WO1999058490A2 - Nouveaux aryl-hydro naphtalene alcane-amines - Google Patents

Nouveaux aryl-hydro naphtalene alcane-amines Download PDF

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WO1999058490A2
WO1999058490A2 PCT/EP1999/003095 EP9903095W WO9958490A2 WO 1999058490 A2 WO1999058490 A2 WO 1999058490A2 EP 9903095 W EP9903095 W EP 9903095W WO 9958490 A2 WO9958490 A2 WO 9958490A2
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formula
phenyl
dimethyl
naphthaleneethanamine
compounds
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PCT/EP1999/003095
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WO1999058490A3 (fr
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Dirk Leysen
Jan Kelder
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Akzo Nobel N.V.
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Priority to AU40376/99A priority Critical patent/AU4037699A/en
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Publication of WO1999058490A3 publication Critical patent/WO1999058490A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to novel aryl-hydronaphthalenalkanamines, to a process for the preparation thereof and to the use of these compounds for the preparation of compositions for the blockade of serotonergic receptors in living organisms.
  • Aryl-hydronaphthalenalkanamines and the preparation thereof are described in Morrison and Rinderknecht (1950).
  • a 1-phenyl-3,4-dihydro- ⁇ /, ⁇ /-dimethyl-2- naphthalenemethanamine and a 1-phenyl-1 ,2,3,4-tetrahydro- ⁇ /, ⁇ /-dimethyl-2- naphthalenemethanamine were prepared in view of a putative structural relationship to morphine and were expected to have an analgesic effect. However, these compounds did not have the analgesic effect aimed for and have not found their way to any other use.
  • the present invention provides aryl-hydronaphthalenalkanamines, which unexpectedly have biological activity due the blockade of serotonergic 5-HT 2C - receptors.
  • the compounds of this invention are aryl-hydronaphthalenalkanamines having the structural formula (I),
  • R 1 and R 2 each independently are H, C C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl or C ⁇ -C 6 -alkoxy-CrC 6 -alkyl; preferred is that R 1 is methyl and R 2 is a hydrogen or a methyl;
  • R 3 is (H,H) or (H,CH 3 );
  • R 4 is hydrogen or one or more substituents at the 5, 6, 7 or 8 position of the naphthyl group
  • Ar is a phenyl, naphthyl or heteroaryl group, each of which optionally having one or more substituents;
  • Alk is C 2 -C 6 -alkylene, C 3 -C 6 -alkenylene or C 3 -C 6 -alkynylene, each of which has 2 - 3 carbon atoms between the naphthalene-ring and the amine function, and can be branched, unbranched or cyclised; the dotted line between a-b is an optional double bond; the cis position is preferred; or addition salts and solvates thereof.
  • a compound of this invention can have chiral centres at the carbon atoms labelled as a and b. For these locations the racemic mixtures as well as the enantiomers are made available by this invention.
  • a substituent is a group selected from CrC 6 -alkyl, CrCe-alkoxy, CrC ⁇ -alkylthio, C C 6 -alkylsulfonyl, C 2 -C 6 alkenyloxy, C 2 -C 6 -alkenylthio, C 2 -C 6 -alkenylsulfonyl, C 2 -C 6 - alkynyloxy, C 2 -C 6 -alkynylthio, C 2 -C 6 -alkynylsulfonyl, aminocarbonyl, cyano , halo, trihalomethyl, aminosulfonyl, nitro and di(C 1 -C 6 )-alkylamino.
  • CrC ⁇ -alkyl is a branched, unbranched or cyclised saturated hydrocarbon with 1 - 6 carbon atoms.
  • C 2 -C 6 alkenyl is a branched, unbranched or cyclised unsaturated hydrocarbon with 2
  • C 2 -C 6 -alkynyl is a branched, unbranched or cyclised unsaturated hydrocarbon with 2
  • a heteroaryl group means a C 2 -C 14 -aromatic group including one or two aromatic rings containing one or more (for example, one to three) heteroatoms selected from oxygen, sulfur, and nitrogen.
  • groups are thienyl, furanyl, benzofuranyl, 1 ,2-benzoisoxazolinyl, pyridinyl, thiadiazolinyl, indazolinyl, benzofuranyl, quinolinyl, and isoquinolinyl.
  • Halo- or halogen means F, Cl, Br or I.
  • Preferred embodiments of this invention are compounds wherein R 1 is methyl and R 2 is a hydrogen or a methyl; R 3 is H,H; R 4 is hydrogen; Ar is phenyl with halo- or trihalomethyl-substituents;
  • Alk is ethylene
  • Most preferred compounds of this invention are ( ⁇ )-c/s-1 ,2,3,4-tetrahydro- ⁇ /, ⁇ /- dimethyl-1-phenyl-2-naphthaleneethanamine and ( ⁇ )-c/s-1-(4-fluorophenyl)-1 ,2,3,4- tetrahydro- ⁇ /, ⁇ /-dimethyl-2-naphthaleneethanamine and the (+)-enantiomers of these compounds.
  • the compounds of the present invention possess biological activity due to the partial or complete blockade of the serotonin 5-HT 2C receptor. Such a property can be used in medical and veterinary practice. While it is possible for a compound of the present invention to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention also makes available a pharmaceutical composition comprising a compound according to formula I in admixture with a pharmaceutically acceptible carrier. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition while not being deleterious to the recipients thereof. Furthermore, a compound according to formula I can be used for the manufacture of a composition to effectuate partial or complete blockade of serotonergic 5-HT 2C receptors in an organism.
  • Serotonin has the function of a hormone or a neurotransmitter in most living organisms. Serotonin acts in the organism by interacting with its receptors. The serotonin receptor changes its conformation when serotonin binds to it. This conformational change induces in turn changes in the biochemical processes in an organism. Compounds which bind to serotonin receptors, without inducing the serotonin induced conformational change, will prevent access of serotonin to the receptor and thus prevent its natural action. Such blockade of serotonin receptors changes the physiology of an organism.
  • the 5-HT 2C receptor is important for functions of the central nervous system. Since it was shown that serotonin in the brain of mammals mediates fear and other emotional reactions, the compounds of this invention can be used in medicines for treating anxiety and other diseases of the mind and the central nervous system. This can be demonstrated with in vitro and in vivo methods and reveals itself in therapeutic usefulness of compounds of this invention. In particular, these compounds can be used for the preparation of a medicament for the treatment of psychiatric and neurological diseases, such as anxiety disorders, affective disorders, psychotic disorders, adjustment disorders, somatisation disorder, central pain disorder, migraine, anorexia nervosa and in the prophylaxis of diseases such as migraine and epilepsy.
  • psychiatric and neurological diseases such as anxiety disorders, affective disorders, psychotic disorders, adjustment disorders, somatisation disorder, central pain disorder, migraine, anorexia nervosa and in the prophylaxis of diseases such as migraine and epilepsy.
  • the treatment of generalised anxiety is expected to be improved by the use of compounds of this invention as medicines.
  • the compounds can be administered on a regular basis, in suitable amounts, to a mammal, such as a human, believed to be suffering from the particular condition.
  • the compounds in this invention with the highest selectivity for the 5-HT 2C receptor, in particular when there is a much smaller affinity for the 5-HT ⁇ receptor, are preferred compounds in view of a reduced chance for side effects.
  • Such compounds are in particular the most preferred compounds ( ⁇ )-c/s-1 ,2,3,4-tetrahydro- ⁇ /, ⁇ /- dimethyl-1-phenyl-2-naphthaleneethanamine and ( ⁇ )-c/s-1-(4-fluorophenyl)-1 ,2,3,4- tetrahydro- ⁇ /, ⁇ /-dimethyl-2-naphthaleneethanamine and their (+)-enantiomers, which can be used as medicines in relatively low doses in view of their high potency. With such properties the chance for side effects is even further reduced.
  • the compounds of this invention can be made by various routes of synthesis.
  • This reduction may be carried out using methods well known in the art or readily available from the chemical literature. Such methods include the reaction with hydrogen in the presence of a suitable hydrogenation catalyst, either heterogeneous or homogeneous; transfer hydrogenation using transition-metal catalysts or by using non-catalytical reagents such as zinc and acids, hydrazine and hydrides in the presence of transition metal salts.
  • the reduction is typically carried out by catalytical hydrogenation, using a heterogeneous catalyst, such as platinum, rhodium, ruthenium and preferably palladium on charcoal, in the presence of a polar solvent such as methanol or ethanol, at temperatures of 0°C to 60°C and a hydrogen pressure between 1 and 5 atm.
  • optically active homogeneous, as well as heterogeneous catalysts may be used.
  • optically active homogeneous, as well as heterogeneous catalysts may be used.
  • Compounds of formula (II) wherein R 1 and R 2 are different from -H can also be obtained by reaction of compounds of formula (II) wherein R 1 and/or R 2 are hydrogen, with an appropriate alkylating agent.
  • Suitable alkylating agents include halides and organic and inorganic esters.
  • the reaction may be carried out in the presence of a base in a polar solvent such as an alcohol or ⁇ /,/V-dimethylformamide at an elevated temperature.
  • these compounds can be prepared by reductive alkylation, for example the Leuchart-Wallach reaction, using carbonyl compounds such as ketones or aldehydes and formic acid or formamides or the Eschweiler-Clarke reaction.
  • compounds of formula (II), especially when R 1 and/or R 2 are -H may also be prepared by reduction of an appropriate amide, prepared from compounds of formula (IV), wherein R 5 is a d-C 6 -alkyl group, by for example ester hydrolysis, formation of an acyl halide or anhydride and reaction with a suitable amine.
  • R 5 is a d-C 6 -alkyl group
  • Compounds of formula (IV) are well known from the literature, for example C.L. Hewett, J. Chem. Soc, 596 (1936) and M.S. Newman and L.M. Joshel, J. Am. Chem. Soc, 62, 972 (1940).
  • sodium borohydride in the presence of certain catalysts, borane, sodium in propanol, trichlorosilane and preferentially chlooralanes or lithium aluminium hydride in a non- protic solvent such as diethyl ether or tetrahydrofuran at elevated temperatures can be used.
  • compounds of formula (II), wherein R 1 and R 2 are both -H can be prepared from compounds of formula (V) by reduction of the nitrile group into a primary amine by well known standard conditions such as lithium aluminium hydride, borane-methyl sulfide complex, catalytical hydrogenation or sodium borohydride in the presence of cobalt(ll) chloride or Raney nickel.
  • compounds of formula (II) may be synthesised from compounds of formula (V) by reduction of the nitrile into an aldehyde, for example using tin(ll) chloride and hydrochloric acid or a metal hydride reducing agent followed by hydrolysis, and subsequent transformation of the aldehyde group into an amine by reductive alkylation using ammonia, a primary or secondary amine in the presence of, for example, hydrogen and a hydrogenation catalyst.
  • compounds of formula (II) may be prepared by dehydroxylation of compounds of formula (VI) by catalytic hydrogenolysis, for example using Raney nickel as a catalyst, or reduction using hydrides such as lithium aluminium hydride, sodium borohydride or triethylsilane in the presence of Lewis acids.
  • Alcohols of formula (VI) can also be reduced indirectly by conversion of the -OH function into a leaving group such as a sulfonate or an halide and subsequent reduction using lithium aluminium hydride, sodium borohydride or diisobutylaluminium hydride.
  • compounds of formula (III) may be synthesised by dehydration of alcohols of formula (VI) using acids such as sulfuric acid or phosphoric acid, metallic oxides or other well known dehydrating agents.
  • compounds of formula (III), wherein R 1 and R 2 are both different from hydrogen may be obtained by a cross-coupling reaction of compounds of formula (VII), wherein L 1 is an appropriate leaving group, preferentially a halide or triflate group, with an optionally substituted aryl- or heteroaryl-lithium, -magnesium, -zinc and preferably -boron reagent using well known palladium salts or complexes, bases and polar solvents, as described in Palladium Reagents and Catalysts, J. Tsuji, pages 209-227, 1995.
  • Compounds of formula (VII) may be prepared by the conversion of compounds of formula (VIII) into vinyl halides using inorganic acid halides, preferentially by treatment with phosphorus pentachloride, or into vinyl triflates, for example, by treatment with a strong base such as lithium hexamethyldisilazane and a triflating reagent such as N-phenyltrifluoromethanesulfonamide in an apolar solvent at temperatures ranging from -70°C to 60°C.
  • a strong base such as lithium hexamethyldisilazane
  • a triflating reagent such as N-phenyltrifluoromethanesulfonamide
  • compounds of formula (VI) may be obtained by addition of an organometallic reagent such as a Grignard or aryllithium reagent, derived using methods well known to a person skilled in the art from a compound Ar- L 2 , wherein Ar is as hereinbefore described and L 2 is a suitable leaving group such as a nitro-, mesylate- or triflate- group or a halide, including fluoro, chloro, bromo or iodo, to a compound of formula (VIII).
  • organometallic reagent such as a Grignard or aryllithium reagent
  • compounds of formula (VIII) may be prepared from compounds of formula (IX), wherein R 5 is a C C 6 -alkyl, by ester hydrolysis, subsequent decarboxylation and aromatic acylation.
  • Ester hydrolysis can be catalysed by acids or bases.
  • the decarboxylation can be effectuated by well known methods such as heating the free acid or its salt, eventually in the presence of catalysts, for example various inorganic salts or a suitable crown ether.
  • a Friedel-Crafts acylation may be applied.
  • compounds of formula (VIII) can be obtained from compounds of formula (IX) by treatment with an inorganic base such as sodium or potassium hydroxide in a polar solvent such as a mixture of alcohols with water and heated at elevated temperature.
  • an inorganic base such as sodium or potassium hydroxide
  • a polar solvent such as a mixture of alcohols with water and heated at elevated temperature.
  • the intermediate dicarboxylic acid is decarboxylated by heating at elevated temperatures, for instance ranging from 100°C to 300°C, and cyclised by reacting the residue with a proton acid, preferentially concentrated sulfuric acid at elevated temperatures, for example ranging from 20°C to 100°C.
  • compounds of formula (IX) may be prepared from compounds of formula (X), or alternatively from compounds of formula (XI), by alkylation with an appropriate reagent, containing a suitable leaving group such as a nitro-, mesylate- or triflate- group or a halide, including fluoro, chloro, bromo or iodo.
  • a base may be used, preferentially a strong base as for example sodium hydride, in a polar non-protic solvent such as dimethyl sulfoxide or N,N-dimethylformamide at temperatures ranging from 0°C to 150°C.
  • a polar non-protic solvent such as dimethyl sulfoxide or N,N-dimethylformamide at temperatures ranging from 0°C to 150°C.
  • crown ethers or phase transfer conditions can be employed.
  • the individual enantiomers of compounds of formula (II) may be prepared as hereinbefore described or obtained from a mixture of stereoisomers using any method well known in the art for separating such isomers into their constituent enantiomers. For example, using methods described in Stereochemistry of organic Compounds, E.L. Eliel and S.H. Wilen, chapter 7, 1994. In particular they may be obtained by conversion to diastereomers by methods such as salt formation with optically active acids followed by fractional crystallisation or by differential absorption using columns packed with chiral material, for example by preparative chiral liquid or gas chromatography.
  • a compound of this invention can be mixed with one or more suitable carriers.
  • suitable carriers are various carbohydrates, gum acacia, calcium phosphate, gelatin, talc, magnesium stearate or mineral oil.
  • Suitable pharmaceutical compositions include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • a dosage unit may contain between 0.005 mg and 2000 mg of a compound of the present invention.
  • dosage units of the pharmaceutical composition of the invention per day is sufficient for obtaining a therapeutic effect. The therapy may be continued for as long as necessary or desired.
  • compositions may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical Preparations and their manufacture). Such methods include the process of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients, carrying out said process by exclusion of contamination with traces of pathogens and harmful chemicals.
  • Accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.
  • compositions adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as powder or granulates; as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.
  • compositions adapted for rectal administration may be presented as a suppository or enema.
  • compositions include aqueous and non- aqueous sterile injection fluids.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • compositions adapted for sublingual administration may be presented as liquid, solids or lozenges, which can comprise a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water-dispersible carrier material.
  • carrier materials are well known in the art and can be polysaccharides like hydrolysed dextran, dextrin, mannitol, and alginates, or mixtures thereof, or mixtures thereof with other carrier materials like polyvinylalcohol, polyvinylpyrrolidone and water-soluble cellulose derivatives, like hydroxypropyl cellulose.
  • Compositions adapted for nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
  • compositions may, for example, be presented in a suitable sustained release form, for example, in a device such as the MinipumpTM
  • Example 2 2-[2-(Dimethylamino)ethyl]-3,4-dihydro-1(2H)-naphthalenone A total of 46.8 grams of crude [2-(dimethylamino)ethyl](2-phenylethyl)-propanedioic acid diethyl ester were dissolved into a solution of 33.5 grams of potassium hydroxide in 180 ml of water and 90 ml of ethanol. The reaction mixture was heated at 100°C during 3 hours, cooled to 0°C and treated with 50 ml of concentrated hydrochloric acid. The resulting mixture was evaporated to dryness under reduced pressure. The residue was heated at 160°C during 4 hours.
  • Example 6 1-(4-Fluorophenyl)-3,4-dihydro- ⁇ /,N-dimethyl-2-naphthaleneethanamine ethanedioate (1 :1)
  • Example 7 c/s-1 ,2,3,4-Tetrahydro- ⁇ /, ⁇ /-dimethyl-1-phenyl-2- naphthaleneethanamine hydrochloride
  • Example 8 (-)-c/s-1 ,2,3,4-Tetrahydro- /, ⁇ /-dimethyl-1-phenyl-2- naphthaleneethanamine (Z)-2-butenedioate (1 :1) and (+)-c/s-1 ,2,3,4-tetrahydro- ⁇ /, ⁇ /- dimethyl-1-phenyl-2-naphthaleneethanamine (Z)-2-butenedioate (1 :1) by chiral HPLC separation
  • NIH/3T3 cells are stably transfected with cloned human 5-HT 2C receptors.
  • Mesulergine binds reversibly to these receptors.
  • the binding can be assessed by separation of bound and non-bound mesulergine.
  • Specific binding of labelled mesulergine can be inhibited by 5-HT agonists (e.g. serotonin) and 5-HT antagonists.
  • 5-HT agonists e.g. serotonin
  • 5-HT antagonists e.g. serotonin
  • binding activity of compounds of this invention to cloned human 5HT 2C receptors is demonstrated by measuring the inhibition of mesulergine binding to these receptors.
  • Tris(hydroxymethyl)aminomethane Tris
  • MgCI ⁇ Tris(hydroxymethyl)aminomethane
  • pargyline Tris(hydroxymethyl)aminomethane
  • the buffer is prepared by dissolving Tris (6,06 g; 0,05 mol), ethylenediaminetetraacetic acid (EDTA; 0,19 g; 0,5 mmol), MgCl2.6H 2 O (2,033 g;
  • Tris(hydroxymethyl)aminomethane (0,6 g; 0,005 mol) is dissolved in approx 950 ml water. This solution is adjusted to pH 7,4 with HCI (4 mol l -1 ) and made up to 1 I with water. The buffer is freshly prepared before use.
  • Mianserin.HCI (0,301 mg) is dissolved in 10 ml water (concentration 10 -4 mol l -1 ). An aliquot of 0,050 ml is used for the determination of non-specific binding (final concentration 10"5 mol l" 1 reaction mixture).
  • NIH/3T3 cells are stably transfected with human 5HT2C clone 9.
  • the cells are grown in 3,6 1 DMEM/HAM F12 (1 : 1) + 5 % (v/v) newborn-bovine serum (Hyclone) on Cultispher-G (5 g l _1 ) microcarriers in a Celligen bioreactor.
  • the cells are cultivated under stirring at 37 °C, pH 7 - 7,4.
  • Fresh medium is added continuously by perfusion at a rate of 1 ,8 I DMEM/HAM per day and after two weeks a final cell density of approx 5,5 x 10 ⁇ cells mM was obtained.
  • Eppendorf tubes (sufficient for one 96-wells micromedia rack or 96 reaction tubes) is allowed to thaw and resuspended in 45 ml Tris-MgCl2 buffer using a Polytron homogenizer (15 s, max speed).
  • Tris-MgCl2 buffer, labelled mesulergine solution (0,050 ml) and 3T3 cell homogenate (0,40 ml) are successively pipetted in triplicate into wells of a micromedia rack or into glass test tubes. Immediately after the addition of the homogenate, the mixture is incubated by shaking for 60 min at room temperature. The incubation is terminated by filtration of the whole volume through the Whatman GF/B glass fibre, presoaked in Prosil 28 (1 % v/v) for 1 h, into either: 1. the Skatron 96-wells Harvester. Each residue is washed for 10 s with about 10 ml ice-cold Tris buffer. Each filter + residue is sealed with a Meltilex dry scintillation plate, using a heatsealer, and transferred to a LKB-Betaplate counter. The samples are counted once for 2 min. or:
  • Test or reference compound solution (0,050 ml), labelled mesulergine solution (0,050 ml) and 3T3 cell homogenate (0,40 ml) are pipetted in triplicate into wells of a micromedia rack or into glass test tubes. The procedure is further processed as described under a.
  • the sample is counted once for 2,5 min using a liquid scintillation counter.
  • Test compounds are dissolved in the vehicle (Ultrapure water or HCI (0,1 mol l" 1 ) followed by neutralization to pH 7 - 8) and usually investigated in triplicate at
  • Counting figures can be expressed as counts per min (cpm) or can be corrected for quenching and converted as numbers of desintegrations per min (dpm). For each concentration of test compound the mean cpm- or dpm value is calculated. The mean percentage change of specific binding for each concentration, IC5o-values and affinity constants Kj for the binding of the test compound to the
  • 5HT2C receptor are calculated using methods well known in the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouveau aryl-hydronaphtalène alcane-amine possédant la formule structurelle (I). L'invention concerne également une composition pharmaceutique comprenant ce composé et l'utilisation de ce composé pour effectuer un blocage partiel ou complet des récepteurs sérotoninérgiques 5-HT2C dans un organisme. L'invention concerne également un procédé de préparation de ce composé.
PCT/EP1999/003095 1998-05-08 1999-05-03 Nouveaux aryl-hydro naphtalene alcane-amines WO1999058490A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40376/99A AU4037699A (en) 1998-05-08 1999-05-03 Novel aryl-hydro naphthalenal kanamines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98201462.3 1998-05-08
EP98201462 1998-05-08

Publications (2)

Publication Number Publication Date
WO1999058490A2 true WO1999058490A2 (fr) 1999-11-18
WO1999058490A3 WO1999058490A3 (fr) 2000-01-20

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AU (1) AU4037699A (fr)
WO (1) WO1999058490A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
WO2002055975A1 (fr) * 2000-12-27 2002-07-18 Kazuhito Sakano Detecteur de phase, procede d'etablissement de valeur de reference de detecteur de phase, thermometre a infrarouge, et procede de mesure de temperature sur ce thermometre
US6465467B1 (en) 1999-05-21 2002-10-15 Biovitrum Ab Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
WO2005123681A1 (fr) * 2004-06-22 2005-12-29 Grünenthal GmbH 3-pyridyl-benzocycloalkylmethylamines saturees et insaturees destinees au traitement de douleurs, de depressions et d'etats d'angoisse
EP1978961A2 (fr) * 2006-01-06 2008-10-15 Sepracor, Inc. Inhibiteurs de recaptage de monoamine a base de tetralone
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845221A (en) * 1988-04-15 1989-07-04 American Home Products Corporation Serotonergic substituted piperazinyl tetralins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845221A (en) * 1988-04-15 1989-07-04 American Home Products Corporation Serotonergic substituted piperazinyl tetralins

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071180B2 (en) 1999-05-21 2006-07-04 Biovitrum Ab Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
US7534794B2 (en) 1999-05-21 2009-05-19 Biovitrum Ab Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
US6465467B1 (en) 1999-05-21 2002-10-15 Biovitrum Ab Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
KR100722090B1 (ko) * 1999-05-21 2007-05-25 바이오비트럼 에이비 신규 화합물, 이의 용도 및 이의 제조 방법
WO2000076984A3 (fr) * 1999-05-21 2001-02-08 Pharmacia & Upjohn Ab Nouveaux composes, et utilisation et preparation de ces derniers
US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US7247633B2 (en) 2000-11-20 2007-07-24 Biovitrum Ab Pyrimidine compounds and their use
WO2002055975A1 (fr) * 2000-12-27 2002-07-18 Kazuhito Sakano Detecteur de phase, procede d'etablissement de valeur de reference de detecteur de phase, thermometre a infrarouge, et procede de mesure de temperature sur ce thermometre
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
US8278338B2 (en) 2004-06-22 2012-10-02 Gruenenthal Gmbh Saturated and unsaturated 3-pyridyl-benzocycloalkylmethyl-amines for use in treating pain, depression and/or anxiety
JP2008503523A (ja) * 2004-06-22 2008-02-07 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 苦痛、うつ病及び（又は）不安障害の治療に使用するための飽和及び不飽和３−ピリジル−ベンゾシクロアルキルメチル−アミン類
WO2005123681A1 (fr) * 2004-06-22 2005-12-29 Grünenthal GmbH 3-pyridyl-benzocycloalkylmethylamines saturees et insaturees destinees au traitement de douleurs, de depressions et d'etats d'angoisse
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
EP1978961A2 (fr) * 2006-01-06 2008-10-15 Sepracor, Inc. Inhibiteurs de recaptage de monoamine a base de tetralone
JP2009527462A (ja) * 2006-01-06 2009-07-30 セプラコア インコーポレーテッド テトラロン系モノアミン再取り込み阻害剤
EP1978961A4 (fr) * 2006-01-06 2010-10-27 Sepracor Inc Inhibiteurs de recaptage de monoamine a base de tetralone

Also Published As

Publication number Publication date
WO1999058490A3 (fr) 2000-01-20
AU4037699A (en) 1999-11-29

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