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WO2000005225A1 - Derives de biphenyle - Google Patents

Derives de biphenyle Download PDF

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Publication number
WO2000005225A1
WO2000005225A1 PCT/EP1999/004803 EP9904803W WO0005225A1 WO 2000005225 A1 WO2000005225 A1 WO 2000005225A1 EP 9904803 W EP9904803 W EP 9904803W WO 0005225 A1 WO0005225 A1 WO 0005225A1
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WO
WIPO (PCT)
Prior art keywords
methyl
formula
biphenyl
methoxy
phenyl
Prior art date
Application number
PCT/EP1999/004803
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English (en)
Inventor
Henning Böttcher
Christoph Van Amsterdam
Jürgen Harting
Hakan Vilhelm WIKSTRÖM
Yi Liao
Original Assignee
Merck Patent Gmbh
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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to BR9912299-5A priority Critical patent/BR9912299A/pt
Priority to JP2000561181A priority patent/JP2002521377A/ja
Priority to CA002338209A priority patent/CA2338209A1/fr
Priority to KR1020017000849A priority patent/KR20010070997A/ko
Priority to EP99934632A priority patent/EP1098892A1/fr
Priority to SK49-2001A priority patent/SK492001A3/sk
Priority to PL99345283A priority patent/PL345283A1/xx
Priority to HU0102622A priority patent/HUP0102622A3/hu
Priority to AU50338/99A priority patent/AU5033899A/en
Publication of WO2000005225A1 publication Critical patent/WO2000005225A1/fr
Priority to NO20010333A priority patent/NO20010333D0/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P35/00—Antineoplastic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • 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
    • C07D295/12—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 or doubly bound nitrogen atoms
    • C07D295/135—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Definitions

  • the invention relates to novel Biphenyl de ⁇ vatives of formula
  • X is -CONH-, -SO 2 NH-, -NHCO- or -NHSO 2 -,
  • Y is CH or N
  • a 3 , A 5 in each case independently of one another are alkyl having 1 to 6 C atoms, A 0 , A 7 in each case independently of one another are H or 5 (CH 2 ) P CH 3 ,
  • R 1 is 4-A 5 -piperazin-1-yl, 4-A 5 -homopiperaz ⁇ nyl, 1-pyrro- lidinyl which is substituted once by R 4 or -Z-R 4 ,tician n 1-piperidinyl which is substituted once by R 4 or -Z-R ,
  • R 2 is 5-methyl-1 ,3,4-oxadiazol-2-yl or 5-methyl-1 ,2,4-
  • R ° ' R* i ⁇ eac ⁇ case independently of one another are NHA 5 ,
  • N(A ) 2 4-morpholinyl, 1-pyrrolidinyi or 1-piperidinyi, Z is alkylene having 1 to 6 C atoms, n is 0 or 1 , p is O, 1 or 2,
  • Biphenylamide derivatives are disclosed, for example, in WO 96/31508 or as described by P.J. Pauwels in Gen. Pharmac. Vol. 29, No. 3, 293-303
  • Benzanilide derivatives are known from EP 0 533 267, EP 0 533 268 or from WO 94/15920.
  • the invention was based on the object of finding novel compounds which have valuable properties, in particular those which can be used for the preparation of pharmaceuticals.
  • Serotonin is distributed in the central nervous system (CNS), platelets and the gastrointestinal tract.
  • CNS central nervous system
  • There are multiple types of receptors for serotonin such as 5-HT-IA, 5-HT 1 BI 5-HT 1C or 5-HTID-
  • the 5-HT- ⁇ c receptor recently has been renamed to 5-HT 2C .
  • Changes in transmission of serotonin in the CNS can modify e.g. mood, psychomotor activity, appetite, memory and blood pressure. Release of - .) -
  • serotonin from platelets can mediate vasospasm while changes in free serotonin levels in the gastrotestinai tract can modify sectretion and motiiity.
  • 5-HT 1 B receptors activation of 5-HT 1 B receptors might lead to an increase in anxiety and locomotion and to a decrease in food intake, sexual activity and agressive behaviour.
  • selective blockade of central 5-HT 1 B/ D autoreceptors should facilitate 5-HT transmission and may therefore offer a novel antidepressant therapy (P.J. Pauwels in Gen. Pharmac. Vol. 29, No. 3, 293-303 (1997)).
  • Other studies suggest that supersensitive 5-HT- I B/ D receptors may have a role in the pathophysiology of obsessive-compulsive disorder (OCD) (O.T. Dolberg et al., Eur. Neuropsychopharmac. 5, 161-162 (1995)).
  • OCD obsessive-compulsive disorder
  • Compounds of the formula I can be used in the treatment of diseases which are related to interferences in the serotoninergic systems.
  • Compounds show potent 5-HT ⁇ B and/or 5-HT 1D antagonistic properties.
  • Compounds showing 5-HT I D antagonistic properties may be identified by a high level of affinity in the in vitro human cortex and guinea-pig striatum radioligand binding assays described by Hoyer et al., Neuroscience Letters, 1988, 85, 357-362.
  • the affinity of a compound for a 5-HT 1A receptor is measured using the in vitro test described by Gozlan et al., Nature, 1983, 305, 140-142.
  • the affinity of the compounds for the 5-HT ⁇ D receptors in calf caudate membranes (mainly constituting the homologous bovine 5-HT 1B receptor) as well as the 5-HT 1B antagonistic properties in the K + -stimulated release of [ 3 H]-5-HT from preloaded rat occipital cortical slices, can be determined analogous to S.Berg et al. in J. Med. Chem. 1998, 41 , 1934-1942.
  • the effect of the compounds on the 5-HT turnover in rat brain in vivo can be determined by using the 5-HTP accumulation technique (S.Berg et al.)
  • the compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and/or of cardiovascular disorders.
  • CNS disorders such as mood disorders, including depression and dysthymia, anxiety disorder including generalized anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnestic disorders and age-associated memory impairment. They can be used for treating Parkinson's disease, dementia in Parkinson's disease, neuroieptic-induced parkinson and tardive dyskinesias. Moreover, they can be used in the treatment of 5-HT- dependent tumor ceil growth, of disorders of eating behaviors, including anorexia ⁇ ervosa and bulimia.
  • cardiovascular disorders characterized by the malfunction of peripheral 5-HT 1B/D receptors, in the treatment or prophylaxis of endocrine disorders, vasospasm, hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, and sexual dysfunction.
  • the compounds of the formula I and their physiologically acceptable salts can therefore be used as pharmaceutical active compounds for anxiolytics, antidepressants, antipsychotics, neuroleptics and/or antihypertensives, and for positively affecting obsessive-compulsive behaviour, eating disorders such as bulimia, tardive dyskinesias, learning disorders and age- dependent memory disorders.
  • the compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. They can further be employed as intermediates for the preparation of further pharmaceutical active compounds.
  • the invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of formula I according to Claim 1 and salts and solvates thereof, characterized in that a) a compound of formula II
  • L is CI, Br, I or an OH group functionally modified to form a reactive group, especially a suitable leaving group, and R and A 3 are as defined, is reacted with' a boronic acid derivative of formula III
  • X, Y, A 1 , A , Q and n are as defined,
  • R and A 3 are as defined, X' is CO or SO 2 and
  • L is Cl, Br, I or an OH group functionally modified to form a reactive group, especially a suitable leaving group,
  • R is -CO-NH-Z-R 3 or -CO-R 1
  • L is Cl, Br, I or a free or reactive functionally modified OH group , I Q and X, Y, A 1 , A 2 , A 3 , Q and n are as defined,
  • R' is NH-Z-R 3 or R 1
  • R 3 and R 1 are as defined
  • a basic compound of the formula I is converted into a salt thereof by treatment with an acid.
  • radicals R, X, Y, X', R', A 1 , A 2 , A 3 , A 5 , Q, L and n have the meanings indicated in the formulae I, II, III, IV, V, VI and VII if not expressly stated otherwise.
  • the invention likewise relates to medicaments of the formula I and their physiologically acceptable salts and solvates having serotonin (5-HT 1B and/or 5-HT- ⁇ D ) antagonistic action.
  • the invention relates to the compounds of the formula I according to Claim 1 and to their salts and solvates.
  • Solvates means addition compounds of the compounds of formula I according to Claim 1 with inert solvents.
  • Solvates are e.g. the mono- or dihydrates or alcoholates, e.g. with methanol or ethanol.
  • a 1 preferably is H, methyl, ethyl, CH 2 CH 2 F, CF 3 , S0 2 CH 3 or SO 2 CF 3 .
  • a 2 preferably is H, methyl or ethyl.
  • a 3 and A 5 are by preference in each case independently of one another alkyl having 1-6 C atoms.
  • a 3 preferably is methyl, ethyl or propyl.
  • a 5 preferably is methyl, ethyl or propyl.
  • Q preferably is H, furthermore preferably methoxy or ethoxy.
  • X preferably is -CONH- or -SO 2 NH-.
  • z preferably means methylene, ethylene or propylene.
  • N-A 5 -pyrroiidinyl-amino means A 5
  • -N(A 6 )(ZR 3 ) preferably means -NH(CH 2 NHCH 3 ), -NH(CH 2 CH 2 NHCH 3 ), -NH(CH 2 CH 2 NMe 2 ), -NMe(CH 2 CH 2 NMe 2 ), -NH(CH 2 CH 2 CH 2 NMe 2 ), - -NNMMee((CCHH 22 CCHH 22 CCHH 22 NNlM ⁇ e 2 ).
  • NA S A 7 preferably means NH 2 , NHCH 3 , NHC 2 H 5 , N(CH 3 ) 2 or N(C 2 H 5 ) 2 .
  • R 1 preferably means 4-methyl-piperazin-1-yl, morphoiin-4-yl, 4-methyl- homopiperazinyl, 2-dimethylaminomethyl-pyrrolidin-1-yl, 2-dimethylamino- methyl-piperidin-1 -yl, N-methyl-pyrrolidin-2-yl-amino, N-methyl-piperidin-3- or -4-yl-amino, N-methyl-pyrrolidin-2-yl-methyiamino or N-methyl- piperidinyl-methyl-amino.
  • Ac is acyl and preferably means acetyl, propionyl or benzoyl.
  • me or Me is methyl
  • et or Et is ethyl.
  • alkyl has 1 , 2, 3, 4, 5 or 6 C atoms, preferably 1 , 2, 3, 4 or 5 C atoms, and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n- pentyl, neopentyl or isopentyl.
  • NHA 5 is preferably methylamino and also ethylamino, ⁇ -propyiamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert- butylamino.
  • N(A 5 ) 2 is preferably dimethylamino and also diethylamino, di-n- propylamino, diisopropylamino or di-n-butylamino.
  • Alkylene preferably means unbranched methylene, ethylene, propylene, butylene, pentylene or hexyie ⁇ e. Furthermore, alkyiene means branched alkylene residues.
  • the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned radicals has one of the meanings given above as being preferred.
  • Some preferred groups of compounds can be expressed by the following sub-formulae la to Ih, which correspond to the formula I and in which the radicals which are not described in greater detail have the meanings given for formula I, but in which
  • a 3 is alkyl having 1 to 6 C atoms
  • a 3 is alkyl having 1 to 6 C atoms
  • a 3 is alkyl having 1 to 6 C atoms
  • a 1 is H or alkyl having 1 to 6 C atoms
  • a 2 is alkyl having 1 to 6 C atoms
  • a 5 is alkyl having 1 to 6 C atoms
  • a 3 is alkyl having 1 to 6 C atoms
  • a 1 is H or alkyl having 1 to 6 C atoms
  • a 2 is alkyl having 1 to 6 C atoms, 00/05225
  • a 5 is alkyl having 1 to 6 C atoms
  • X is SO 2 NH
  • a 3 is alkyl having 1 to 6 C atoms
  • a 1 is H or alkyl having 1 to 6 C atoms
  • a 2 is alkyl having 1 to 6 C atoms
  • a 5 is alkyl having 1 to 6 C atoms
  • X is SO 2 NH
  • Y is CH
  • a 3 is alkyl having 1 to 6 C atoms
  • a 1 is H or alkyl having 1 to 6 C atoms
  • a 2 is alkyl having 1 to 6 C atoms
  • a 5 is alkyl having 1 to 6 C atoms
  • X is CONH
  • Y is CH.
  • the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se and they are described in the literature (for example in the standard publications such as Houben-Weyl, Methoden der organischen Chemie [Methods in Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known and suitable for the abovementioned reactions. It is also possible to make use of variants which are known per se and not mentioned in greater detail in the present text.
  • L is a reactive esterified OH group
  • this is by preference alkyl- sulfonyloxy having 1-6 C atoms (preferably methylsulfonyioxy or trifluoro- 00/05225
  • methyisulfo ⁇ yloxy or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolyl-sulfonyioxy, furthermore also 2-naphthalenesulfonyi-oxy).
  • the starting materials may also be formed in situ, so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction stepwise.
  • the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting substances of the formulae II and III are known in some cases. If they are not known, they can be prepared by methods known per se.
  • reaction of the compounds II and III is carried out in the presence or absence of an inert solvent at temperatures between approximately -20 and approximately 180°, preferably between 40 and 130° and the presence of e.g. Pd(PPh 3 ) 4 (Suzuki-reaction) .
  • an acid-binding agent for example an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkaline earth metal hydroxide, alkaline earth metal carbonate or alkaline earth metal bicarbonate, or of another salt of a weak acid of the alkali metal or alkaline earth metals, preferably of potassium, sodium or calcium, or an addition of an organic base such as triethylamine, dimethylamine or pyridine or quinoline or of an excess of the amine component may be advantageous.
  • an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkaline earth metal hydroxide, alkaline earth metal carbonate or alkaline earth metal bicarbonate, or of another salt of a weak acid of the alkali metal or alkaline earth metals preferably of potassium, sodium or calcium
  • an organic base such as triethylamine, dimethylamine or pyridine or quinoline or of an excess of the amine component
  • suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1 ,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-but-a ⁇ ol or tert-butanol; ethers such as diethyl ether, diisopropyi ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether (methyiglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylace
  • a compound of formula I by reacting a compound of formula IV with a compound of formula V.
  • Some of the compounds of formula IV and V, especially of formula V, are known; the unknown compounds can easily be prepared analogously to the known compounds.
  • compounds of formula IV can be prepared by reacting the corresponding carboxylic acid or the sulfonic acid with SOCl 2 . 0
  • the reaction of compounds IV and V proceeds according to methods which are known from the literature for the formation of amides or suifonamides.
  • the components can be melted with one another directly, without the presence of a solvent, at normal pressure or at elevated pressure, an inert gas such as e.g. N 2 being added to increase the 5 pressure.
  • the optimum reaction time is between a few minutes and 14 days, and the reaction temperature is between about 0° and 150°, usually between 20° and 130°.
  • reaction of compounds VI and VII proceeds according to methods which are known from the literature for the formation of amides.
  • E ⁇ xamples for the N-acylation of compounds of formula VII of suitable derivatives of the compounds of formula VI are acid halides, preferably chlorides, azides, anhydrides, imidazolides (which can be obtained, for example, from carbodiimidazoles), activated esters or O-acyiureas, which are obtained from suitable carboximides, such as dialkylcarbodiimides, e.g. cyclohexyl-carbodiimide. It may be necessary, before carrying out this reaction, to exclude further amino groups contained in the compound of the formula VII from the acyiation reaction by introduction of suitable protective groups.
  • the reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium.
  • an organic base such as triethylamine, dimethylaniiine, pyridine or quinoline or of an excess of the compound of the formula VII or of the alkylating derivative of the formula VI may also be favourable.
  • the reaction time depending on the conditions used, is between a few minutes and 14 days, and the reaction temperature is between approximately 0° and 150°, normally between 20° and 130°. Suitable solvants are those mentioned previously.
  • amino protective group is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easiiy removable after the desired chemical reaction has been carried out at another position in the molecule.
  • groups are, in particular, unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP), aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. benzyl, 4- ⁇ itrobenzyl, triphenylmethyl).
  • acyl group in this connection is to be interpreted in the widest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxy- carbonyl, aryioxycarbonyi and especially aralkoxycarbonyl groups.
  • acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenacetyl; aroyl such as benzoyl or tolyl; aryloxyalkanoyi such as phenoxy-acetyl; alkoxycarbonyl such as methoxy- carbonyl, ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl, iso-propoxy- carbonyi, tert-butoxycarbonyl (BOC), 2-iodo-ethoxycarbonyl; aralkyi- oxycarbonyl such as benzyloxy-carbonyl (CBZ), 4-methoxybenzyi- oxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC).
  • Preferred amino protective groups are BOC, DNP and BOM, and further CBZ, benzyl and acetyl. A crucial factor in the choice of
  • the amides of formula I, wherein R is -CO-NH-Z-R 3 or -CO-R 1 can be prepared e.g. by coupling the amine and the carboxylic acid using P-EDC (polymer-bound 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide according to M. Desai et al., Tetrahedron Letters 1993, 34 (48), 7685- 7688) an inert solvent at temperatures between approximately -20 and approximately 100°, preferably between -10 and 60°. Suitable solvants are those mentioned previously.
  • Compounds of the formula I can furthermore preferably be obtained by reductive amination of compounds of the formula I.
  • the starting substances are known in some cases. If they are not known, they can be prepared by methods known per se. 0/05225
  • the reducing ami ⁇ ation can be carried out in the presence of reducing agents such as, for example, NaBH 3 CN, NaBH 4 and NaBH(OAc) 3 .
  • reducing agents such as, for example, NaBH 3 CN, NaBH 4 and NaBH(OAc) 3 .
  • the reaction is carried out in solvents and at temperatures as described above.
  • a compound of the formula I into another compound of the formula I by converting one or more radicals R, Q, A 1 , and/or A 2 into one or more other radicals R, A 1 , and/or A 2 , e.g. by converting a group R 2 for example by hydrogenation on Raney Nickel or Pd-carbon in an inert solvent such as methanol or ethanol, to an amidino group and/or hydrolysing an ether group to a hydroxyl group.
  • an inert solvent such as methanol or ethanol
  • Free amino groups can further be acylated in a customary manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and +30°.
  • a functionally modified amino and/or hydroxyl group in a compound of the formula I can be liberated by solvoiysis or hydrogenolysis according to customary methods.
  • a compound of the formula I which contains an NHCOOalkyl group can thus be converted into the corresponding compound of the formula I which, instead of this, contains an NH 2 group.
  • a base of the formula I may be converted with an acid to give the corresponding acid addition salt, for example by reacting equivalent amounts of the base and of the acid in an inert solvent such as acetone, followed by evaporation.
  • Particularly suitable acids for this reaction are those which give physiologically acceptable salts.
  • inorganic acids for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphorus acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poiybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • citric acid gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethane- sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene- mono- and -disulfonic acids, laurylsulfuric acid. Salts with acids which are physiologically not acceptable, e.g. picrates, can be used for isolating
  • the free bases of the formula I may, if desired, be liberated from their salts by using bases (e.g. sodium hydroxide, sodium carbonate, potassum hydroxide or potassium carbonate).
  • bases e.g. sodium hydroxide, sodium carbonate, potassum hydroxide or potassium carbonate.
  • the invention further relates to the use of the compounds of the formula I and/or their physiologically acceptable salts or solvates for the preparation of pharmaceutical products, in particular by non-chemical routes. They can be brought into a suitable pharmaceutical form together with at least one 20 solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more other active ingredients.
  • the invention furthermore relates to pharmaceutical products comprising at least one compound of the formula I and/or a physiologically acceptable
  • Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topicai adminstration and 30 which do not react with the novei compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, giycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Forms which are used for oral administration are, in particular, tablets, pills, sugar-coated tablets, D capsules , powders, granules, syrups, liquids or drops, forms for rectal administration are, in particular suppositories, forms for pare ⁇ teral administration are, in particular, solvents, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, and forms for topical administration are ointments, creams or powders.
  • the novel compounds may also be lyophiiized and the resulting lyophilisates used for example for the preparation of injectable products.
  • the abovementioned products can be in sterilized form and/or comprise auxiliaries such as glidants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colourings, flavourings and/or other active ingredients, e.g. one or more vitamins.
  • auxiliaries such as glidants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colourings, flavourings and/or other active ingredients, e.g. one or more vitamins.
  • the invention also relates to compounds of the formula I according to Claim 1 and the physiologically acceptable salts and solvates thereof as serotonin (5-HT 1B/D ) antagonists.
  • the invention relates to the compounds of the formula I according to Claim 1 and the physiologically acceptable salts and solvates thereof for the treatment or prophylaxis of mood disorders, including depression and dysthymia, anxiety disorder including generalized anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post- traumatic stress disorder, memory disorders, including dementia, amnestic disorders and age-associated memory impairment, Parkinson's disease, 5- HT-dependent tumor cell growth, disorders of eating behaviors, including anorexia nervosa and bulimia, cardiovascular disorders characterized by the malfunction of peripheral 5-HT 1B D receptors, endocrine disorders, vasospasm, hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, and sexual dysfunction.
  • mood disorders including depression and dysthymia
  • anxiety disorder including generalized anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post- traumatic stress disorder
  • memory disorders including dementia, am
  • the invention relates to the compounds of the formula I according to Claim 1 and the physiologically acceptable salts and solvates thereof for the treatment or prophylaxis of depression, generalized anxiety , obsessive compulsive disorder and bulimia.
  • the substances according to the invention are preferably administered in analogy to other known commercially available preparations for the indications claimed (e.g. imipramine, fluoxetine, ciomipramine), preferably in doses of between approximately 0.1 and 500 mg, in particular between 5 and 300 mg per dose unit.
  • the daily dose is preferably between approximately 0.01 and 10 mg/kg of body weight.
  • the specific dose for each patient depends on all sorts of factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the excretion rate, pharmaceutical substance combination and severity of the particular disorder to which the therapy relates. Oral administration is preferred.
  • the invention additionally relates to the use of compounds of the formula I according to Claim 1 and/or of the physiologically acceptable salts or solvates thereof for the preparation of a pharmaceutical for the treatment or prophylaxis of depression, generalized anxiety, obsessive compulsive disorder and bulimia.
  • the invention also relates to the use of compounds of the formula I according to Claim 1 and/or of the physiologically acceptable salts or solvates thereof for the treatment or prophylaxis , generalized anxiety, obsessive compulsive disorder and bulimia.
  • the pharmaceutical activity of the racemates or of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers.
  • the final product or else even the intermediates can be resolved into enantiomeric compounds by chem i cal or phys i cal measures known to the person skilled in the art or even employed in the synthesis as such.
  • dias.ere.mers are formed from the mixture by reaction with an optically active resolving agent.
  • Suitable resolving agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid mai i c acd, lactic acid, suitably N-protected amino acids (e.g N-benzoyl- ' prol i ne or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid mai i c acd, lactic acid, suitably N-protected amino acids (e.g N-benzoyl- ' prol i ne or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • a chromatographic resolution of enantiomers with the aid of an optically active resolving agent (e g d i n i trobenzoyiphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers attached to s,l.ca gel).
  • an optically active resolving agent e g d i n i trobenzoyiphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers attached to s,l.ca gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as, for example, hexane/isopropanol/acetonitrile e.g. in the ratio 82:15:3.
  • customary working up means: if necessary, water is added the m i xture is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10, extracted with ethyl acetate or d,chloromethane, and the organic phase is separated off, dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallization. Rf on silica gel; eluant: ethyl acetate/methanol 9:1.
  • Tri-isopropyloxyboron was added to a solution of 329 mg of N-[4- methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]-4-bromo-benzosuifonamide in 15 ml dry THF which was cooled to -80° under nitrogen.
  • 3.8 ml n-BuLi 2.5 M in hexane was added dropwise to the solution. The mixture was stirred for 3 h at that temperature followed by stirring for 15 hours at room temperature. After adding 5 ml water, stirring for 1 hour, the solvents were removed.
  • Example 3 18 mg Tetrakis [triphenylphosphine]palladium(0) was added under nitrogen atmosphere to a mixture of 180 mg "B”, 189 mg 2-(4-bromo-3-methyl- phe ⁇ yl)-5-methyl-1 ,3,4-oxadiazole ("C") and 230 mg Na 2 CO 3 .10 H 2 O in 10 mi DME (dimethoxyethane). The mixture was refluxed for 15 hours and the solvent removed.
  • N-[4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]-2'-methyl-4'-(5- methyl-1 ,2,4-oxadiazole-3-yl)-biphenyl-4-sulfonamide is obtained.
  • N-[4-Methoxy-3-(4-methyl-piperazine-1 -yl)-phenyl]-2'-methyl-4'-(5- methyl-1 ,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide was dissolved into a mixture of 50 mi of methanol and 10 ml of acetic acid, followed by the addition of Raney-Ni slurry in water. The mixture was hydrogenated for 12 hours. Filtration, washing with acetic acid and evaporation of the filtrate afforded an oil residue. After customary working up N-[4-methoxy-3-(4- methyl-piperazine-1-yl)-phenyl]-2'-methyl-4'-amidinyl-biphenyl-4- carboxamide
  • obta i ned 140 mg, m.p.159-162°; IR (KBr) 3300, 2935, 2801, 1645,
  • N-[4-hydroxy-3-(4-methyl-piperazin-1-yl)-phenyl]-2'-methyl-4'- (5-methyl-1 ,3,4-oxadiazol-2-yl)-biphenyl-4-carboxamide is obtained: m.p. 149-152°; IR (KBr) 3504, 3350, 3294, 1646, 1505, 1262, 1241 cm "1 .
  • Example 13 A solution of 40 mg N-[4-hydroxy-3-(4-methyl- P iperazin-1- y l)-p he nyl]-2'- methyl-4'-(5-methyl-1 ,3,4-oxadiazol-2-yl)-biphenyl-4-carboxamide and 0 1 ml tr i ethylamine in 3 ml CH 2 CI 2 is cooled to 0° and treated with 0 06 ml methylsulfonyl chloride for 1 hour. To the mixture is added 0.1 ml 2N
  • N-[4-trifluoromethanesulfonyioxy-3-(4-methyl-piperazin-1-yl)- phenyl]-2 , -methyl-4 , -(5-methyl-1 ,2,4-oxadiazol-3-yl)-biphenyl-4- carboxamide is obtained, m.p. 140°;
  • Example 14 A solution of 120 mg N-[4-h y droxy-3-(4-meth y i-piperazin-1-yl ) - P hen y i]-2'- meth y i-4'-(5-meth y l-1 ⁇ Aoxadiazol-S-yO-biphenyM-carboxamide, 52 mg BrCH 2 CH 2 F and 600 mg CsCO 3 in 15 mi acetonitrile is refluxed for 3 hours. Acetonitrile is removed and after customary working-up 94 mg N-[4-
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogen phosphate in 3 I of twice-distilled water is brought to pH 6.5 with 2N hydrochloric acid, filter-sterilized, filled into vials, lyophilized under steriie conditions and sealed in sterile form. Each vial comprises 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, and the mixture is poured into moulds and left to cool.
  • Each suppository comprises 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 -2H 2 O, 28.48 g of Na 2 HPO 4 -12H 2 O and 0.1 g of benzalkonium chloride in 940 mi of twice-distilled water. The pH is brought to 6.8, and the solution is made up to 1 I and sterilized by irradiation. This solution can be used in the form of eyedrops.
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is tableted in the customary manner in such a way that each tablet comprises 10 mg of active ingredient.
  • Example F Sugar-coated tablets
  • a mixture is tableted analogously to Example E, and the tablets are subsequently coated in the customary manner with a coating of sucrose, potato starch, talc, tragacanth and colouring.
  • Example G capsules
  • a solution of 1 kg of active ingredient of the formula I in 60 I of twice-distilled water is filter-sterilized, filled into ampoules, lyophilized under sterile conditions and sealed in sterile form. Each ampoule comprises 10 mg of active ingredient.
  • Example I Spray for inhalation 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution, and the solution is filled into commercially available pump-operated spray containers. The solution can be sprayed into mouth or nose. One actuation (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

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Abstract

L'invention concerne des dérivés de biphényle de la formule (I) dans laquelle R, X, Y, A?1, A2, A3¿, Q et n sont comme définis dans la revendication 1; ces dérivés de biphényle et leurs sels sont actifs sur le système nerveux central et possèdent des propriétés antagonistes de la sérotonine.
PCT/EP1999/004803 1998-07-20 1999-07-08 Derives de biphenyle WO2000005225A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR9912299-5A BR9912299A (pt) 1998-07-20 1999-07-08 Derivados de bifenila
JP2000561181A JP2002521377A (ja) 1998-07-20 1999-07-08 ビフェニル誘導体
CA002338209A CA2338209A1 (fr) 1998-07-20 1999-07-08 Derives de biphenyle
KR1020017000849A KR20010070997A (ko) 1998-07-20 1999-07-08 비페닐 유도체
EP99934632A EP1098892A1 (fr) 1998-07-20 1999-07-08 Derives de biphenyle
SK49-2001A SK492001A3 (en) 1998-07-20 1999-07-08 Biphenyl derivatives
PL99345283A PL345283A1 (en) 1998-07-20 1999-07-08 Biphenyl derivatives
HU0102622A HUP0102622A3 (en) 1998-07-20 1999-07-08 Biphenyl derivatives, process for producing them and pharmaceutical compositions containing them
AU50338/99A AU5033899A (en) 1998-07-20 1999-07-08 Biphenyl derivatives
NO20010333A NO20010333D0 (no) 1998-07-20 2001-01-19 Bifenylderivater

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EP98113488 1998-07-20

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AU (1) AU5033899A (fr)
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Cited By (20)

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WO2002040024A1 (fr) * 2000-11-14 2002-05-23 Merck Patent Gmbh Utilisations nouvelles d'agonistes 5-ht1a et d'inhibiteurs de recaptage de serotinine combines
WO2002092585A1 (fr) * 2001-05-11 2002-11-21 Biovitrum Ab Composes arylsulfonamide pour le traitement de l'obesite, de diabetes de type ii et de troubles du systeme nerveux central
WO2003024448A2 (fr) 2001-09-14 2003-03-27 Methylgene, Inc. Inhibiteurs de l'histone-deacetylase
WO2003037887A1 (fr) * 2001-11-01 2003-05-08 Astrazeneca Ab Composes isoquinoleines therapeutiques
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2006040182A1 (fr) * 2004-10-14 2006-04-20 Abbott Gmbh & Co. Kg Composes heterocycliques convenant pour traiter des troubles sensibles a une modulation du recepteur d3 de la dopamine
WO2007077457A2 (fr) * 2006-01-06 2007-07-12 The Royal Veterinary College Traitement de la fourbure chez le cheval
WO2007118899A1 (fr) * 2006-04-19 2007-10-25 Abbott Gmbh & Co. Kg Arylsulfones hétérocycliques pouvant être employés pour traiter des troubles qui répondent à la modulation du récepteur de la sérotonine 5ht6
US7381728B2 (en) 2004-07-28 2008-06-03 Glaxo Group Limited Piperazine derivatives useful for the treatment of gastrointestinal disorders
US7713978B2 (en) 2006-03-31 2010-05-11 Nigel Paul King Compounds
US7718650B2 (en) 2001-05-11 2010-05-18 Biovitrum Ab Aryl sulfonamide compounds for treating obesity
US7842715B2 (en) 2006-05-19 2010-11-30 Wyeth Llc N-benzoyl- and N-benzylpyrrolidin-3-ylamines as histamine-3 antagonists
US8188301B2 (en) 2007-06-05 2012-05-29 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission
US8497273B2 (en) 2006-04-19 2013-07-30 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor
US8507469B2 (en) 2007-03-23 2013-08-13 Abbott Gmbh & Co. Kg Azetidin compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8633197B2 (en) 2007-06-08 2014-01-21 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8835437B2 (en) 2007-06-08 2014-09-16 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8946228B2 (en) 2007-06-08 2015-02-03 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8981094B2 (en) 2007-06-08 2015-03-17 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9107946B2 (en) 2008-06-05 2015-08-18 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist

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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040024A1 (fr) * 2000-11-14 2002-05-23 Merck Patent Gmbh Utilisations nouvelles d'agonistes 5-ht1a et d'inhibiteurs de recaptage de serotinine combines
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
EA009647B1 (ru) * 2001-05-11 2008-02-28 Биовитрум Аб Арилсульфонамидные соединения и их применение для лечения ожирения и диабета типа ii
US6969710B2 (en) 2001-05-11 2005-11-29 Biovitrum Ab Compounds
US7173035B2 (en) 2001-05-11 2007-02-06 Biovitrum Ab Arylsulfonamide compounds
US7718650B2 (en) 2001-05-11 2010-05-18 Biovitrum Ab Aryl sulfonamide compounds for treating obesity
WO2002092585A1 (fr) * 2001-05-11 2002-11-21 Biovitrum Ab Composes arylsulfonamide pour le traitement de l'obesite, de diabetes de type ii et de troubles du systeme nerveux central
US7566715B2 (en) 2001-05-11 2009-07-28 Biovitrum Ab Substituted sulfonamide compounds useful for the prophylaxis and treatment of conditions relating to obesity, type II diabetes and/or disorders of the central nervous system
US7319097B2 (en) 2001-05-11 2008-01-15 Biovitrum Ab Compounds
WO2003024448A2 (fr) 2001-09-14 2003-03-27 Methylgene, Inc. Inhibiteurs de l'histone-deacetylase
WO2003037887A1 (fr) * 2001-11-01 2003-05-08 Astrazeneca Ab Composes isoquinoleines therapeutiques
US7381728B2 (en) 2004-07-28 2008-06-03 Glaxo Group Limited Piperazine derivatives useful for the treatment of gastrointestinal disorders
WO2006040182A1 (fr) * 2004-10-14 2006-04-20 Abbott Gmbh & Co. Kg Composes heterocycliques convenant pour traiter des troubles sensibles a une modulation du recepteur d3 de la dopamine
US7851463B2 (en) 2004-10-14 2010-12-14 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
AU2005293698B2 (en) * 2004-10-14 2011-12-15 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
EP2311802A1 (fr) * 2004-10-14 2011-04-20 Abbott GmbH & Co. KG Composes hétérocycliques convenant pour traiter des maladies sensibles une modulation du récepteur d3 de la dopamine
US8470810B2 (en) 2004-10-14 2013-06-25 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
EP2311803A1 (fr) * 2004-10-14 2011-04-20 Abbott GmbH & Co. KG Composes heterocycliques convenant pour traiter des troubles sensibles a une modulation du recepteur D3 de la dopamine
WO2007077457A3 (fr) * 2006-01-06 2007-08-30 Royal Veterinary College Traitement de la fourbure chez le cheval
WO2007077457A2 (fr) * 2006-01-06 2007-07-12 The Royal Veterinary College Traitement de la fourbure chez le cheval
US7713978B2 (en) 2006-03-31 2010-05-11 Nigel Paul King Compounds
US8642642B2 (en) 2006-04-19 2014-02-04 Abbott Laboratories Heterocyclic arylsulphones suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor
WO2007118899A1 (fr) * 2006-04-19 2007-10-25 Abbott Gmbh & Co. Kg Arylsulfones hétérocycliques pouvant être employés pour traiter des troubles qui répondent à la modulation du récepteur de la sérotonine 5ht6
US8497273B2 (en) 2006-04-19 2013-07-30 Abbott Gmbh & Co. Kg Heterocyclic compounds suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor
US7842715B2 (en) 2006-05-19 2010-11-30 Wyeth Llc N-benzoyl- and N-benzylpyrrolidin-3-ylamines as histamine-3 antagonists
US8507469B2 (en) 2007-03-23 2013-08-13 Abbott Gmbh & Co. Kg Azetidin compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8188301B2 (en) 2007-06-05 2012-05-29 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission
US8835437B2 (en) 2007-06-08 2014-09-16 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8633197B2 (en) 2007-06-08 2014-01-21 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8946228B2 (en) 2007-06-08 2015-02-03 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US8981094B2 (en) 2007-06-08 2015-03-17 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9120821B2 (en) 2007-06-08 2015-09-01 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9227935B2 (en) 2007-06-08 2016-01-05 Janssen Pharmaceutical N.V. Piperidine/piperazine derivatives
US9499567B2 (en) 2007-06-08 2016-11-22 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9688696B2 (en) 2007-06-08 2017-06-27 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
US9107946B2 (en) 2008-06-05 2015-08-18 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist
US9724418B2 (en) 2008-06-05 2017-08-08 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist

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NO20010333D0 (no) 2001-01-19
AU5033899A (en) 2000-02-14
JP2002521377A (ja) 2002-07-16
HUP0102622A2 (hu) 2001-12-28

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