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WO2004096771A1 - Composes biaryle exerçant une activite sur le recepteur de 5ht5a - Google Patents

Composes biaryle exerçant une activite sur le recepteur de 5ht5a Download PDF

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Publication number
WO2004096771A1
WO2004096771A1 PCT/EP2004/004658 EP2004004658W WO2004096771A1 WO 2004096771 A1 WO2004096771 A1 WO 2004096771A1 EP 2004004658 W EP2004004658 W EP 2004004658W WO 2004096771 A1 WO2004096771 A1 WO 2004096771A1
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Prior art keywords
compound
pharmaceutically acceptable
formula
acceptable salt
phenyl
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Steven Mark Bromidge
David Francis Corbett
Thomas Daniel Heightman
Stephen Frederick Moss
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • 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
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    • 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
    • C07C211/27—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 having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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    • 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
    • C07C217/58—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 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/37—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • 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
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
    • C07D295/125—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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Definitions

  • the present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and to their use in the treatment of various disorders.
  • the 5-HT5A receptor is a receptor for 5-HT which is widely distributed in human brain (Rees et al., FEBS Letters 355 242-246 [1994]). 5-HT mediates a wide range of physiological and pathological processes in the CNS. However, to date, no compounds having selective affinity at the 5-HT5A receptor have been reported.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Y is a single bond, -CH2-, -(CHt ⁇ te-.
  • -CH CH-, -CH2O-, -OCH2-, C3_7cycloalkylene or NH; and
  • R4 is optionally substituted phenyl or optionally substituted C3_7cycloalkyl;
  • Z is a single bond, -CH2-, -(CH2)2 _ or -( ⁇ 2)3-;
  • R7 is NR8R9 where R ⁇ and R 9 are independently hydrogen or C-j. ⁇ alkyl, or R7 is optionally substituted phenyl, optionally substituted 5- or 6- membered heteroaryl ring or optionally substituted 5- or 6- membered heteroalicyclic ring;
  • A is a single bond, -CH 2 -, -(CH 2 )2" > -CH 2 CH 2 0-, or -CH2OCH2-;
  • E is optionally substituted phenyl, optionally substituted indanyl, optionally substituted methylenedioxyphenyl, or an optionally substituted 5- or 6-membered heteroaryl ring.
  • R7 when it is phenyl, 5- or 6- membered heteroaryl ring or 5- or 6- membered heteroalicyclic ring
  • R4 and E may be optionally substituted with 1 , 2 or 3 substiluents which may be the same or different and are selected from halogen, C 1-6 alkyl, C 3- 6 cycloalkyl, phenylC 1-3 alkyl, CF 3 , C ⁇ -6 alkoxy, OCF 3 , hydroxy, cyano, nitro, hydroxyC 1-6 alkyl, COC 1-6 alkyl, C0 2 R 5 , S0 2 R 5 , NR 5 R 6 , CONR 5 R 6 and S0 2 NR 5 R 6 where R 5 and R 6 are independently hydrogen or C- ⁇ -6 alkyl.
  • halogen and its abbreviation “halo” refer to fluorine, chlorine, bromine or iodine.
  • Chalky refers to an alkyl group having from one to six carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C ⁇ . ⁇ alkoxy refers to a straight chain or branched chain alkoxy (or “alkyloxy”) group having from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy, tert-pentoxy and hexoxy.
  • C3_7cycloalkyl refers to a cycloalkyl group having from 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heteroaryl ring refers to a heteroaryl ring wherein at least one atom is nitrogen, oxygen or sulfur.
  • heteroaryl rings include pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, furazanyl, furyl and thienyl.
  • Examples of 6 membered heteroaryl rings include pyridyl, pyridazinyl, py midinyl, pyrazinyl and pyranyl.
  • 5- or 6- membered heteroalicyclic ring refers to a heteroalicyclic ring having 5 or 6 atoms in total, at least one atom being nitrogen, oxygen or sulfur.
  • 5 or 6 membered heteroalicyclic rings include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, dioxanyl and dithianyl.
  • the term refers to benzyl, phenethyl or phenylpropyl.
  • hydroxyC-i.galkyl refers to a C- j .galkyl group substituted by a hydroxy group, such as -CH2OH.
  • and Ar2 are a 6 membered heteroaryl ring
  • suitable examples include pyridyl, pyrimidyl and pyrazinyl.
  • Ar- j and Ar2 is phenyl, and the other is phenyl or pyridyl.
  • R7 or E is a heteroaryl ring
  • suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl.
  • R7 is a heteroalicyclic ring, preferably it is homopiperazine, azepine, piperidyl, piperazinyl, pyrrolidinyl or morpholinyl.
  • R7 is Me 2 N-, 3-pyridyl, N-benzylpiperidin-4-yl, piperdin-2-yl, piperidin-3-yl, morpholinyl, 1-methylpiperazin-4-yl, 2-methylpyrazin-5-yl, 3,5-dimethylpyrazol-1-yl, methoxyphenyl, cyanophenyl or nitrophenyl.
  • R4 can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom.
  • R4 is phenyl, cyclopentyl or methylenedioxyphenyl.
  • A is a single bond, -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 2 0-.
  • E is optionally substituted phenyl, optionally substituted pyridyl or methylenedioxyphenyl.
  • Preferred compounds are compounds of general formula (la), (lb) and (lc):
  • R7, Z, R1 , A and E are as defined for formula (I).
  • Particularly preferred compounds according to the invention are compounds E1-E41 as described below and pharmaceutically acceptable salts thereof.
  • the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. geometric (or "cis-trans") isomers, diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention includes within its scope all such isomers, including mixtures.
  • this invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II):
  • an optional dehydrating agent may be used followed by a reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as 1 ,2-dichloroethane, dichloromethane, THF, DMF or mixtures thereof, optionally containing methanol or acetic acid.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a solvent such as 1 ,2-dichloroethane, dichloromethane, THF, DMF or mixtures thereof, optionally containing methanol or acetic acid.
  • the dehydrating agent is sodium sulfate
  • the reducing agent is sodium triacetoxyborohydride
  • the solvent is 1 ,2-dichloroethane containing acetic acid.
  • a compound of formula (I) obtained from the above process may be converted to another compound of formula (I) by standard techniques.
  • a compound of formula (I) wherein R1 is hydrogen may be converted to a compound of formula (I) wherein R1 is a group of formula (a) and X is S0 2 by reacting with an appropriate sulfonyl chloride such as beta-styrylsulfonyl chloride.
  • Standard protection and deprotection techniques such as those described in Greene T.W. Protective groups in organic synthesis, New York, Wiley (1981), can be used.
  • primary amines can be protected as phthalimide, benzyl, t-butyloxycarbonyl, benzyloxycarbonyl or trityl derivatives.
  • Carboxylic acid groups can be protected as esters.
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures well known in the art.
  • protecting groups such as t-butyloxycarbonyl may be removed using an acid such as hydrochloric or trifluroroacetic acid in a suitable solvent such as dichloromethane, diethylether, isopropanol or mixtures thereof.
  • solid phase protection groups may also be employed, such as Wang resin, which is commercially available, optionally employing a suitable linker.
  • Such solid phase protection groups have the advantage that work-up and purification of intermediates and products can be achieved simply by washing the support with suitable solvents.
  • Compounds of formula (III) may be prepared by coupling a compound of formula (IV):
  • Ar2, A and E are as defined for formula (I) and L is a leaving group such as halogen, in the presence of a suitable reducing agent.
  • Ar2 is as defined for formula (I) and L is a leaving group such as halogen, and a compound of formula (VII):
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the affinities of the compounds of this invention for 5-HT5A can be determined by measuring the inhibition by the compound of [3H]-LSD binding to washed cell membrane homogenates prepared from cells stably expressing the receptor. All compounds tested according to the binding assay described above were found to have K, values of ⁇ 400nM.
  • the intrinsic activity of the compounds of this invention can be determined according to the [35S]GTP ⁇ S functional assay which is described in WO 99/07700.
  • Compounds of formula (I) and their pharmaceutically acceptable salts are of use in the treatment of certain CNS disorders such as depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders (which includes generalised anxiety and social anxiety disorder), schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviours (including anorexia nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment of a CNS disorder such as depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders (which includes generalised anxiety and social anxiety disorder), schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviours (including anorexia nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyss
  • Compounds of the invention may be administered in combination with other active substances such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
  • active substances such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, and metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine and metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • the invention further provides a method of treatment of a CNS disorder such as depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders (which includes generalised anxiety and social anxiety disorder), schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviours (including anorexia nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs
  • the present invention provides a method of treatment of depression, anxiety, sleep disorders or schizophrenia, in mammals including humans, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders (which includes generalised anxiety and social anxiety disorder), schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviours (including anorexia nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep a a
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);, fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate);, tabletting lubricants lubricants (e.g. magnesium stearate, talc or silica);, disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • tabletting lubricants lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
  • Wang resin (15.88g, Ummol.g "1 , 27mmol) was suspended in anhydrous DCM and di-2- pyridylcarbonate and triethylamine were added. The mixture was shaken overnight under argon. The resin was filtered and washed 4 times with DCM then dried at room temperature in vacuo and used without further characterisation..
  • the resin was suspended in anhydrous DCM and the amine (2 equiv.) added. The suspension was then shaken under argon at room temperature for 24h. The resin was then filtered, washed with DCM, THF(x3) and DCM (x3) then dried in vacuo at 40°C.
  • 2-Pyridyl carbonate resin (5.56g, 7.4mmol) was suspended in dry 1 ,2-dichloroethane (70ml) in a glass tube.
  • N-(indan-2-yl)-4-bromobenzylamine (4.47g, 14.8mmol) was added to the mixture and the tube was then rotated in an oven at 50 C for 27h.
  • Resins were loaded into IRORI microkans (0.035mmol.kan "1 ) containing a radiofrequency tag, and the kans were suspended in DME (1ml per kan) in a 3-necked flask. Vacuum was applied and released several times to ensure that the kans were properly filled with solvent. The flask was fitted with an overhead stirrer, condenser and thermometer then purged with argon for 1.5 hours. Fresh Pd(PPh 3 ) 4 (0.15 equiv.) was added followed by 4- formylbenzeneboronic acid (3 equiv.) after about five minutes.
  • Kans containing the resin-bound biphenyl aldehydes (0.035mmol per kan), Na 2 S0 4 (5 equiv.) and 1 ,2-dichoroethane (DCE) (1ml per kan) were placed into flasks and vacuum applied and released.
  • the amine R2NH 2 (5 equiv.) was added as a solution in DCE ( ⁇ 8mmol/ml) followed by acetic acid (5 equiv.). The mixture was shaken under argon for 3 hours before adding solid sodium triacetoxyborohydride (4 equiv.). The mixture was then shaken for a further 24 hours under argon.
  • the reaction mixture was decanted and the kans rinsed with DCM (x3), THF, THF-H 2 0 (1 :1), H 2 0 and THF-H 2 0 (1 :1). They were then transferred to a kan washer and washed with THF, THF-H 2 0 (1 :1), H 2 0(x2), THF- H 2 0 (1 :1), THF, DMF, THF (x3) and DCM (x3).
  • the kans containing resin product were dried in vacuo at 40°C.
  • amines used are: N-(2-aminoethyl)morpholine, 3-(aminomethyl)pyridine, 4- amino-1-benzylpiperidine, N,N-dimethylethylenediamine, 3-methoxyphenethylamine, 3- phenylpropylamine,
  • Kans containing the resin-bound secondary amines (0.035mmol per kan) were placed in a flask with DCM (1ml per kan) and vacuum applied and released. Triethylamine was added (12 equiv.) followed by the acid chloride (10 equiv.) dissolved in a little DCM. The reaction was placed under argon and shaken at room temperature for 18h. The reagent solution was removed from the flask and the kans rinsed with DCM (x3). They were then washed in a kan washer with DCM (x2), THF (x3) and DCM (x3). The kans containing resin product were then dried overnight in vacuo at 40°C.
  • the kans containing resin-bound products were arrayed into cleavage plates and treated with 2ml of 20% TFA DCM for 2 hours.
  • the solutions were filtered into preweighed vials and the kans washed with a further 1 ml DCM.
  • the solvent was removed in vacuo at 40°C to afford the cleaved products. This procedure also removes any N-BOC protecting groups.
  • R1 dimethylaminoethyl
  • R2 cyclopentylethyl
  • R3 phenethyl
  • R1 dimethylaminoethyl
  • R2 phenylethenyl
  • R3 phenethyl

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Abstract

L'invention concerne des composés de formule (I) ainsi que des sels pharmaceutiquement acceptables de ces composés. Dans ladite formule (I), l'un des Ar1 et Ar2 représente un phényle lié en position 1,4, tandis que l'autre désigne un phényle lié en position 1,4 ou un noyau hétéroaryle à 6 chaînons lié en position 1,4 ; R1 représente hydrogène ou un groupe de formule (a), formule dans laquelle X désigne C=O ou SO2 ; Y représente une liaison simple, -CH2-, -(CH2)2-, -CH=CH-, -CH2O-, -OCH2-, un groupe cycloalkylène en C3-7 ou NH ; et R4 représente un phényle éventuellement substitué ou un groupe cycloalkyle en C3-7 ; Z désigne une liaison simple, -CH2-, -(CH2)2- ou -(CH2)3- ; R7 représente NR8R9, formule dans laquelle R8 et R9 représentent indépendamment l'un de l'autre hydrogène ou un groupe alkyle en C1-6, ou R7 désigne un phényle éventuellement substitué, un noyau hétéroaryle à 5 ou 6 chaînons éventuellement substitué ou un noyau hétéroalicyclique à 5 ou 6 chaînons éventuellement substitué ; A représente une liaison simple, -CH2-, -(CH2)2-, -CH2CH2O-, ou -CH2OCH2- ; et E représente un méthylènedioxyphényle, un indanyle ou un phényle éventuellement substitué ou un noyau hétéroaryle à 5 ou 6 chaînons. La présente invention se rapporte en outre à des procédés de préparation de ces composés ainsi qu'à leurs utilisations en médecine, par exemple pour traiter des troubles du système nerveux central tels que la dépression, l'anxiété, les troubles du sommeil ou la schizophrénie.
PCT/EP2004/004658 2003-04-29 2004-04-28 Composes biaryle exerçant une activite sur le recepteur de 5ht5a Ceased WO2004096771A1 (fr)

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