WO1999023073A1 - Derives de biphenyle en tant que produits pharmaceutiques - Google Patents

Derives de biphenyle en tant que produits pharmaceutiques Download PDF

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Publication number
WO1999023073A1
WO1999023073A1 PCT/EP1998/006880 EP9806880W WO9923073A1 WO 1999023073 A1 WO1999023073 A1 WO 1999023073A1 EP 9806880 W EP9806880 W EP 9806880W WO 9923073 A1 WO9923073 A1 WO 9923073A1
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WO
WIPO (PCT)
Prior art keywords
compound
free base
formula
methoxy
trifluoromethyl
Prior art date
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PCT/EP1998/006880
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English (en)
Inventor
Esteban Pombo Villar
Manuel Koller
Silvio Ofner
Robert Swoboda
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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.)
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Priority claimed from GBGB9723134.4A external-priority patent/GB9723134D0/en
Priority claimed from GBGB9723133.6A external-priority patent/GB9723133D0/en
Priority to NZ503815A priority Critical patent/NZ503815A/en
Priority to AU14872/99A priority patent/AU740448B2/en
Priority to CA002308151A priority patent/CA2308151A1/fr
Priority to PL98339922A priority patent/PL339922A1/xx
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to KR1020007004762A priority patent/KR20010031699A/ko
Priority to BR9813897-9A priority patent/BR9813897A/pt
Priority to SK641-2000A priority patent/SK6412000A3/sk
Priority to EP98958884A priority patent/EP1037876A1/fr
Priority to JP2000518948A priority patent/JP2001521923A/ja
Priority to IL13558098A priority patent/IL135580A0/xx
Publication of WO1999023073A1 publication Critical patent/WO1999023073A1/fr
Priority to NO20002321A priority patent/NO20002321D0/no

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • C07C211/29—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 carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel biphenyl derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
  • Ri and R 2 are hydrogen, (C 1-4 )alkyl, (C ⁇ - )alkox>-, (C ⁇ - )alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or (C -5)alkanoyl
  • R 3 is hydrogen, hydroxy, (C -4 )alkyl, (C 1- )alkoxy, (C 3 -6)cycloalkyloxy, halogen, cyano, (C 2- 5)alkanoyl, carbamoyl, (C ⁇ -4)alkylsulfonyloxy or trifluoromethylsulfonyloxy
  • R4 is hydrogen, hydroxy or (C ⁇ - )alkoxy
  • R 5 is a group of formula (a), (b), (c) or (d)
  • R 6 is (C 1- )alkyl
  • X is a straight or branched alkylene chain with 1 to 4 carbon atoms
  • R and R 8 independently, are hydrogen, alkyl or phenyl(C ⁇ - 4 )alkyl, or form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino, piperazinyl or morpholino group, or a group of formula (e)
  • Z is O, CH 2 or CH 2 -CH 2 and R9, Rio, R11, R12, 3 and R] , independently,are H, halogen, (C ⁇ - 4 )alkyl or (C 1- )alkoxy, in free base or acid addition salt form.
  • the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • alkyl, alkoxy and alkylthio radicals preferably are straight chain radicals. They preferably have 1 to 3 carbon atoms, -more preferably they are methyl, methoxy and methylthio groups. The following significances and their combinations are preferred:
  • R] and R independently, are hydrogen, (C ⁇ - )alkyl, ( . ⁇ alkoxy, halogen or trifluoromethyl,
  • R 3 is hydrogen or in para to the phenyl substituent is hydroxy, ( - ⁇ alkoxy, (C3-6) cycloalkyloxy, cyano or carbamoyl,
  • R is H
  • R 5 is a group of formula (a) or (d).
  • R 6 is preferably methyl or propyl.
  • R and R 8 are preferably hydrogen, or, together with the nitrogen atom to which they are attached, a group of formula (e).
  • Z is preferably O and R9 to Ru, independently, are preferably hydrogen or methyl.
  • Ri, R 2 , R3 and R-4 are as defined above and R5 is a group of formula (a), (b) or (c).
  • Ri, R 2 , R3 and 4 are as defined above and R 5 is a group of formula (d).
  • the invention provides a process for the production of the compounds of formula I and their salts, whereby a compound of formula LI
  • R 3 , R4, and R5 are as defined above and Y is halogen or trifluoromethyl sulfonate, is reacted with a compound of formula HI
  • the reaction may be effected in known manner, preferably by transition metal-catalysed aryl-aryl coupling, e.g. as described in Example 1.
  • Hal is preferably bromine or iodine, particularly iodine.
  • the compounds may be obtained by other well established metal-catalysed aryl-aryl coupling procedures, using for example aryl-stannyl, -zinc, -halide or Grignard precursors.
  • the nitrogen in the group of formula (c) may be protected e.g. by an alkoxycarbonyl group, which can be removed after the reaction with the compound of formula HI according to well-known procedures. See for example Example 11.
  • a compound having the formula I but wherein R 5 is a 3-pyridyl group may first be prepared as described above for the compounds of formula I, and the pyridvl group subsequently converted into the desired tetrahydropyridyl over a corresponding pyridinium salt, according to well-known procedures, for example over the pyridinium iodide as described in Example 1.
  • the corresponding compounds wherein R5 is of ⁇ formula (b) may be prepared first, and subsequently hydrogenated according to well-known procedures, e.g. as described in Example 5.
  • Acid addition salts may be produced in known manner from the free base forms and vice- versa.
  • Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include for example the hydrochloride, the hydrogen maleate, the hydrogen fumarate and the hydrogen malonate.
  • the starting materials of formula LI are known or may be produced by halogenating compounds of formula IV
  • R , R-4 and R5 are as defined above, in accordance with known procedures.
  • agents of the invention exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
  • the agents of the invention provide long-lasting protection against maximal electroshock- induced convulsions in mice at doses of about 1 to 100 mg kg p.o. and about 0.32 to 32 mg/kg i.p. [cf. E.A. Swinyard, J. Am.Pharm. Assoc. Scient. Ed. 38, 201 (1949) and J.Pharmacol. Exptl. Therap. 106, 319 (1952)
  • the agents of the invention are therefore useful in the treatment of epilepsy and other convulsive states such as high pressure neurological syndrome.
  • the agents of the invention reduce ischaemia-induced neuronal damage and ensuing symptoms in the middle cerebral artery (MCA) occlusion model in rats at a dosage of 1-50 mg/kg i.p, i.v. and p.o. [cf. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53- 60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)].
  • the agents of the invention are therefore useful in the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia and/or ischaemia, e.g. ischemic damage to grey and white matter, stroke, reperfusion injury, subarachnoid haemorrhage, brain and spinal cord injury/trauma, high intracranial pressure, multi-infarct dementia or vascular dementia, and any surgical procedure potentially associated with cerebral anoxia, hypoxia and/or ischemia (e.g. cardiac bypass, operations on extracerebral vessels).
  • ischemic damage to grey and white matter e.g. ischemic damage to grey and white matter
  • stroke reperfusion injury
  • subarachnoid haemorrhage e.g. ischemic damage to grey and white matter
  • stroke reperfusion injury
  • subarachnoid haemorrhage e.g. ischemic damage to grey and white matter
  • brain and spinal cord injury/trauma e.g. ischemic damage to grey and white matter
  • the agents of the invention display binding to the veratridine-sensitive sodium channel with IC50S of from about 0.1 to about 100 ⁇ M.
  • IC50S IC50S of from about 0.1 to about 100 ⁇ M.
  • J.B Brown Journal of Neuroscience 6, 2064-2070 (1986). They block veratridine-induced glutamate release in rat hippocampal slice preparations at concentrations of about 0.1-1 mM.
  • the experiment is performed according to a modification of M. J. Leach et al. in Epilepsia 27, 490-497 (1986) and Stroke 24, 1063-1067 (1993), using exogenous glutamate.
  • the agents of the invention are accordingly indicated for use in the treatment of any pathology, disorder or clinical condition involving glutamate release in their etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders, social withdrawal), hormonal conditions (excess GH [e.g.
  • LH prostate hypertrophy, menopausal syndrome] secretion, corticosterone secretion in stress
  • metabolic induced brain damage hyperoglycaemia,- ⁇ non-ketotic
  • agents of the invention are indicated for use in the treatment of any pathology involving neuronal damage, for example neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including HLV)-induced neurodegeneration, Amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, olivoponto- cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.
  • neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including HLV)-induced neurodegeneration, Amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, olivoponto- cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.
  • ALS Amyotrophic lateral sclerosis
  • OPCA olivoponto- cerebellar atrophy
  • the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • the agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
  • the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of epilepsy, stroke and brain or spinal trauma.
  • the present invention furthermore provides a -.pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent.
  • Such compositions may be manufactured in conventional manner.
  • Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention.
  • the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma.
  • the present invention provides a method for the treatment of any condition mentioned above, e.g. epilepsy, stroke and brain or spinal trauma, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.
  • Example 1 3 - ( 4-methoxy-4 , -trifluoromethyl-biphenyl-3 -yl)- 1 -methyl- 1 ,2.5.6-tetrahydro- pyridine
  • the aqueous phase is extracted with toluene (150 ml) and the combined organic phases are washed with water (100 ml) and brine (100 ml), dried (MgSO 4 ), treated with activated charcoal (1 g), filtered through Hyflo and evaporated to give a yellow oil.
  • This oil is dissolved in EtOH (50 ml) and treated with 3N ethanolic HC1 (25 ml).
  • the hydrochloride salt precipitates upon addition of ether (20 g, 76%), m.p. 229-231°.
  • Trie hydrogen maleinate has a m.p. of 123-125° (EtOH/Et 2 O).
  • the hydrochloride has a m.p. of 187-194°.
  • the hydrogen oxalate has a m.p. of 137-142°.
  • the suspension is then filtered, the solid washed with AcOH-and the filtrates evaporated.
  • the residue is treated with saturated aqueous K 2 CO until a basic solution ensues, which is extracted with EtOAc.
  • the organic extracts are washed with brine (30 ml), dried (MgSO 4 ) and evaporated to give the product as a light brown oil.
  • the hydrogen maleinate has a m.p. of 93-96° (EtOH/Et 2 O, dec).
  • the hydrochloride has a m.p. of 254-262°.
  • the hydrochloride has a m.p. of 237-247°.
  • Example 8 3 - (4-methoxy-4 , -trifluoromethyl-biphenyl-3 -yl )- 1 -propyl-piperidine
  • the hydrogen fumarate of the racemate has a m.p. of 178-180° (EtOH/Et 2 O, dec).
  • the racemate is resolved into its enantiomers by HPLC on Chiralcel OJ, column 25 x 0.46 cm, Mobile phase: Hexane-EtOH 9:1 with 0.1% TFA. Flow rate: ImL/min.
  • the first enantiomer elutes with retention time 8.35 min and the second with 10.25 min.
  • Example 11 3-(4-methoxy-4 , -trifluoromgthyl-biphenyl-3-yl)-l-methyl-pyrrolidine
  • l-ethoxycarbonyl-3-(2-methoxyphenyl)-pyrrolidine A solution of ethylchloroformate (0.61 ml, 673 mg, 6.21 mmol) in CH 2 C1 2 (3 ml) is added dropwise over 10 minutes to a cold (£__5°, ice-bath) solution of N-ethyI-N,N- diisopropylamine (1.3 ml, 911 mg, 7.01 mmol) and 3-(2-methoxyphenyl)-pyrrolidine (1.00 g, 5.65 mmol) in CH C1 2 (15 ml).
  • the hydrogen maleate has a m.p. of 150-153° (EtOH/Et 2 O).
  • the compound can also be obtained by dimethylation of the compound of Example 12 according to known procedures, e.g. by Eschweiler-Clarke methylation.
  • Example 12 Obtained analogously to Example 12 as a yellow oil.
  • the hydrochloride has a m.p. of 210-212°
  • the compound can also be obtained by Eschweiler-Clarke methylation of the compound of Example 14.
  • the hydrogen maleate has a m.p. of 157-160° (EtOH).
  • Example 17 N.N-dime yl-2-[(4-me.moxy-4 , -trifluoromethyl-biphenyl-3-yl)ethyl]amine
  • the hydrogen maleate has a m.p. of 136-137° (EtOH).
  • the compound can also be obtained by Eschweiler-Clarke methylation of the compound of Example 16.
  • Example 18 N-propyl-2-r4-me oxy-4'-trifluoromethyl-biphenyl-3-yl)1-ethylamine Obtained analogously to Example 12.
  • the hydrogen maleate has a m.p. of 178-180° (EtOH/Et 2 O).
  • the hydrogen maleate has a m.p. of 131-133°
  • the compound can also be obtained as follows:
  • Example 20 ( , lS*.2S .6R*,7R i!' )- 4-[2-(4-methoxy-4 , -trifluoromethyl-biphenyl-3-yl)- ethyl1-10-oxa-4-aza-tricvclo[5.2.1.0(2.6)1decane Obtained analogously to Example 12.
  • The- hydrogen male ate has a m.p. of 163-164° (EtOH/Et 2 O).
  • the compound can also be obtained as follows:
  • Example 20A The product from Example 20A is reduced with lithium aluminium hydride in THF to give the product as a brown oil which is crystallised as its hydrogen maleate salt.
  • Example 21 (1S*.2S .6R*.7R*)- 4-r2-(4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)- ethyl] - 10-oxa-4-aza-2.6-dimethyl-tricyclo [5.2.1.0 ( 2.6 )] decane
  • the hydrochloride has a m.p. of 229-231°.
  • the compound can also be obtained as follows:
  • Example 23 Af, -dimethyl-2-(4 , -isopropyl-4-methoxy-biphenyl-3-yl)-ethylamine
  • the hydrogen maleate has a m.p. of 123-124°
  • the compound can also be obtained by Eschweiler-Clarke methylation of the compound of Example 22.
  • the hydrochloride has a m.p. of 191-205°.
  • the hydrochloride has a m.p. of 151-159°.
  • the compound can also be obtained by Eschweiler-Clarke methylation of the compound of Example 24.
  • the hydrogen oxalate has a m.p. of 145-159°.
  • Example 27 N > N-dimemyl-2-(2 , -chloro-4-methoxy-biphenyl-3-yl)-l-methyl-ethyla ⁇ ine Obtained analogously to Example 12.
  • the hydrochloride has a m.p. of 141-145°.
  • a 500 ml-flask is charged with 140 ml of toluene and 28 ml of 2M Na 2 CO 3 and gased with argon for 1 h. Then 3.94 g of (+)-[2-(5-bromo-2-methoxy-phenyl)-l-methyl- ethyl]-dimethyl-amine, 4.95 g of 4-trifluoromethyl-phenylboronic acid and 374 mg of tetrakis(triphenylphosphine)palladium are added and the mixture is refluxed for 12 h.
  • the product prepared under B is arylated with 4-trifluoromethyl-phenylboronic acid according to example 28F to afford the hydrochloride of the title compound as white plates, m.p. 148 - 163°.
  • Example 30 [l-(4-methoxy-4 , -trifluoromethyl-biphenyl-3-ylmethyl)-propyl1-N.N- dimethyl-amine A. l-methoxy-2-(2-nitro-but-l-enyl)-benzene
  • Example 32 N.N-diethyl-[2-(4-methoxy-4 > -trifluoromethyl-biphenyl-3-yl)-l-methyl- ethyl] -amine

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
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Abstract

L'invention concerne les composés présentant la formule (I) dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans le descriptif. Ces composés constituent des produits pharmaceutiques d'une grande utilité.
PCT/EP1998/006880 1997-11-03 1998-10-30 Derives de biphenyle en tant que produits pharmaceutiques WO1999023073A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
IL13558098A IL135580A0 (en) 1997-11-03 1998-10-30 Biphenyl derivatives as pharmaceuticals
JP2000518948A JP2001521923A (ja) 1997-11-03 1998-10-30 医薬としてのビフェニル誘導体
AU14872/99A AU740448B2 (en) 1997-11-03 1998-10-30 Biphenyl derivatives as pharmaceuticals
CA002308151A CA2308151A1 (fr) 1997-11-03 1998-10-30 Derives de biphenyle en tant que produits pharmaceutiques
PL98339922A PL339922A1 (en) 1997-11-03 1998-10-30 Derivatives of diphenyl as pharmacological agents
NZ503815A NZ503815A (en) 1997-11-03 1998-10-30 Biphenyl compounds, pharmaceuticals thereof and their use for the treatment of epilepsy, stroke and brain or spinal trauma
KR1020007004762A KR20010031699A (ko) 1997-11-03 1998-10-30 약제로서의 비페닐 유도체
BR9813897-9A BR9813897A (pt) 1997-11-03 1998-10-30 Derivados de bifenila como farmacêuticos
SK641-2000A SK6412000A3 (en) 1997-11-03 1998-10-30 Biphenyl derivatives as pharmaceuticals
EP98958884A EP1037876A1 (fr) 1997-11-03 1998-10-30 Derives de biphenyle en tant que produits pharmaceutiques
NO20002321A NO20002321D0 (no) 1997-11-03 2000-05-02 Bifenylderivater som farmasøytiske midler

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9723134.4A GB9723134D0 (en) 1997-11-03 1997-11-03 Organic compounds
GB9723133.6 1997-11-03
GBGB9723133.6A GB9723133D0 (en) 1997-11-03 1997-11-03 Organic compounds
GB9723134.4 1997-11-03

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WO1999023073A1 true WO1999023073A1 (fr) 1999-05-14

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US6858592B2 (en) 2001-06-29 2005-02-22 Genzyme Corporation Aryl boronic acids for treating obesity
US7041280B2 (en) 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
WO2010112211A1 (fr) 2009-03-31 2010-10-07 Technische Universität München Procédé d'arylation de phénols et d'éthers phényliques à noyau substitué
US20110207709A1 (en) * 2008-10-30 2011-08-25 Carruthers Nicholas I Modulators of serotonin receptor
US8642583B2 (en) 2008-10-30 2014-02-04 Janssen Pharmaceutica Nv Serotonin receptor modulators

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TW200840566A (en) * 2006-12-22 2008-10-16 Esteve Labor Dr Heterocyclyl-substituted-ethylamino-phenyl derivatives, their preparation and use as medicaments

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6858592B2 (en) 2001-06-29 2005-02-22 Genzyme Corporation Aryl boronic acids for treating obesity
US7041280B2 (en) 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
US7049304B2 (en) 2001-06-29 2006-05-23 Genzyme Corporation Aryl boronic acids for treating obesity
US7456156B2 (en) 2001-06-29 2008-11-25 Genzyme Corporation Aryl boronic acids for treating obesity
US20110207709A1 (en) * 2008-10-30 2011-08-25 Carruthers Nicholas I Modulators of serotonin receptor
US8575364B2 (en) 2008-10-30 2013-11-05 Janssen Pharmaceutica Nv Modulators of serotonin receptor
US8642583B2 (en) 2008-10-30 2014-02-04 Janssen Pharmaceutica Nv Serotonin receptor modulators
US8957059B2 (en) 2008-10-30 2015-02-17 Janssen Pharmaceutica Nv Modulators of serotonin receptors
US9981909B2 (en) 2008-10-30 2018-05-29 Janssen Pharmaceutica Nv Serotonin receptor modulators
WO2010112211A1 (fr) 2009-03-31 2010-10-07 Technische Universität München Procédé d'arylation de phénols et d'éthers phényliques à noyau substitué
DE102009015697A1 (de) 2009-03-31 2010-10-07 Markus Dr. Heinrich Verfahren zur Arylierung von ringsubstituierten Phenolen und Phenylethern

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PL339922A1 (en) 2001-01-15
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TR200001122T2 (tr) 2000-08-21
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NO20002321D0 (no) 2000-05-02
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AU740448B2 (en) 2001-11-01
AU1487299A (en) 1999-05-24
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CO5011067A1 (es) 2001-02-28
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