), 4,57 (m, 2 H), 7,53 (m, 3 H), 7,80 (d, J = 8 Hz, 1 H), 8,06 (m, 2 H), 8,29 (d, J = <1>H-NMR (DMSO-d6) 8 0.82 (m, 2 H) , 1.22 (m, 2 H) , 2.88 (br s, 1 H), 3.37 (m, 2 H), 3.59 (m, 4 H), 4.57 (m, 2 H), 7.53 (m, 3 H), 7.80 (d, J = 8 Hz, 1 H), 8, 06 (m, 2 H), 8.29 (d, J =

8 Hz, 1 H), 11,47 (br s, 1 H); HPLC-MS: m/z 281 (MH+) ; Rt = 8 Hz, 1 H), 11.47 (br s, 1 H); HPLC-MS: m/z 281 (MH + ); Rt =

1,43 minutter. 1.43 minutes.

Eksempel 44 ( generell fremgangsmåte ( B)) Example 44 (general procedure (B))

3-( 4- syklopropylpiperazin- l- yl)- 6-( 3, 4- dimetoksyfenyl) pyridazin-hydroklorid 3-(4-cyclopropylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyridazine hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 3-klor-6-(3,4-dimetoksyfenyl)pyridazin. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine.

<:>H-NMR (DMS0-d6) 8 0, 83 (m, 2 H) , 1,22 (m, 2 H) , 2,88 (br s, 1 H) , 3,36 (m, 2 H) , 3,60 (m, 4 H) , 3,84 (s, 3 H) , 3,87 (s, 3 H), 4,53 (m, 2 H), 7,14 (d, J = 8 Hz, 1 H), 7,66 (m, 2 H), 7,86 (d, J = 8 Hz, 1 H), 8,37 (d, J = 8 Hz, 1 H), 11,43 (br s, <:>H-NMR (DMS0-d6) 8 0.83 (m, 2 H) , 1.22 (m, 2 H) , 2.88 (br s, 1 H) , 3.36 (m, 2 H) , 3.60 (m, 4 H) , 3.84 (s, 3 H) , 3.87 (s, 3 H), 4.53 (m, 2 H), 7.14 (d, J = 8 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 8 Hz, 1 H), 8.37 (d, J = 8 Hz, 1 H), 11, 43 (br p,

1 H); HPLC-MS: m/z 341 (MH+) ; Rt = 1,45 minutter. 1H); HPLC-MS: m/z 341 (MH + ); Rt = 1.45 minutes.

Eksempel 45 ( generell fremgangsmåte ( B)) Example 45 (general procedure (B))

4- klor- 6-( 4- isopropylpiperazin- l- yl)- 3- fenylpyridazin- hydroklorid 4- chloro- 6-( 4- isopropylpiperazin-1- yl)- 3- phenylpyridazine hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-isopropylpiperazin og 4,6-diklor-3-fenylpyridazin. This compound was prepared using the general procedure (B) from 1-isopropylpiperazine and 4,6-dichloro-3-phenylpyridazine.

<1>H-NMR (DMSO-de) 5 1,31 (d, J = 7 Hz, 6 H) , 3,13 (m, <1>H-NMR (DMSO-de) δ 1.31 (d, J = 7 Hz, 6 H) , 3.13 (m,

2 H), 3, 40-3, 65 (m, 5 H) , 4,63 (m, 2 H) , 7,50 (m, 3 H), 7,63 (m, 2 H), 7,78 (s, 1 H), 11,01 (br s, 1 H); HPLC-MS: m/z 317 (MH+) ; Rt = 2,11 minutter. Eksempel 46 ( generell fremgangsmåte ( B)) 3-( 4- syklopropylpiperazin- l- yl)- 6-( 3- trifluormetylfenyl) pyridazin- hydroklorid 2 H), 3, 40-3, 65 (m, 5 H) , 4.63 (m, 2 H) , 7.50 (m, 3 H), 7.63 (m, 2 H), 7, 78 (s, 1 H), 11.01 (br s, 1 H); HPLC-MS: m/z 317 (MH + ); Rt = 2.11 minutes. Example 46 (general method (B)) 3-(4-cyclopropylpiperazin-1-yl)-6-(3-trifluoromethylphenyl)pyridazine hydrochloride

Denne forbindelsen ble fremstilt ved å anvende den generelle fremgangsmåte (B) fra 1-syklopropylpiperazin og 3-klor-6-(3-trifluormetylfenyl)pyridazin. This compound was prepared using the general procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(3-trifluoromethylphenyl)pyridazine.

<1>H-NMR (DMSO-de) 5 0, 83 (m, 2 H) , 1,22 (m, 2 H) , 2,89 <1>H-NMR (DMSO-de) δ 0.83 (m, 2H) , 1.22 (m, 2H) , 2.89

(br s, 1 H), 3,35 (m, 2 H), 3,59 (m, 4 H), 4,63 (m, 2 H), 7,68 (d, J = 8 Hz, 1 H), 7,77 (m, 1 H), 7,84 (m, 1 H), 8,32 (d, J = 8 Hz, 1 H), 8,40 (m, 2 H), 11,40 (br s, 1 H); HPLC-MS: m/z 349 (MH+) ; Rt = 2,43 minutter. (br s, 1 H), 3.35 (m, 2 H), 3.59 (m, 4 H), 4.63 (m, 2 H), 7.68 (d, J = 8 Hz, 1 H), 7.77 (m, 1 H), 7.84 (m, 1 H), 8.32 (d, J = 8 Hz, 1 H), 8.40 (m, 2 H), 11, 40 (br s, 1 H); HPLC-MS: m/z 349 (MH + ); Rt = 2.43 minutes.

Eksempel 47 ( generell fremgangsmåte ( C)) Example 47 (general procedure (C))

1-( bifenyl- 3- yl)- 4-( syklopentyl) piperazin 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine

En blanding av 3-brombifenyl (300 mg, 1,28 mmol), 1-syklopentylpiperazin (238 mg, 1,54 mmol), natrium-tert.-butoksid (173 mg, 1,8 mmol), tris(dibenzylidenaceton)dipalladium (12 mg, 0,01 mmol) og racemisk 2,2'-bis(difenylfosfino)-1,1'-binaftyl (24 mg, 0,04 mmol) i toluen (11 ml) ble blandet under nitrogen i en lukket reaksjonsbeholder. Reaksjonsblandingen ble omrørt ved A mixture of 3-bromobiphenyl (300 mg, 1.28 mmol), 1-cyclopentylpiperazine (238 mg, 1.54 mmol), sodium tert-butoxide (173 mg, 1.8 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.01 mmol) and racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (24 mg, 0.04 mmol) in toluene (11 mL) were mixed under nitrogen in a closed reaction vessel . The reaction mixture was stirred at

80 °C i 3 dageri en lukket reaksjonsbeholder. Den ble avkjølt til romtemperatur og vasket med vann (2 x 10 ml). De kombinerte organiske lag ble ekstrahert med 1 N saltsyre (2 x 20 ml). De kombinerte vandige ekstrakter ble gjort basisk med en 1 N vandig natriumhydroksidoppløsning og ekstrahert med tert.-butylmetyl-eter (3 x 20 ml). Tert.-butylmetyleterlagene ble tørket over magnesiumsulfat. Oppløsningsmidlet ble fjernet under vakuum, hvorved man fikk 220 mg av tittelforbindelsen. <1>H-NMR (CDC13, to sett signaler, brede signaler) 5 1,35-1,85 (m, 6 H) , 1,95 (m, 2 H) , 2,55 (m, 1 H) , 2,70 (m, 4 H) , 3,30 (m, 4 H), 6,95 (d, 1 H), 7,05 (d, 1 H), 7,15 (s, 1 H), 7,35 (t, 2 H), 7,45 (t, 2 H), 7,60 (d, 2 H). HPLC-metode B: eluering ved 10,45 minutter. 80 °C for 3 days in a closed reaction vessel. It was cooled to room temperature and washed with water (2 x 10 ml). The combined organic layers were extracted with 1 N hydrochloric acid (2 x 20 mL). The combined aqueous extracts were basified with a 1 N aqueous sodium hydroxide solution and extracted with tert-butyl methyl ether (3 x 20 mL). The tert-butyl methyl ether layers were dried over magnesium sulfate. The solvent was removed under vacuum to give 220 mg of the title compound. <1>H-NMR (CDC13, two sets of signals, broad signals) δ 1.35-1.85 (m, 6 H) , 1.95 (m, 2 H) , 2.55 (m, 1 H) , 2.70 (m, 4 H) , 3.30 (m, 4 H), 6.95 (d, 1 H), 7.05 (d, 1 H), 7.15 (s, 1 H) , 7.35 (t, 2H), 7.45 (t, 2H), 7.60 (d, 2H). HPLC method B: elution at 10.45 minutes.

Tittelforbindelsen ble overført til dens hydroklorid-salt ved å oppløse den i etylacetat (5 ml). En 3,2 M oppløsning av hydrogenklorid i etylacetat (5 ml) ble tilsatt. Oppløsnings-midlet ble fjernet under vakuum. Resten ble oppløst i etanol The title compound was converted to its hydrochloride salt by dissolving it in ethyl acetate (5 mL). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol

(50 ml). Oppløsningsmidlet ble fjernet i vakuum. (50ml). The solvent was removed in vacuo.

Eksempel 48 ( generell fremgangsmåte ( C)) Example 48 (general procedure (C))

l- syklopentyl- 4-[ 4-( 2-( pyrrolidin- l- yl) etoksy) fenyl] piperazin l- cyclopentyl- 4-[ 4-( 2-( pyrrolidin- l- yl) ethoxy) phenyl] piperazine

86 mg av tittelforbindelsen ble syntetisert som beskrevet for 1-(bifenyl-3-yl)-4-(syklopentyl)piperazin, ved å anvende 1-(2-(4-bromfenoksy)etyl)pyrrolidin i stedet for 3-brombifenyl. 86 mg of the title compound was synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 1-(2-(4-bromophenoxy)ethyl)pyrrolidine in place of 3-bromobiphenyl.

<X>H-NMR (DMSO-de) 8 1,55 (m, 2 H) , 1,75 (m, 2 H) , 1,85 <X>H-NMR (DMSO-de) 8 1.55 (m, 2H) , 1.75 (m, 2H) , 1.85

(m, 4 H), 2,00 (m, 4 H), 3,10 (m, 6 H), 3,40-3,70 (m, 9 H), 4,30 (t, 2 H), 7,00 (AB, 4 H), 10,80 (br, 1 H), 11,10 (br,1 H). HPLC-metode C: eluering ved 2,24 minutter. MS: beregnet for [M + H]<+>: 344, funnet: 344. (m, 4 H), 2.00 (m, 4 H), 3.10 (m, 6 H), 3.40-3.70 (m, 9 H), 4.30 (t, 2 H) , 7.00 (AB, 4 H), 10.80 (br, 1 H), 11.10 (br, 1 H). HPLC method C: elution at 2.24 minutes. MS: calculated for [M + H]<+>: 344, found: 344.

Tittelforbindelsen ble overført til dens hydroklorid-salt ved å oppløse den i etylacetat (5 ml). En 3,2 M oppløsning av hydrogenklorid i etylacetat (5 ml) ble tilsatt. Oppløsnings-midlet ble fjernet under vakuum. Resten ble oppløst i etanol (50 ml). Oppløsningsmidlet ble fjernet under vakuum. The title compound was converted to its hydrochloride salt by dissolving it in ethyl acetate (5 mL). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum.

Eksempel 49 ( generell fremgangsmåte ( C)) Example 49 (general procedure (C))

1-( bifenyl- 4- yl)- 4-( syklopentyl) piperazin 1-(biphenyl-4-yl)-4-(cyclopentyl)piperazine

180 mg av tittelforbindelsen ble syntetisert som beskrevet for 1-(bifenyl-3-yl)-4-(syklopentyl)piperazin, ved å anvende 4-brombifenyl i stedet for 3-brombifenyl. <1>H-NMR (CDC13) 8 1,80-2,00 (m, 8 H), 2,55 (m, 1 H) , 2,70 (m, 4 H), 3,20 (m, 4 H), 7,00 (d, 2 H), 7,30 (m, 1 H), 7,40 (t, 2 H) og 7,55 (m, til sammen 4 H). HPLC-metode C: eluering ved 4,52 minutter. Tittelforbindelsen ble overført til dens hydroklorid-salt ved å oppløse den i etylacetat (5 ml). En 3,2 M oppløsning av hydrogenklorid i etylacetat (5 ml) ble tilsatt. Oppløsnings-midlet ble fjernet under vakuum. Resten ble oppløst i etanol (50 ml). Oppløsningsmidlet ble fjernet under vakuum. Eksempel 50 ( generell fremgangsmåte ( C)) [ 3-( 4-( syklopentyl) piperazin- l- yl) fenyl]-( 4- fluorfenyl) metanon 180 mg of the title compound was synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 4-bromobiphenyl instead of 3-bromobiphenyl. <1>H-NMR (CDC13) δ 1.80-2.00 (m, 8 H), 2.55 (m, 1 H), 2.70 (m, 4 H), 3.20 (m, 4 H), 7.00 (d, 2 H), 7.30 (m, 1 H), 7.40 (t, 2 H) and 7.55 (m, total 4 H). HPLC method C: elution at 4.52 minutes. The title compound was converted to its hydrochloride salt by dissolving it in ethyl acetate (5 mL). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol (50 mL). The solvent was removed under vacuum. Example 50 (general procedure (C)) [3-(4-(cyclopentyl)piperazin-1-yl)phenyl]-(4-fluorophenyl)methanone

300 mg av tittelforbindelsen ble syntetisert som beskrevet for 1-(bifenyl-3-yl)-4-(syklopentyl)piperazin, ved å anvende 3-brom-4'-fluorbenzofenon i stedet for 3-brombifenyl. 300 mg of the title compound was synthesized as described for 1-(biphenyl-3-yl)-4-(cyclopentyl)piperazine, using 3-bromo-4'-fluorobenzophenone in place of 3-bromobiphenyl.

<X>H-NMR (CDCI3) 8 1,45 (m, 2 H) , 1,60 (m, 2 H) , 1,75 (m, 2 H), 1,90 (m, 2 H), 2,55 (kvintett, 1 H), 2,70 (m, 4 H), 3,30 (m, 4 H), 7,15 (m, 4 H), 7,35 (m, 2 H), 7,85 (m, 2 H). HPLC-metode C: eluering ved 4,22 minutter. MS: beregnet for [M + H]<+>: 353, funnet: 353. <X>H-NMR (CDCl 3 ) δ 1.45 (m, 2 H), 1.60 (m, 2 H), 1.75 (m, 2 H), 1.90 (m, 2 H), 2.55 (quintet, 1 H), 2.70 (m, 4 H), 3.30 (m, 4 H), 7.15 (m, 4 H), 7.35 (m, 2 H), 7.85 (m, 2H). HPLC method C: elution at 4.22 minutes. MS: calculated for [M + H]<+>: 353, found: 353.

Tittelforbindelsen ble overført til dens hydroklorid-salt ved å oppløse den i etylacetat (5 ml). En 3,2 M oppløsning av hydrogenklorid i etylacetat (5 ml) ble tilsatt. Oppløsnings-midlet ble fjernet under vakuum. Resten ble oppløst i etanol The title compound was converted to its hydrochloride salt by dissolving it in ethyl acetate (5 mL). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 mL) was added. The solvent was removed under vacuum. The residue was dissolved in ethanol

(50 ml). Oppløsningsmidlet ble fjernet under vakuum. (50ml). The solvent was removed under vacuum.

Farmakologiske metoder Pharmacological methods

Forbindelsenes evne til å reagere med histamin H3-reseptoren kan bestemmes ved hjelp av de følgende in vitro-bindingsanalyser. The ability of the compounds to react with the histamine H3 receptor can be determined by the following in vitro binding assays.

Bindingsanalyse I Binding analysis I

Hjernebark fra rotte homogeniseres i iskald K-Hepes, Cerebral cortex from rats is homogenized in ice-cold K-Hepes,

5 mM MgCl2, pH 7,1-buffer. Etter to differensialsentrifugeringer oppslemmes den siste pelleten på nytt i nyfremstilt Hepes-buffer inneholdende 1 mg/ml bacitracin. Alikvoter av membransuspensjonen (400 (ag/ml) inkuberes i 60 minutter ved 25 °C med 30 pM [<125>I]-jodproxifan, en kjent histamin H3-reseptorantagonist, og testforbindelsen ved forskjellige konsentrasjoner. Inkubasjonen stanses ved fortynning med iskaldt medium, etterfulgt av hurtigfiltrering gjennom "Whatman GF/B"-filtre forbehandlet i 1 time med 0,5 % polyetylenimin. Radioaktiviteten som er tilbake på filtrene, telles ved å anvende en "Cobra II-auto"-gammateller. Radioaktiviteten på filtrene er indirekte proporsjonal med bindingsaffiniteten til den testede forbindelse. Resultatene analyseres ved hjelp av ikke-lineær regresjonsanalyse. 5 mM MgCl2, pH 7.1 buffer. After two differential centrifugations, the last pellet is resuspended in freshly prepared Hepes buffer containing 1 mg/ml bacitracin. Aliquots of the membrane suspension (400 (ug/ml) are incubated for 60 min at 25 °C with 30 pM [<125>I]-iodoproxifan, a known histamine H3 receptor antagonist, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium , followed by rapid filtration through "Whatman GF/B" filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity remaining on the filters is counted using a "Cobra II-auto" gamma counter. The radioactivity on the filters is indirect proportional to the binding affinity of the tested compound.The results are analyzed using non-linear regression analysis.

Bindingsanalyse II Binding analysis II

H3-reseptoragonistliganden R-a-metyl [3H]histamin (RAMHA) inkuberes med isolerte hjernebarkcellemembraner fra rotte ved 25 °C i 1 time, etterfulgt av en filtrering av inkubatet gjennom "Whatman GF/B"-filtre. Radioaktiviteten som er tilbake på filtrene, måles ved å anvende en beta-teller. Wistar-rotter av hannkjønn (150-200 g) dekapiteres, og hjernebark dissekeres hurtig ut og nedfryses umiddelbart på tørris. Vev holdes ved -80 °C inntil membranpreparering. Under membranprepa-reringen holdes vevet på is hele tiden. Rottehjernebark homogeniseres i 10 volumer (vekt/vekt) iskald Hepes-buffer (20 mM Hepes, 5 mM MgCl2, pH 7,1 (KOH), + 1 mg/ml bacitracin) ved å anvende et "Ultra-Turrax"-homogeniseringsapparat i 30 sekunder. Homogenatet sentrifugeres ved 140 g i 10 minutter. Supernatanten overføres til et nytt prøverør og sentrifugeres i 30 minutter ved 23 000 g. Pellet oppslemmes på nytt i 5-10 ml Hepes-buffer, homogeniseres og sentrifugeres i 10 minutter ved 23 000 g. Dette kortvarige sentrifugeringstrinnet gjentas to ganger. Etter den siste sentrifugeringen oppslemmes pelleten på nytt i 2-4 ml Hepes-buffer, og proteinkonsentrasjonen bestemmes. Membranene fortynnes til en proteinkonsentrasjon på 5 mg/ml under anvendelse av Hepes-buffer, alikvoteres og lagres ved -80 °C inntil bruk. The H3 receptor agonist ligand R-α-methyl [3H]histamine (RAMHA) is incubated with isolated rat cerebral cortex cell membranes at 25°C for 1 hour, followed by a filtration of the incubate through "Whatman GF/B" filters. The radioactivity that remains on the filters is measured by using a beta counter. Male Wistar rats (150-200 g) are decapitated, and the cerebral cortex is quickly dissected out and immediately frozen on dry ice. Tissue is kept at -80 °C until membrane preparation. During the membrane preparation, the tissue is kept on ice the whole time. Rat cerebral cortex is homogenized in 10 volumes (w/w) of ice-cold Hepes buffer (20 mM Hepes, 5 mM MgCl2, pH 7.1 (KOH), + 1 mg/ml bacitracin) using an "Ultra-Turrax" homogenizer in 30 seconds. The homogenate is centrifuged at 140 g for 10 minutes. The supernatant is transferred to a new test tube and centrifuged for 30 minutes at 23,000 g. The pellet is resuspended in 5-10 ml of Hepes buffer, homogenized and centrifuged for 10 minutes at 23,000 g. This short centrifugation step is repeated twice. After the last centrifugation, the pellet is resuspended in 2-4 ml of Hepes buffer, and the protein concentration is determined. The membranes are diluted to a protein concentration of 5 mg/ml using Hepes buffer, aliquoted and stored at -80 °C until use.

50 (il testforbindelse, 100 ul membran (200 fig/ml) , 50 µl test compound, 100 µl membrane (200 µg/ml),

300 ul Hepes-buffer og 50 ul R-a-metyl[3H] histamin (1 nM) blandes i et prøverør. Forbindelsene som skal testes, oppløses i DMSO og fortynnes videre i H20 til de ønskede konsentrasjoner. Radio-ligand og membraner fortynnes i Hepes-buffer + 1 mg/ml bacitracin. Blandingen inkuberes i 60 minutter ved 25 °C. Inkubasjon avsluttes ved å tilsette 5 ml iskald 0,9 % NaCl, etterfulgt av hurtigfiltrering gjennom "Whatman GF/B"-filtre forbehandlet i 1 time med 0,5 % polyetylenimin. Filtrene vaskes med 2 x 5 ml iskald NaCl. Til hvert filter tilsettes en 3 ml scintillasjons-blanding, og radioaktiviteten som er tilbake, måles med en "Packard Tri-Carb"-beta-teller. ICso-verdier beregnes ved hjelp av ikke-lineær regresjonsanalyse av bindingskurver (minst 6 punkter) ved å anvende Windows-programmet GraphPad Prism, GraphPad software, USA. 300 µl of Hepes buffer and 50 µl of R-α-methyl[ 3 H] histamine (1 nM) are mixed in a test tube. The compounds to be tested are dissolved in DMSO and further diluted in H20 to the desired concentrations. Radio-ligand and membranes are diluted in Hepes buffer + 1 mg/ml bacitracin. The mixture is incubated for 60 minutes at 25 °C. Incubation is terminated by adding 5 ml of ice-cold 0.9% NaCl, followed by rapid filtration through "Whatman GF/B" filters pretreated for 1 hour with 0.5% polyethyleneimine. The filters are washed with 2 x 5 ml ice-cold NaCl. To each filter is added 3 ml of scintillation mixture, and the radioactivity that remains is measured with a "Packard Tri-Carb" beta counter. IC 50 values are calculated by non-linear regression analysis of binding curves (at least 6 points) using the Windows program GraphPad Prism, GraphPad software, USA.

Bindingsanalyse III Binding analysis III

Den humane H3-reseptor klones ved hjelp av PCR og underklones i pcDNA3-ekspresjonsvektoren. Celler som uttrykker H3-reseptoren stabilt, genereres ved overføring av H3-ekspre-sjonsvektorene til HEK293-celler og anvendelse av G418 for å selektere med hensyn på H3-kloner. De humane H3-HEK293-kloner dyrkes i DMEM (GIBCO-BRL) med glutamax, 10 % kalvefosterserum, The human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3 expression vectors into HEK293 cells and using G418 to select for H3 clones. The human H3-HEK293 clones are grown in DMEM (GIBCO-BRL) with glutamax, 10% fetal calf serum,

1 % penicillin/streptavidin og 1 mg/ml G418 ved 37 °C og 5 % C02. Før innhøsting skylles sammenflytende celler med PBS og inkuberes med "Versene" (proteinase, GIBCO-BRL) i ca. 5 minutter. Cellene skylles med PBS og DMEM, og cellesuspensjonen samles opp i et rør og sentrifugeres i 5-10 minutter ved 1500 rpm i en "Heraeus Sepatech Megafuge 1.0". Pelleten oppslemmes på nytt i 10-20 vol. Hepes-buffer (20 mM Hepes, 5 mM MgCl2, pH 7,1 (KOH)), og homogeniseres i 10-20 sekunder ved å anvende et "Ultra-Turrax"-homogeniseringsapparat. Homogenatet sentrifugeres i 30 minutter ved 23 000 g. Pelleten oppslemmes på nytt i 5-10 ml Hepes-buffer, homogeniseres i 5-10 sekunder med "Ultra-Turrax"-apparatet og sentrifugeres i 10 minutter ved 23 000 g. Etter dette sentrifugeringstrinnet oppslemmes membranpelleten på nytt i 2-4 ml Hepes-buffer, homogeniseres med en sprøyte eller teflonhomogenisator, og proteinkonsentrasjonen bestemmes. Membranene fortynnes til en proteinkonsentrasjon på 1-5 mg/ml i Hepes-buffer, alikvoteres og holdes ved -80 °C inntil bruk. 1% penicillin/streptavidin and 1 mg/ml G418 at 37 °C and 5% CO2. Before harvesting, confluent cells are rinsed with PBS and incubated with "Versene" (proteinase, GIBCO-BRL) for approx. 5 minutes. The cells are rinsed with PBS and DMEM, and the cell suspension is collected in a tube and centrifuged for 5-10 minutes at 1500 rpm in a "Heraeus Sepatech Megafuge 1.0". The pellet is resuspended in 10-20 vol. Hepes buffer (20 mM Hepes, 5 mM MgCl2, pH 7.1 (KOH)), and homogenized for 10-20 seconds using an "Ultra-Turrax" homogenizer. The homogenate is centrifuged for 30 minutes at 23,000 g. The pellet is resuspended in 5-10 ml of Hepes buffer, homogenized for 5-10 seconds with the "Ultra-Turrax" apparatus and centrifuged for 10 minutes at 23,000 g. After this centrifugation step the membrane pellet is resuspended in 2-4 ml of Hepes buffer, homogenized with a syringe or Teflon homogenizer, and the protein concentration is determined. The membranes are diluted to a protein concentration of 1-5 mg/ml in Hepes buffer, aliquoted and kept at -80 °C until use.

Alikvoter av membransuspensjonen inkuberes i 60 minutter ved 25 °C med 30 pM [<125>I]-jod<pr>oxifan, en kjent forbindelse med høy affinitet for H3-reseptoren, og testforbindelsen ved forskjellige konsentrasjoner. Inkubasjonen stanses ved fortynning med iskaldt medium, etterfulgt av hurtigfiltrering gjennom "Whatman GF/B"-filtre forbehandlet i 1 time med 0,5 % polyetylenimin. Radioaktiviteten som er tilbake på filtrene, telles ved å anvende en "Cobra II-auto"-gammateller. Radioaktiviteten på filtrene er indirekte proporsjonal med bindingsaffiniteten til den testede forbindelse. Resultatene analyseres ved hjelp av ikke-lineær regresjonsanalyse. Aliquots of the membrane suspension are incubated for 60 min at 25 °C with 30 pM [<125>I]-iodo<pr>oxiphane, a known compound with high affinity for the H3 receptor, and the test compound at various concentrations. Incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through "Whatman GF/B" filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity remaining on the filters is counted using a "Cobra II auto" gamma counter. The radioactivity on the filters is indirectly proportional to the binding affinity of the tested compound. The results are analyzed using non-linear regression analysis.

Når de testes, oppviser de foreliggende forbindelser med formel (I) generelt en høy bindingsaffinitet overfor histamin H3-reseptoren. When tested, the present compounds of formula (I) generally exhibit a high binding affinity to the histamine H3 receptor.

Forbindelsene ifølge oppfinnelsen har fortrinnsvis en ICso-verdi som bestemt ved hjelp av én eller flere av analysene, som er mindre enn 10 uM, mer foretrukket mindre enn 1 uM, og enda mer foretrukket mindre enn 500 nM, slik som mindre enn 100 nM. The compounds of the invention preferably have an IC 50 value as determined by one or more of the assays, which is less than 10 µM, more preferably less than 1 µM, and even more preferably less than 500 nM, such as less than 100 nM.

Funksjonsanalyse I Functional analysis I

Evnen til forbindelsene når det gjelder å interagere med histamin H3-reseptoren som agonister, inversagonister og/eller antagonister, bestemmes ved hjelp av en in vitro-funksjonsanalyse ved å benytte membraner fra HEK293-celler som uttrykker de humane H3-reseptorene. The ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists is determined by an in vitro functional assay using membranes from HEK293 cells expressing the human H3 receptors.

H3-reseptoren klones ved hjelp av PCR og underklones i pcDNA3-ekspresjonsvektoren. Celler som uttrykker H3-reseptoren stabilt, genereres ved å transfektere H3-ekspresjonsvektorene i HEK293-celler og anvende G418 for å selektere med hensyn på H3-kloner. De humane H3-HEK293-kloner dyrkes i DMEM med glutamax, 10 % kalvefosterserum, 1 % penicillin/streptavidin og 1 mg/ml G418 ved 37 °C og 5 % C02. The H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3 expression vectors into HEK293 cells and using G418 to select for H3 clones. The human H3-HEK293 clones are grown in DMEM with glutamax, 10% fetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G418 at 37°C and 5% CO 2 .

De H3-reseptoruttrykkende celler vaskes én gang med fosfatbufret saltoppløsning (PBS) og innhøstes ved å anvende "Versene" (GIBCO-BRL). PBS tilsettes, og cellene sentrifugeres i 5 minutter ved 188 g. Cellepelleten oppslemmes på nytt i stimu-leringsbuffer til en konsentrasjon på 1 x IO<6> celler/ml. cAMP-akkumulering måles ved å anvende "Flash Plate"-cAMP-analysen (NEN, Life Science Products). Analysen utføres generelt som beskrevet av produsenten. The H3 receptor expressing cells are washed once with phosphate buffered saline (PBS) and harvested using "Versene" (GIBCO-BRL). PBS is added, and the cells are centrifuged for 5 minutes at 188 g. The cell pellet is resuspended in stimulation buffer to a concentration of 1 x 10<6> cells/ml. cAMP accumulation is measured using the "Flash Plate" cAMP assay (NEN, Life Science Products). The analysis is generally performed as described by the manufacturer.

I korte trekk tilsettes 50 ul cellesuspensjon til hver brønn i Flash-platen, som også inneholdt 25 ul 40 uM isoprenalin, for å stimulere cAMP-generering, og 25 fil testforbindelse (enten agonister eller inversagonister alene, eller agonist og antagonist i kombinasjon). Analysen kan kjøres i "agonist-innstil-ling", noe som betyr at testforbindelsen tilsettes i økende konsentrasjoner alene til cellene, og cAMP måles. Dersom cAMP går opp, er den en inversagonist; dersom cAMP ikke endres, er den en nøytral antagonist, og dersom cAMP går ned, er den en agonist. Analysen kan også kjøres i "antagonist-innstillingen", noe som betyr at en testforbindelse tilsettes i økende konsentrasjoner sammen med økende konsentrasjoner av en kjent H3-agonist (f.eks. RAMHA). Dersom forbindelsen er en antagonist, forårsaker økende konsentrasjoner av den en høyredreining i H3-agonistens dose-responskurver. Sluttvolumet i hver brønn er 100 ul. Testforbindelsene oppløses i DMSO og fortynnes i H20. Blandingen ristes i 5 minutter og får stå i 25 minutter ved romtemperatur. Reaksjonen stanses med 100 ul "Detection Mix" pr. brønn. Platene lukkes så med plast, ristes i 30 minutter, får stå over natten, og radioaktiviteten telles til sist i "Cobra II-auto"-gammatopptelleren. ECso-verdier beregnes ved hjelp av ikke-lineær regresjonsanalyse av dose-responskurver (minst 6 punkter) ved å anvende "GraphPad Prism". Kb-verdier beregnes ved hjelp av "Schild plot"-analyse. Briefly, 50 µl of cell suspension is added to each well of the Flash plate, which also contained 25 µl of 40 uM isoprenaline, to stimulate cAMP generation, and 25 µl of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination). The assay can be run in "agonist mode", which means that the test compound is added in increasing concentrations alone to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP decreases, it is an agonist. The assay can also be run in the "antagonist setting", which means that a test compound is added in increasing concentrations together with increasing concentrations of a known H3 agonist (eg RAMHA). If the compound is an antagonist, increasing concentrations of it cause a rightward shift in the H3 agonist dose-response curves. The final volume in each well is 100 ul. The test compounds are dissolved in DMSO and diluted in H20. The mixture is shaken for 5 minutes and allowed to stand for 25 minutes at room temperature. The reaction is stopped with 100 ul "Detection Mix" per well. The plates are then closed with plastic, shaken for 30 minutes, allowed to stand overnight, and the radioactivity is finally counted in the "Cobra II-auto" gamma counter. EC 50 values are calculated by non-linear regression analysis of dose-response curves (at least 6 points) using "GraphPad Prism". Kb values are calculated using "Schild plot" analysis.

Funksjonsanalyse II Functional analysis II

Evnen til forbindelsene når det gjelder å binde og interagere med den humane H3-reseptoren som agonister, inversagonister og/eller antagonister, bestemmes ved hjelp av en funksjonsanalyse kalt [35S] -GTPyS-analysen. Analysen måler aktiver-ingen av G-proteiner ved å katalysere utbyttingen av guanosin-5'-difosfat (GDP) med guanosin-5'-trifosfat (GTP) i a-under-enheten. De GTP-bundne G-proteiner dissosierer til to under-enheter, Gcxgtp og GØy, som igjen regulerer intracellulære enzymer og ionekanaler. GTP hydrolyseres hurtig ved hjelp av Ga-under-enheten (GTPaser), og G-proteinet deaktiveres og er klart for en ny GTP-vekslingssyklus. For å studere funksjonen til ligand-indusert aktivering av G-proteinkoblet reseptor (GPCR) ved hjelp av en økning i guaninnukleotidveksling i G-proteinene, bestemmes bindingen av [35S] -guanosin-5' -0- (3-tio) trif osf at [35S] GTPyS, en ikke-hydrolysert analog av GTP. Denne prosessen kan overvåkes in vitro ved å inkubere cellemembraner inneholdende den G-proteinkoblede reseptor H3 med GDP og [<35>S]GTPyS. Cellemembraner erholdes fra CHO-celler som uttrykker den humane H3-reseptoren stabilt. Cellene vaskes to ganger i PBS, innhøstes med PBS + 1 mM EDTA, pH 7,4, og sentrifugeres ved 1000 rpm i 5 minutter. Cellepelleten homogeniseres i 10 ml iskald Hepes-buffer (20 mM Hepes, 10 mM EDTA, pH 7,4 (NaOH)), under anvendelse av et "Ultra-Turrax"-homogeniseringsapparat i 30 sekunder og sentrifugeres i 15 minutter ved 20 000 rpm. Etter dette sentrifugeringstrinnet oppslemmes membranpelleten på nytt i 10 ml iskald Hepes-buffer (20 mM Hepes, 0,1 mM EDTA, pH 7,4 (NaOH)), og homogeniseres som beskrevet ovenfor. Denne fremgangsmåten gjentas to ganger, bortsett fra det siste homogeniserings-trinnet, proteinkonsentrasjonen bestemmes, og membraner fortynnes til en proteinkonsentrasjon ved 2 mg/ml, alikvoteres og holdes ved -80 °C inntil bruk. The ability of the compounds to bind and interact with the human H3 receptor as agonists, inverse agonists and/or antagonists is determined by a functional assay called the [35S]-GTPγS assay. The assay measures the activation of G proteins by catalyzing the exchange of guanosine-5'-diphosphate (GDP) with guanosine-5'-triphosphate (GTP) in the α subunit. The GTP-bound G proteins dissociate into two subunits, Gcxgtp and GØy, which in turn regulate intracellular enzymes and ion channels. GTP is rapidly hydrolyzed by the Gα subunit (GTPases), and the G protein is deactivated and ready for a new GTP exchange cycle. To study the function of ligand-induced activation of G protein-coupled receptor (GPCR) by means of an increase in guanine nucleotide exchange in the G proteins, the binding of [35S]-guanosine-5'-0-(3-thio)trifosf is determined that [35S]GTPyS, a non-hydrolyzed analog of GTP. This process can be monitored in vitro by incubating cell membranes containing the G protein-coupled receptor H3 with GDP and [<35>S]GTPyS. Cell membranes are obtained from CHO cells stably expressing the human H3 receptor. The cells are washed twice in PBS, harvested with PBS + 1 mM EDTA, pH 7.4, and centrifuged at 1000 rpm for 5 minutes. The cell pellet is homogenized in 10 ml of ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA, pH 7.4 (NaOH)), using an "Ultra-Turrax" homogenizer for 30 seconds and centrifuged for 15 minutes at 20,000 rpm . After this centrifugation step, the membrane pellet is resuspended in 10 ml of ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA, pH 7.4 (NaOH)), and homogenized as described above. This procedure is repeated twice, except for the final homogenization step, the protein concentration is determined, and membranes are diluted to a protein concentration of 2 mg/ml, aliquoted and kept at -80°C until use.

For å studere tilstedeværelsen og styrken til en inversagonist/antagonist tilsettes H3-reseptoragonistliganden R-a-metylhistamin (RAMHA). Evnen til testforbindelsen når det gjelder å motvirke effekten av RAMHA, måles. Når effekten av en agonist studeres, tilsettes RAMHA ikke til analysemediet. Testforbindelsen fortynnes i analysebufferen (20 mM Hepes, 120 mM NaCl, 10 mM MgCl2, pH 7,4 (NaOH)) ved forskjellige konsentrasjoner, etterfulgt av tilsetning av IO"<8> nM RAMHA (bare i det tilfellet at en inversagonist/antagonist undersøkes) , 3 uM GDP, 2,5 ug membraner, 0,5 mg SPA-kuler og 0,1 nM [<35>S]GTPyS, og inkuberes i 2 timer ved svak risting ved romtemperatur. Platene sentrifugeres ved 1500 rpm i 10 minutter, og radioaktiviteten måles ved å anvende en "Top"-teller. Resultatene analyseres ved hjelp av ikke-lineær regresjon, og ICso-verdien bestemmes. RAMHA og andre H3-agonister stimulerer bindingen av [<35>S]GTPyS til membraner som uttrykker H3-reseptoren. I antagonist-/invers-agonisttesten måles evnen til økende mengder av testforbindelse når det gjelder å inhibere den forøkte [35S] GTPyS-binding ved hjelp av IO<-8> M RAMHA som en reduksjon i radioaktivitetssignal. IC50-verdien bestemt for en antagonist er evnen til denne forbindelsen når det gjelder å inhibere effekten av IO"<8> M RAMHA med 50 %. I agonisttesten måles evnen til økende mengder av testforbindelse som en økning i radioaktivitetssignal. ECso-verdien bestemt for en agonist er evnen til denne forbindelsen når det gjelder å øke signalet med 50 % av det maksimale signalet som oppnås ved hjelp av IO"5 M RAMHA. To study the presence and potency of an inverse agonist/antagonist, the H3 receptor agonist ligand R-α-methylhistamine (RAMHA) is added. The ability of the test compound to counteract the effects of RAMHA is measured. When the effect of an agonist is studied, RAMHA is not added to the assay medium. The test compound is diluted in the assay buffer (20 mM Hepes, 120 mM NaCl, 10 mM MgCl2, pH 7.4 (NaOH)) at various concentrations, followed by the addition of 10"<8> nM RAMHA (only in the case that an inverse agonist/antagonist investigated), 3 µM GDP, 2.5 µg membranes, 0.5 mg SPA beads, and 0.1 nM [<35>S]GTPyS, and incubated for 2 h with gentle shaking at room temperature. Plates are centrifuged at 1500 rpm in 10 minutes, and the radioactivity is measured using a "Top" counter. The results are analyzed by non-linear regression, and the IC 50 value is determined. RAMHA and other H3 agonists stimulate the binding of [<35>S]GTPyS to membranes which express the H3 receptor. In the antagonist/inverse agonist test, the ability of increasing amounts of test compound to inhibit the increased [35S] GTPγS binding is measured by IO<-8> M RAMHA as a decrease in radioactivity signal. IC50 -value determined for an antagonist is the ability of that compound to inhibit the effect of IO "<8> M RAMHA by 50%. In the agonist test, the ability to increase amounts of the test compound is measured as an increase in radioactivity signal. The EC 50 value determined for an agonist is the ability of that compound to increase the signal by 50% of the maximum signal obtained with 10"5 M RAMHA.

Antagonistene og agonistene ifølge oppfinnelsen har fortrinnsvis en verdi for IC50/EC5o som bestemt ved hjelp av én eller flere av analysene, som er lavere enn 10 uM, mer foretrukket lavere enn 1 um og enda mer foretrukket lavere enn 500 nM, slik som lavere enn 100 nM. The antagonists and agonists according to the invention preferably have a value for IC50/EC50 as determined by one or more of the assays, which is lower than 10 µM, more preferably lower than 1 µM and even more preferably lower than 500 nM, such as lower than 100 nM.

Rottemodellen med åpent bur og foring til fastsatt tid The rat model with an open cage and lining for a fixed time

Evnen til de foreliggende forbindelser når det gjelder å redusere vekt, bestemmes ved å anvende in vivo-rottemodellen med åpent bur og foring til fastsatt tid. The ability of the present compounds to reduce weight is determined using the in vivo fixed-cage and chow rat model.

Sprague-Dawley(SD)-hannrotter med en alder på ca. 1,5-2 måneder og en vekt på ca. 200-250 g innkjøpes fra Møllegård Breeding and Resarch Centre A/S (Danmark). Etter ankomst får de noen dager med akklimatisering før de plasseres i individuelle åpne plastbur. De vendes til tilstedeværelsen av for (Altromin-pelletert rottefor) i hjembur bare i løpet av 7 timer om morgenen fra 0730 til 1430 alle ukedager. Vann er til stede ad libitum. Når inntaket av for har stabilisert seg etter 7- Male Sprague-Dawley (SD) rats aged approx. 1.5-2 months and a weight of approx. 200-250 g is purchased from Møllegård Breeding and Research Center A/S (Denmark). After arrival, they are given a few days of acclimatization before being placed in individual open plastic cages. They are turned to the presence of feed (Altromin pelleted rat feed) in home cages only during 7 hours in the morning from 0730 to 1430 every weekday. Water is available ad libitum. When the intake of for has stabilized after 7-

9 dager, er dyrene klare til bruk. 9 days, the animals are ready for use.

Hvert dyr brukes bare én gang for å unngå overførings-effekter mellom behandlinger. Under forsøksperiodene administreres testforbindelsen intraperitonealt eller oralt 30 minutter før starten av periodene. Én gruppe dyr får administrert testforbindelsen ved forskjellige doser, og en kontrollgruppe med dyr gis en oppløsning uten testforbindelse. For- og vanninntak overvåkes 1, 2 og 3 timer etter administreringen. Each animal is used only once to avoid carryover effects between treatments. During the experimental periods, the test compound is administered intraperitoneally or orally 30 minutes before the start of the periods. One group of animals is administered the test compound at different doses, and a control group of animals is given a solution without the test compound. Pre- and water intake is monitored 1, 2 and 3 hours after administration.

Eventuelle bivirkninger kan hurtig oppdages (tønne-rulling, rufset pels etc), ettersom dyrene holdes i gjennom-siktige plastbur for å muliggjøre kontinuerlig overvåkning. Any side effects can be quickly detected (barrel-rolling, ruffled fur, etc.), as the animals are kept in transparent plastic cages to enable continuous monitoring.

Claims (39)

1. Forbindelse, karakterisert ved at den har den generelle formel (II) : hvor R<2> er hydrogen eller Ci_4-alkyl, (i) R<1> er: • forgrenet C4_6-alkyl, forgrenet C4-6~alkenyl eller forgrenet C4_6-alkynyl, med det forbehold at R<1 >ikke er isobutyl, eller • C3_5-sykloalkyl, C3_7-sykloalkenyl, C3-6-sykloalkyl- Ci-3-alkyl eller C3_6-sykloalkenyl-Ci-3-alkyl, og A er: eller (ii) R<1> er: • etyl, n-propyl eller isopropyl, og A er: R3 er hydrogen, Z og X er uavhengig av hverandre -N= eller -C(H)=, W er -C(R<10>)=, Y er -N= eller -C(R<U>)=, R4, R10 og R1<1>, er uavhengig av hverandre: hydrogen, halogen, hydroksy, trifluormetyl, tri fluormetoksy, -SCF3, amino, cyan, nitro eller -C-(=0)NR<14>R15, Ci-10-alkyl, C2-io-alkenyl, C3-8-sykloalkyl, Cis~ alkoksy, C3-8-sykloalkyl-Ci-6-alkoksy, Ci-6-alkyl-amino, di-Ci_6-alkylamino, C3-8-sykloalkyloksy, Ci_6-alkylsulfanyl, Ci_6-alkylsulfonyl, C2-io_alkanoyl, Ci-g-sykloalkanoyl, C3-8-heterosyklyl eller C4_9-heterosykloalkanoyl, C4-g-heterosykloalkoksy, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<16>, fenyl, fenyl-Ci-6-alkyl eller fenyl-Ci-6-alkoksy, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<17>, fenoyl, fenoyloksy eller fenylamino, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<18>, eller R10 og R<11> i nabostillinger danner til sammen en Ci-6-alkylenbro eller en -0-Ci-6-alkylen-0-bro, R<14> og R<15> er uavhengig av hverandre hydrogen, Ci-6-alkyl eller fenyl-Ci-6-alkyl, eller R14 og R15 kan til sammen danne en C3_6-alkylenbro, R<16> er uavhengig av hverandre valgt fra fenyl, C3-8-sykloalkyl, halogen, trif luormetyl, trif luormetoksy, NR19R20 og Ci-6-alkoksy, R<17> er uavhengig av hverandre valgt fra halogen, hydroksy, trif luormetyl, trif luormetoksy, Ci-6-alkoksy, Ci-6~ alkyl, amino, Ci-6-alkylsulfonyl, Ci-6-alkylamino, di-Ci-6-alkyl-amino, cyan, fenyl og C3.8-sykloalkyl, R<18> er uavhengig av hverandre valgt fra fenyl, Ci-10-alkyl, C3-8-sykloalkyl, halogen, trifluormetyl, trifluormetoksy, Ci_6-alkoksy, cyan, amino, Ci-6-alkylamino, di-Ci_6-alkylamino og hydroksy, R<1>9 og R2<0> er uavhengig av hverandre hydrogen eller Ci-6-alkyl, eller R<19> og R20 kan til sammen danne en C3-6-alkylenbro, med det forbehold at forbindelsen ikke kan være: eller samt hvilken som helst diastereomer eller enantiomer eller tautomer form derav, inkludert blandinger av disse, eller et farmasøytisk akseptabelt salt derav.1. Connection, characterized in that it has the general formula (II): where R<2> is hydrogen or C1_4-alkyl, (i) R<1> is: • branched C4_6-alkyl, branched C4-6~alkenyl or branched C4_6-alkynyl, with the proviso that R<1> is not isobutyl, or • C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl- C 1-3 alkyl or C 3-6 cycloalkenyl C 1-3 alkyl, and A is: or (ii) R<1> is: • ethyl, n-propyl or isopropyl, and A is: R 3 is hydrogen, Z and X are independently -N= or -C(H)=, W is -C(R<10>)=, Y is -N= or -C(R<U>)=, R4, R10 and R1<1>, are independent of each other: hydrogen, halogen, hydroxy, trifluoromethyl, tri fluoromethoxy, -SCF3, amino, cyan, nitro or -C-(=0)NR<14>R15, C1-10-alkyl, C2-io-alkenyl, C3-8-cycloalkyl, Cis~ Alkoxy, C3-8-Ci-6-Ci-6-Alkoxy, C1-6-Alkyl-Amino, Di-Ci-6-Alkylamino, C3-8-Cycloalkyloxy, C1-6-Alkylsulfanyl, C1-6-Alkylsulfonyl, C2-10_Alkanoyl, C1-G- cycloalkanoyl, C3-8-heterocyclyl or C4_9-heterocycloalkanoyl, C4-g-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R<16>, phenyl, phenyl-Ci-6-alkyl or phenyl-Ci-6 -Alkoxy, which may optionally be substituted with one or more substituents selected from R<17>, phenol, phenoyloxy or phenylamino, which optionally may be substituted with one or more substituents selected from R<18>, or R10 and R<11> in adjacent positions together form a C1-6-alkylene bridge or a -0-Ci-6-alkylene-0-bridge, R< 14> and R<15> are independently hydrogen, C1-6-alkyl or phenyl-C1-6-alkyl, or R14 and R15 may together form a C3-6-alkylene bridge, R<16> is independently selected from phenyl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19 R 20 and C 1-6 alkoxy, R<17> is independently selected from halogen, hydroxy, trifluoromethyl, trifluoro methoxy, C 1-6 alkoxy, C1-6~ alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1-6-alkyl-amino, cyan, phenyl and C3.8-cycloalkyl, R<18> is independently selected from phenyl, C 1-10 alkyl, C 3-8 cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkoxy, cyan, amino, C 1-6 alkylamino, di-C 1-6 alkylamino and hydroxy, R<1>9 and R2< 0> is independently hydrogen or C1-6 alkyl, or R<19> and R20 can together form a C3-6 alkylene bridge, with with the caveat that the connection cannot be: or as well as any diastereomeric or enantiomeric or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof. 2. Forbindelse ifølge krav 1, karakterisert ved at R<1> er forgrenet C4-6~alkyl, C3-5~sykloalkyl eller C3-6-sykloalkyl-Ci_3-alkyl, med det forbehold at R<1> ikke er isobutyl.2. Connection according to claim 1, characterized in that R<1> is branched C4-6~alkyl, C3-5~cycloalkyl or C3-6-cycloalkyl-Ci_3-alkyl, with the proviso that R<1> is not isobutyl. 3. Forbindelse ifølge krav 2, karakterisert ved at R<1> er 1,1-(dimetyl)propyl, 1-etylpropyl, syklopropylmetyl, syklopropyl, syklobutyl, syklopentyl eller 1-syklopropyl-l-metyletyl.3. Connection according to claim 2, characterized in that R<1> is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl. 4. Forbindelse ifølge krav 3, karakterisert ved at R<1> er 1-etylpropyl, syklopropylmetyl, syklopropyl eller syklopentyl.4. Connection according to claim 3, characterized in that R<1> is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl. 5. Forbindelse ifølge krav 1, karakterisert ved at R<1> er forgrenet C4-6~alkyl eller C3_5-sykloalkyl, med det forbehold at R<1> ikke er isobutyl.5. Connection according to claim 1, characterized in that R<1> is branched C4-6~alkyl or C3-5-cycloalkyl, with the proviso that R<1> is not isobutyl. 6. Forbindelse ifølge krav 5, karakterisert ved at R<1> er 1-etylpropyl, syklopropyl eller syklopentyl.6. Connection according to claim 5, characterized in that R<1> is 1-ethylpropyl, cyclopropyl or cyclopentyl. 7. Forbindelse ifølge hvilket som helst av kravene 1-6, karakterisert ved atZer -C(H)=.7. Compound according to any one of claims 1-6, characterized by atZer -C(H)=. 8. Forbindelse ifølge hvilket som helst av kravene 1-6, karakterisert ved atZer -N=.8. Compound according to any one of claims 1-6, characterized by atZer -N=. 9. Forbindelse ifølge hvilket som helst av kravene 1-8, karakterisert ved at X er -C(H)=.9. Compound according to any one of claims 1-8, characterized in that X is -C(H)=. 10. Forbindelse ifølge hvilket som helst av kravene 1-8, karakterisert ved at X er -N=.10. Compound according to any one of claims 1-8, characterized in that X is -N=. 11. Forbindelse ifølge hvilket som helst av kravene 1-10, karakterisert ved at Y er -N=.11. Compound according to any one of claims 1-10, characterized in that Y is -N=. 12. Forbindelse ifølge hvilket som helst av kravene 1-10, karakterisert ved at Y er -C(R<n>)=.12. Compound according to any one of claims 1-10, characterized in that Y is -C(R<n>)=. 13. Forbindelse ifølge hvilket som helst av kravene 1-12, karakterisert ved at R2 er hydrogen.13. Compound according to any one of claims 1-12, characterized in that R2 is hydrogen. 14. Forbindelse ifølge hvilket som helst av kravene 1-12, karakterisert ved at R2 er Ci-4-alkyl.14. Compound according to any one of claims 1-12, characterized in that R 2 is C 1-4 alkyl. 15. Forbindelse ifølge krav 14, karakterisert ved at R2 er metyl eller etyl.15. Compound according to claim 14, characterized in that R2 is methyl or ethyl. 16. Forbindelse ifølge krav 1, karakterisert ved at R<1> er etyl eller isopropyl.16. Connection according to claim 1, characterized in that R<1> is ethyl or isopropyl. 17. Forbindelse ifølge krav 16, karakterisert ved at R<1> er isopropyl.17. Compound according to claim 16, characterized in that R<1> is isopropyl. 18. Forbindelse ifølge krav 16, karakterisert ved at R<1> er etyl.18. Compound according to claim 16, characterized in that R<1> is ethyl. 19. Forbindelse ifølge hvilket som helst av kravene 1-18, karakterisert ved at R14 og R15 uavhengig av hverandre er metyl, etyl eller benzyl.19. Compound according to any one of claims 1-18, characterized in that R14 and R15 are independently methyl, ethyl or benzyl. 20. Forbindelse ifølge hvilket som helst av kravene 1-19, karakterisert ved at R<16> er halogen, trifluormetyl, trif luormetoksy eller Ci_6-alkoksy.20. A compound according to any one of claims 1-19, characterized in that R<16> is halogen, trifluoromethyl, trifluoromethoxy or C1-6-alkoxy. 21. Forbindelse ifølge hvilket som helst av kravene 1-20, karakterisert ved at R<17> er halogen, hydroksy, trif luormetyl, Ci-6-alkoksy, Ci_6-alkyl, Ci-6-alkylsulf onyl eller cyan.21. A compound according to any one of claims 1-20, characterized in that R<17> is halogen, hydroxy, trifluoromethyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl or cyan. 22. Forbindelse ifølge krav 21, karakterisert ved at R<17> er halogen, trifluormetyl, Ci-6-alkoksy eller Ci_6_alkylsulf onyl.22. Connection according to claim 21, characterized in that R<17> is halogen, trifluoromethyl, C1-6-alkyl or C1-6-alkylsulfonyl. 23. Forbindelse ifølge hvilket som helst av kravene 1-22, karakterisert ved at R<18> er Ci_i0-alkyl, halogen, trifluormetyl, Ci-6-alkoksy, cyan, amino eller hydroksy.23. Compound according to any one of claims 1-22, characterized in that R<18> is C1-10-alkyl, halogen, trifluoromethyl, C1-6-alkoxy, cyan, amino or hydroxy. 24. Forbindelse ifølge krav 23, karakterisert ved at R<18> er halogen, Ci-6~ alkoksy eller hydroksy.24. Connection according to claim 23, characterized in that R<18> is halogen, C1-6~ alkoxy or hydroxy. 25. Forbindelse med den generelle formel (II) ifølge krav 1 for anvendelse som en medisin.25. Compound of the general formula (II) according to claim 1 for use as a medicine. 26. Farmasøytisk preparat, karakterisert ved at det som en aktiv bestanddel omfatter minst én forbindelse ifølge hvilket som helst av kravene 1-24, sammen med én eller flere farmasøytisk akseptable bærere eller eksipienser.26. Pharmaceutical preparation, characterized in that it comprises as an active ingredient at least one compound according to any one of claims 1-24, together with one or more pharmaceutically acceptable carriers or excipients. 27. Farmasøytisk preparat ifølge krav 26 i enhetsdoserings-f orm, karakterisert ved at det omfatter fra 0,05 mg til 1000 mg, fortrinnsvis fra 0,1 mg til 500 mg, og spesielt foretrukket fra 0,5 mg til 200 mg av forbindelsen ifølge hvilket som helst av kravene 1-24.27. Pharmaceutical preparation according to claim 26 in unit dosage form, characterized in that it comprises from 0.05 mg to 1000 mg, preferably from 0.1 mg to 500 mg, and particularly preferably from 0.5 mg to 200 mg of the compound according to any one of claims 1-24. 28. Anvendelse av en forbindelse med den generelle formel (II') : hvor R2 er hydrogen eller Ci_4-alkyl, R<1> er: Ci-8-alkyl, C2-8-alkenyl eller C2-8-alkynyl, som eventuelt kan være substituert med én eller flere halogensubstituenter, C3-5-sykloalkyl, C3-7-sykloalkenyl, C3-6-sykloalkyl- Ci_3-alkyl eller C3_6-sykloalkenyl-Ci-3-alkyl, som eventuelt kan være substituert med én eller flere halogensubstituenter, R<1> og R2 danner til sammen en C3-6-alkylenbro, A er: eller R<3> er hydrogen, halogen, hydroksy, trifluormetyl, trifluormetoksy, Ci_i0-alkyl, C2-io-alkenyl, C3_8-sykloalkyl, Ci_6-alkoksy, aryl, aryl-Ci_6-alkyl, amino, Ci-6-alkylamino, di-Ci-6-alkylamino, C3-8-sykloalkyl, C3_8-sykloalkyloksy, cyan, nitro, Ci-6-alkylsulfanyl eller Ci-6-alkylsulfonyl, Z og X er uavhengig av hverandre -N=, -C(H)=, -C(F)=, -C(C1)=, -C(CN)= eller -C(CF3)=, W er -N= eller -C(R<10>)=, Y er -N= eller -C(R<n>)=,R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R1<0>, R<11>, R12 og R1<3> er uavhengig av hverandre: hydrogen, halogen, hydroksy, trifluormetyl, tri fluormetoksy, -SCF3, amino, cyan, nitro eller -C-(=0)NR<14>R15, Ci-io-alkyl, C2-io-alkenyl, C3-8-sykloalkyl, Ci-6- alkoksy, C3_8-sykloalkyl-Ci-6-alkoksy, Ci-6-alkyl-amino, di-Ci-6-alkylamino, C3-8~sykloalkyloksy, Ci_6-alkylsulfanyl, Ci_6-alkylsulfonyl, C2-io-alkanoyl, C4_g-sykloalkanoyl, C3_8-heterosyklyl eller C4-9-heterosykloalkanoyl, C4-g-heterosykloalkoksy, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<16>, aryl, aryl-Ci_6-alkyl, aryl-Ci-6-alkoksy eller heteroaryl, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<17>, aroyl, heteroaroyl, aryloksy, heteroaryloksy, arylamino eller heteroarylamino, som eventuelt kan være substituert med én eller flere substituenter valgt fra R<18>, eller to av R<5>, R<6>, R<7>, R<8>, R9, R<10>, R11, R12 og R<13> i nabostillinger danner til sammen en Ci-6-alkylenbro eller en -0-Ci-6-alkylen-0-bro, R<1>4 og R1<5> er uavhengig av hverandre hydrogen, Ci_6-alkyl eller aryl-Ci-6-alkyl, eller R14 og R15 kan til sammen danne en C3_6-alkylenbro, R<16> er uavhengig av hverandre valgt fra aryl, heteroaryl, C3-a-sykloalkyl, halogen, trifluormetyl, trifluormetoksy, NR<19>R<20> og Ci-e-alkoksy, R<17> er uavhengig av hverandre valgt fra halogen, hydroksy, trif luormetyl, trif luormetoksy, Ci-6-alkoksy, Ci- e~ alkyl, amino, Ci-6-alkylsulfonyl, Ci_6-alkylamino, di-Ci-6-alkyl-amino, cyan, aryl, heteroaryl og C3_8-sykloalkyl, R<18> er uavhengig av hverandre valgt fra aryl, heteroaryl, Ci-io-alkyl, C3-s-sykloalkyl, halogen, trif luormetyl, trifluormetoksy, Ci-6-alkoksy, cyan, amino, Ci-6-alkylamino, di-Ci-6-alkylamino og hydroksy, R19 og R2<0> er uavhengig av hverandre hydrogen eller Ci_6-alkyl, eller R19 og R2<0> kan til sammen danne en C3-6-alkylenbro, samt hvilken som helst diastereomer eller enantiomer eller tautomer form derav, inkludert blandinger av disse, eller et farmasøytisk akseptabelt salt derav, til fremstillingen av et farmasøytisk preparat for profylakse og/eller behandling av overvekt eller fedme, forstyrrelser og sykdommer relatert til overvekt eller fedme, spiseforstyrrelser, IGT, sukkersyke av type 2, sykdommer forbundet med regulering av søvn og våkenhet, narkolepsi, forstyrrelser med oppmerksomhetssvikt, demens og Alzheimers sykdom, allergisk rhinitt, magesår, migrene, tilstander forbundet med epilepsi, bevegelsessykelighet og svimmelhet, depresjon og irritabel tarm-syndrom.28. Use of a compound of the general formula (II'): where R 2 is hydrogen or C 1-4 alkyl, R<1> is: C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl, which may optionally be substituted with one or more halogen substituents, C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl- Ci_3-alkyl or C3-6-cycloalkenyl-Ci-3-alkyl, which may optionally be substituted with one or more halogen substituents, R<1> and R2 together form a C3-6-alkylene bridge, A is: or R<3> is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-10-alkyl, C2-10-alkenyl, C3-8-cycloalkyl, C1-6-alkoxy, aryl, aryl-C1-6-alkyl, amino, C1-6-alkylamino, di-Ci-6-alkylamino, C3-8-cycloalkyl, C3-8-cycloalkyloxy, cyan, nitro, C1-6-alkylsulfanyl or C1-6-alkylsulfonyl, Z and X are independent of each other -N=, -C(H) =, -C(F)=, -C(C1)=, -C(CN)= or -C(CF3)=, W is -N= or -C(R<10>)=, Y is -N = or -C(R<n>)=,R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R1<0>, R<11 >, R12 and R1<3> are independent of each other: hydrogen, halogen, hydroxy, trifluoromethyl, tri fluoromethoxy, -SCF3, amino, cyan, nitro or -C-(=0)NR<14>R15, C1-10-alkyl, C2-10-alkenyl, C3-8-cycloalkyl, C1-6- Alkoxy, C3_8-cycloalkyl-Ci-6-Alkoxy, C1-6-alkyl-amino, di-Ci-6-alkylamino, C3-8~cycloalkyloxy, C1_6-alkylsulfanyl, C1_6-alkylsulfonyl, C2-io-alkanoyl, C4_g- cycloalkanoyl, C3_8-heterocyclyl or C4-9-heterocycloalkanoyl, C4-g-heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R<16>, 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 R<17>, aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from R<18>, or two of R<5>, R<6>, R<7>, R<8>, R9, R<10>, R11, R12 and R<13> in adjacent positions together form a C1-6 alkylene bridge or a -O-Ci-6-alkylene-O-bridge, R<1>4 and R1<5> are independently hydrogen, C1-6-alkyl or aryl-C1-6-alkyl, or R14 and R15 can together form a C3-6-alkylene bridge, R<16> is independently selected from aryl, heteroaryl, C3-a-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR<19>R<20> and C1-e-alkoxy, R<17> is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylsulfonyl, C1-6-alkylamino, di-C1-6- alkyl-amino, cyan, aryl, heteroaryl and C3_8-cycloalkyl, R<18> is independently selected from aryl, heteroaryl, C1-10-alkyl, C3-5-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C1-6-alkoxy, cyan, amino, C1-6-alkylamino, di -Ci-6-alkylamino and hydroxy, R19 and R2<0> are independently hydrogen or C1_6 alkyl, or R19 and R2<0> may together form a C3-6 alkylene bridge, as well as any diastereomer or enantiomeric or tautomeric form thereof, including mixtures thereof , or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation for the prophylaxis and/or treatment of overweight or obesity, disorders and diseases related to overweight or obesity, eating disorders, IGT, diabetes type 2, diseases associated with the regulation of sleep and alertness, narcolepsy, attention deficit disorders, dementia and Alzheimer's disease, allergic rhinitis, peptic ulcer, migraine, conditions associated with epilepsy, motion sickness and vertigo, depression and irritable bowel syndrome. 29. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for reduksjon av vekt.29. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for reducing weight. 30. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for behandling av overvekt eller fedme.30. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the treatment of overweight or obesity. 31. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for undertrykkelse av appetitt eller for igangsettelse av metthetsfølelse.31. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for suppressing appetite or for initiating satiety. 32. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for profylakse og/eller behandling av forstyrrelser og sykdommer relatert til overvekt eller fedme.32. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for prophylaxis and/or treatment of disorders and diseases related to overweight or obesity. 33. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for profylakse og/eller behandling av spiseforstyrrelser, slik som bulimi og overdreven spising.33. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the prophylaxis and/or treatment of eating disorders, such as bulimia and excessive eating. 34. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for behandling av IGT.34. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the treatment of IGT. 35. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for behandling av sukkersyke av type 2.35. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the treatment of type 2 diabetes. 36. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for forsinkelse eller profylakse av utviklingen fra IGT til sukkersyke av type 2.36. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the delay or prophylaxis of the development from IGT to type 2 diabetes. 37. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for forsinkelse eller profylakse av utviklingen fra ikke-insulinkrevende sukkersyke av type 2 til insulinkrevende sukkersyke av type 2.37. Use of a compound as defined in claim 28 for the manufacture of a pharmaceutical preparation for the delay or prophylaxis of the development from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes. 38. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for behandling av allergisk rhinitt, magesår eller anoreksi.38. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the treatment of allergic rhinitis, stomach ulcers or anorexia. 39. Anvendelse av en forbindelse som definert i krav 28 til fremstilling av et farmasøytisk preparat for behandling av Alzheimers sykdom, narkolepsi eller forstyrrelser med oppmerksomhetssvikt.39. Use of a compound as defined in claim 28 for the production of a pharmaceutical preparation for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.
NO20043709A 2002-02-05 2004-09-03 Aryl and heteroarylpiperazines, pharmaceutical preparations comprising at least one such compound, and uses of such compounds for the preparation of pharmaceutical preparations NO328714B1 (en)

Applications Claiming Priority (5)

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

Publications (2)

Publication Number Publication Date
NO20043709L NO20043709L (en) 2004-09-03
NO328714B1 true NO328714B1 (en) 2010-05-03

Family

ID=27739216

Family Applications (1)

Application Number Title Priority Date Filing Date
NO20043709A NO328714B1 (en) 2002-02-05 2004-09-03 Aryl and heteroarylpiperazines, pharmaceutical preparations comprising at least one such compound, and uses of such compounds for the preparation of pharmaceutical preparations

Country Status (12)

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

Families Citing this family (72)

* 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
JP2006505590A (en) 2002-10-23 2006-02-16 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 Phenylpiperidine and phenylpyrrolidine as histamine H3 receptor modulators
RU2006101452A (en) * 2003-07-29 2006-06-27 Ново Нордиск А/С (DK) Pyridazinyl-piperazines and their use as histamine H3 receptor ligands H3
US7514436B2 (en) 2003-07-30 2009-04-07 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7754711B2 (en) * 2003-07-30 2010-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
KR20060036106A (en) * 2003-07-30 2006-04-27 제논 파마슈티칼스 인크. Pyridyl derivatives and their use as therapeutic agents
NZ545265A (en) 2003-07-30 2009-11-27 Xenon Pharmaceuticals Inc Pyridazine derivatives and their use for treating diseases mediated by stearoyl-CoA desaturase (SCD) enzymes
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 (en) * 2004-02-24 2010-12-15 あすか製薬株式会社 Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action
US7423147B2 (en) 2004-03-31 2008-09-09 Janssen Pharmaceutical, N.V. Pyridine compounds as histamine H3 modulators
WO2005097127A2 (en) 2004-04-02 2005-10-20 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
WO2006000914A1 (en) * 2004-06-22 2006-01-05 Pfizer Products Inc. Diazabicyclic histamine-3 receptor antagonists
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
CN101083994A (en) 2004-09-20 2007-12-05 泽农医药公司 Heterocyclic derivatives and their use as therapeutic agents
WO2006034315A2 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes
AU2005329423A1 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2006034312A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coa-desaturase (scd)
AU2005286653A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Pyridine derivatives for inhibiting human stearoyl-CoA-desaturase
MX2007003321A (en) 2004-09-20 2007-06-05 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents.
AR051202A1 (en) 2004-09-20 2006-12-27 Xenon Pharmaceuticals Inc HETEROCICLIC DERIVATIVES AND THEIR USE AS INHIBITORS OF ESTEAROIL-COA DESATURASA
CA2580845A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase
BRPI0517947A (en) * 2004-11-02 2008-10-21 Univ Northwestern pyridazine compound, compositions and methods
MX2007010572A (en) 2005-03-01 2007-10-04 Wyeth Corp Cinnoline compounds and their use as liver x receptor modilators.
BRPI0611187A2 (en) 2005-06-03 2010-08-24 Xenon Pharmaceuticals Inc amino thiazide derivatives as inhibitors of human stearoyl coa desaturase
CN103110635A (en) * 2005-07-04 2013-05-22 海波因特制药有限责任公司 Histamine H3 receptor antagonist
PL1904455T3 (en) * 2005-07-05 2012-01-31 Hoffmann La Roche Pyridazine derivatives
US8686002B2 (en) 2005-08-21 2014-04-01 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as binding partners for 5-HT5 receptors
GB0517184D0 (en) * 2005-08-22 2005-09-28 Glaxo Group Ltd Compounds
NZ566533A (en) 2005-09-16 2010-11-26 Janssen Pharmaceutica Nv Cyclopropyl amines as modulators of the histamine H3 receptor
JO2769B1 (en) 2005-10-26 2014-03-15 جانسين فارماسوتيكا ان. في Fast Dissociting Dopamine 2 Receptor Antagonists
JP2009531376A (en) 2006-03-28 2009-09-03 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 Benzothiazole having histamine H3 receptor activity
CN101754762A (en) * 2006-04-28 2010-06-23 西北大学 The preparation that comprises pyridazine compound that is used for the treatment of neuroinflammatory disorder
WO2007135111A1 (en) * 2006-05-23 2007-11-29 High Point Pharmaceuticals, Llc 6- (4-cyclopropylpiperazin-1-yl) -2 ' -methyl- [3, 4 ' ] -bipyridine and its use as a medicament
NZ571972A (en) * 2006-05-29 2011-09-30 High Point Pharmaceuticals Llc 3- (1, 3-benz0di0x0l-5-yl) -6- (4-cyclopropylpiperazin-1-yl) -pyridazine, its salts and solvates and its use as histamine h3 receptor antagonist
NZ573028A (en) * 2006-05-30 2011-11-25 Janssen Pharmaceutica Nv Substituted pyridyl amide compounds as modulators of the histamine h3 receptor
CA2652158A1 (en) * 2006-05-30 2007-12-06 Matthias Heinrich Nettekoven Piperidinyl pyrimidine derivatives
JP5203360B2 (en) 2006-06-23 2013-06-05 アボット・ラボラトリーズ Cyclopropylamine derivatives as histamine H3 receptor modulators
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
AU2007271187A1 (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 Fast Dissociating Dopamine 2 Receptor Antagonists
JO2849B1 (en) 2007-02-13 2015-03-15 جانسين فارماسوتيكا ان. في Fast -Dissociating Dopamine 2 Receptor Antagonists
ES2400710T3 (en) 2007-04-23 2013-04-11 Janssen Pharmaceutica, N.V. Tia (dia) zoles as fast dissociation dopamine 2 receptor antagonists
US8906921B2 (en) 2007-04-23 2014-12-09 Janssen Pharmaceutica Nv 4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists
EP2155689B1 (en) * 2007-05-31 2015-07-08 Boehringer Ingelheim International GmbH Ccr2 receptor antagonists and uses thereof
EP2014656A3 (en) 2007-06-11 2011-08-24 High Point Pharmaceuticals, LLC New heteocyclic h3 antagonists
BRPI0815038A2 (en) * 2007-08-02 2015-03-17 Hoffmann La Roche USE OF BENZAMIDE DERIVATIVES FOR TREATMENT OF CNS DISORDERS
CA2697941A1 (en) 2007-09-06 2009-03-12 Glaxo Group Limited Piperazine derivative having affinity for the histamine h3 receptor
UA103468C2 (en) 2007-11-20 2013-10-25 Янссен Фармацевтика Н.В. Cycloalkyloxy-and heterocycloalkyloxypyridine compounds as modulators of the histamine h3 receptor
WO2009079593A1 (en) * 2007-12-17 2009-06-25 Janssen Pharmaceutica N.V. 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
WO2010000456A1 (en) 2008-07-03 2010-01-07 Janssen Pharmaceutica Nv Substituted 6- (1-piperazinyl) -pyridazines as 5-ht6 receptor antagonists
EA019048B1 (en) 2008-07-31 2013-12-30 Янссен Фармацевтика Нв Piperazin-1-yl-trifluoromethyl-substituted pyridines as fast dissociating dopamine 2 receptor antagonists
MA33085B1 (en) 2008-12-19 2012-03-01 Boehringer Ingelheim Int Premedine-4 annular carboxamide as antagonists of the receptor ccr2 for the treatment of infections, asthma and COPD
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
JP5632014B2 (en) 2009-12-17 2014-11-26 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 Novel CCR2 receptor antagonists and uses thereof
TWI510241B (en) 2010-02-18 2015-12-01 Vtv Therapeutice Llc Phenyl-heteroaryl derivatives and methods of use thereof
WO2011141477A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
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
WO2011144501A1 (en) 2010-05-17 2011-11-24 Boehringer Ingelheim International Gmbh Ccr2 antagonists and uses thereof
US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
WO2011151251A1 (en) 2010-06-01 2011-12-08 Boehringer Ingelheim International Gmbh New ccr2 antagonists
WO2012037258A1 (en) 2010-09-16 2012-03-22 Abbott Laboratories Processes for preparing 1,2-substituted cyclopropyl derivatives
WO2013010839A1 (en) 2011-07-15 2013-01-24 Boehringer Ingelheim International Gmbh Novel and selective ccr2 antagonists
WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
WO2016020295A1 (en) 2014-08-04 2016-02-11 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
WO2017004537A1 (en) 2015-07-02 2017-01-05 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-4yl)methanone citrate
AU2020405446A1 (en) 2019-12-20 2022-05-26 Nuevolution A/S Compounds active towards nuclear receptors
WO2021198956A1 (en) 2020-03-31 2021-10-07 Nuevolution A/S Compounds active towards nuclear receptors
EP4126874A1 (en) 2020-03-31 2023-02-08 Nuevolution A/S Compounds active towards nuclear receptors

Family Cites Families (28)

* 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 (en) * 1975-04-07 1976-11-05 Parcor DERIVATIVES OF 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
US5001125A (en) * 1984-03-26 1991-03-19 Janssen Pharmaceutica N.V. Anti-virally active pyridazinamines
FR2573075B1 (en) * 1984-09-14 1987-03-20 Innothera Lab Sa NEWS (PYRIDYL-2) -1 PIPERAZINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS
DK111387A (en) * 1986-03-05 1987-09-06 Otsuka Pharma Co Ltd CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES
JP2576862B2 (en) * 1986-03-05 1997-01-29 大塚製薬 株式会社 Carbostyril derivative
AU639529B2 (en) * 1987-03-04 1993-07-29 Higuchi, Yoshinari Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives
DE3803860A1 (en) * 1988-02-09 1989-08-17 Basf Ag N, N'-DISUBSTITUTED PIPERAZINE
US5021421A (en) * 1989-03-03 1991-06-04 Dainippon Pharmaceutical Co., Ltd. 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same
GB9012316D0 (en) * 1990-06-01 1990-07-18 Wellcome Found Pharmacologically active cns compounds
JPH0971564A (en) * 1995-07-06 1997-03-18 Japan Tobacco Inc Benzamidoxime derivative and its use in medicine
WO1997002245A1 (en) * 1995-07-06 1997-01-23 Japan Tobacco Inc. Benzamidoxime derivatives and medicinal use thereof
DZ2376A1 (en) * 1996-12-19 2002-12-28 Smithkline Beecham Plc New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them.
WO1999018077A1 (en) * 1997-10-02 1999-04-15 Eisai Co., Ltd. Fused pyridine derivatives
JP3989102B2 (en) * 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 Condensed pyridine derivatives
AU2935200A (en) * 1999-04-30 2000-11-17 Pfizer Products Inc. Compounds for the treatment of obesity
GB9926302D0 (en) * 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
GB9926303D0 (en) * 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
US6444687B1 (en) * 1999-12-16 2002-09-03 Schering Corporation Substituted imidazole neuropeptide Y Y5 receptor antagonists
FI20000480A0 (en) * 2000-03-01 2000-03-01 Orion Yhtymae Oyj Quinoline and naphthalene derivatives as alpha-2 antagonists
EP2140864A3 (en) * 2001-01-31 2010-01-27 H.Lundbeck A/S Use of GAL3 receptor antagonists for the treatment of depression and / or anxiety and compounds useful in such methods
JP2005529942A (en) * 2002-06-06 2005-10-06 ノボ　ノルディスク　アクティーゼルスカブ Substituted pyrazines and substituted azepines

Also Published As

Publication number Publication date
EP1474401A2 (en) 2004-11-10
WO2003066604A2 (en) 2003-08-14
CN1628109A (en) 2005-06-15
BR0307429A (en) 2004-12-28
WO2003066604A3 (en) 2003-12-04
AU2010200135A1 (en) 2010-02-04
IL162859A0 (en) 2005-11-20
ZA200405694B (en) 2005-09-28
PL372390A1 (en) 2005-07-25
AU2003203148A1 (en) 2003-09-02
NO20043709L (en) 2004-09-03
JP4607458B2 (en) 2011-01-05
JP2005533747A (en) 2005-11-10
MXPA04007612A (en) 2004-11-10
CA2474214A1 (en) 2003-08-14

Similar Documents

Publication Publication Date Title
NO328714B1 (en) Aryl and heteroarylpiperazines, pharmaceutical preparations comprising at least one such compound, and uses of such compounds for the preparation of pharmaceutical preparations
CA2675252C (en) N-substituted glycine derivatives: hydroxylase inhibitors
CA2307111C (en) Novel pyridazine derivatives and drugs containing the same as the active ingredient
RU2288914C2 (en) Novel substituted indoles
TWI257926B (en) Novel 1,2,4-triazole compounds
CA2266050C (en) Piperazine derivatives
TW200918521A (en) Heterocyclic amides and methods of use thereof
CZ20032614A3 (en) N-(2-arylethyl) benzylamines as antagonists of the 5-ht6 receptor
EP2233470A1 (en) Histamine H3 receptor antagonists
CA2603250A1 (en) Diarylamine-containing compounds and compositions, and their use as modulators of steroid hormone nuclear receptors
EP0482208A1 (en) Pyridazinone derivative
HU223601B1 (en) Indole derivatives as 5-ht receptor antagonist
SK119795A3 (en) Indole derivatives as 5-ht1a and/or 5-ht2 ligands
JP6619503B2 (en) CGRP receptor antagonist
JP2014516066A (en) Pyrazole derivative
BR112019017567A2 (en) 1,4,6-TRISSUBSTITUED-2-ALKYL-1H-BENZO [D] IMIDAZOL DERIVATIVES AS DIHYDRO-OROTATE OXYGENASE INHIBITORS
DK169102B1 (en) New piperazinylalkyl-3 (2H) -pyridazinones, method for preparing such compounds and their use in the manufacture of drugs having antihypertensive effect
TW200524872A (en) Process for preparation of pyridine derivatives
JP2011515359A (en) Therapeutic triazole amide derivatives
WO2008053863A1 (en) Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton
US20030236259A1 (en) Novel aryl- and heteroarylpiperazines
TW517052B (en) 2-substituted 1,2-benzoisonthiazole derivatives, their preparation and use
RU2361869C2 (en) New aryl - and heteroarylpiperazines
JP2005526113A (en) Novel piperidinyl-alkylamino-pyridazinone derivatives, their preparation and pharmaceutical compositions containing this compound
JP2007537228A (en) Indol-2-one derivatives for the treatment of diseases of the central nervous system, gastrointestinal system and circulatory system

Legal Events

Date Code Title Description
MM1K Lapsed by not paying the annual fees