WO2004096771A1 - Biaryl compounds having activity at the 5ht5a receptor - Google Patents

Biaryl compounds having activity at the 5ht5a receptor 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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PCT/EP2004/004658
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French (fr)
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Steven Mark Bromidge
David Francis Corbett
Thomas Daniel Heightman
Stephen Frederick Moss
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Glaxo Group Limited
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Publication of WO2004096771A1 publication Critical patent/WO2004096771A1/en

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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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    • C07C211/27—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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    • 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
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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
    • C07C233/40—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
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    • 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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    • C07D211/36—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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    • C07D317/48—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

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed, wherein one of Ar1 and Ar2 is phenyl linked in a 1,4-relationship, and the other is phenyl linked in a 1,4-relationship or a 6 membered heteroaryl ring linked in a 1,4-relationship; R1 is hydrogen, or a group of formula (a), wherein X is C=O or SO2; Y is a single bond, -CH2-, -(CH2)2-, -CH=CH-, -CH2O-, -OCH2-, C3-7cycloalkylene or NH; and R4 is optionally substituted phenyl or C3-7cycloalkyl; Z is a single bond, -CH2-, -(CH2)2- or -(CH2)3-; R7 is NR8R9 where R8 and R9 are independently hydrogen or C1-6alkyl, 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, -CH2-, -(CH2)2-, -CH2CH2O-, or -CH2OCH2-; and E is optionally substituted phenyl, indanyl, methylenedioxyphenyl, or a 5- or 6-membered heteroaryl ring. Methods of preparation and uses thereof in medicine, for example for the treatment of CNS disorders such as depression, anxiety, sleep disorders or schizophrenia, are also disclosed.

Description

BIARY COMPOUNDS HAVING ACTIVITY AT THE 5HT5A RECEPTOR
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.
A structurally novel class of compounds have now been found that exhibit 5-HT5A receptor affinity.
In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000002_0001
(I) wherein one of Ari and Ar2 is phenyl linked in a 1 ,4-relationship, and the other is phenyl linked in a 1 ,4-relationship or a 6 membered heteroaryl ring linked in a 1 ,4-relationship; R1 is hydrogen, or a group of formula (a):
R4χ Y
I x
(a)
wherein
X is C=0 or SO2; Y is a single bond, -CH2-, -(CHtøte-. -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 R9 are independently hydrogen or C-j.βalkyl, 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, -CH2-, -(CH2)2"> -CH2CH20-, or -CH2OCH2-; and
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, C1-6alkyl, C3- 6cycloalkyl, phenylC1-3alkyl, CF3, Cι-6alkoxy, OCF3, hydroxy, cyano, nitro, hydroxyC1-6alkyl, COC1-6alkyl, C02R5, S02R5, NR5R6, CONR5R6 and S02NR5R6 where R5 and R6 are independently hydrogen or C-ι-6alkyl.
The term "halogen" and its abbreviation "halo" refer to fluorine, chlorine, bromine or iodine.
The term "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.
The term "Cη.βalkoxy" 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.
The term "C3_7cycloalkyl" refers to a cycloalkyl group having from 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "heteroaryl ring" refers to a heteroaryl ring wherein at least one atom is nitrogen, oxygen or sulfur. Examples of 5 membered 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.
The term "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. Examples of 5 or 6 membered heteroalicyclic rings include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, dioxanyl and dithianyl.
The term
Figure imgf000003_0001
refers to benzyl, phenethyl or phenylpropyl.
The term "hydroxyC-i.galkyl" refers to a C-j.galkyl group substituted by a hydroxy group, such as -CH2OH. When one of Ar-| and Ar2 is a 6 membered heteroaryl ring, suitable examples include pyridyl, pyrimidyl and pyrazinyl. Preferably one of Ar-j and Ar2 is phenyl, and the other is phenyl or pyridyl.
When 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.
When R7 is a heteroalicyclic ring, preferably it is homopiperazine, azepine, piperidyl, piperazinyl, pyrrolidinyl or morpholinyl.
Preferably R7 is Me2N-, 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. Preferably R4 is phenyl, cyclopentyl or methylenedioxyphenyl.
Preferably Y is a single bond, -CH20-, -(CH2)2-, -CH=CH-, cyclopropyl or NH.
Preferably A is a single bond, -CH2-, -(CH2)2- or -(CH2)20-.
Preferably E is optionally substituted phenyl, optionally substituted pyridyl or methylenedioxyphenyl.
Preferred compounds are compounds of general formula (la), (lb) and (lc):
R7 R1 H E
(la)
Figure imgf000004_0001
(lb)
Figure imgf000004_0002
(lc)
wherein 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.
In a further aspect, 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):
R7 NH2
(II)
wherein R7 and Z are as defined for formula (I), and a compound of formula (III):
Figure imgf000005_0001
wherein Ar-| , Ar2, A and E are as defined for formula (I), in the presence of a suitable reducing agent;
and thereafter optionally: β removing any protecting groups, and/or o converting a compound of formula (I) into another compound of formula (I), and/or • forming a pharmaceutically acceptable salt.
In the above process of the present invention, conditions of the reaction are as for normal reductive amination procedures. Thus, 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. Preferably the dehydrating agent is sodium sulfate, the reducing agent is sodium triacetoxyborohydride and 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. For example, 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 C=0, via an acylation reaction using appropriate acid chlorides.such as cinnamyl chloride and phenoxyacetyl chloride. Similarly, 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 S02 by reacting with an appropriate sulfonyl chloride such as beta-styrylsulfonyl chloride.
It will be appreciated by those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. 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. For example, 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. For example, 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.
In the above process of the present invention, 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):
H Ar,
O
(IV)
wherein Ar-j is as defined for formula (I), and a compound of formula (V):
Figure imgf000007_0001
(V)
wherein 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.
Compounds of formula (V) may be prepared by the coupling of a compound of formula (VI)
Figure imgf000007_0002
(VI)
wherein Ar2 is as defined for formula (I) and L is a leaving group such as halogen, and a compound of formula (VII):
Figure imgf000007_0003
(VII)
wherein A is as defined for formula (I).
Pharmaceutically acceptable salts 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]GTPγS 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 narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders, and certain gastrointestinal disorders such as irritable bowel syndrome.
It is to be understood that "treatment" as used herein includes prophylaxis as well as alleviation of established symptoms.
Thus 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, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders, and certain gastrointestinal disorders such as irritable bowel syndrome. In particular the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a CNS disorder such as depression, anxiety, sleep disorders or schizophrenia.
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.
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.
It will be appreciated that 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 (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders, and certain gastrointestinal disorders such as irritable bowel syndrome, 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.
In particular, 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.
In another aspect, 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 apnea and narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs such as dextroamphetamine, methylamphetamine or a combination thereof), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders, and certain gastrointestinal disorders such as irritable bowel syndrome. In particular, the present 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, anxiety, sleep disorders or schizophrenia.
In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. 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.
In a further aspect, 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). The tablets may be coated according to methods well known in normal pharmaceutical practice.
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. methyl or propyl-p- hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For parenteral administration, 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. Alternatively, 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, 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. Thus, for example, 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.
For intranasal administration, 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. Thus 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. However, as a general guide 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.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Descriptions and Examples illustrate the preparation of compounds of the invention.
Preparation of compounds of the following formulae:
Figure imgf000013_0001
Z = CO, CONH, S02
1. Preparation of amine templates for attachment to resin
Figure imgf000013_0002
General Procedure for Reductive Amination reactions
The amine R1NH2 (2 equiv.) and acetic acid (2 equiv.) were added to a stirred solution of 4-bromobenzaldehyde in anhydrous DCM. The mixture was stirred at room temperature for 45 min. after which sodium triacetoxyborohydride (1.2 equiv.) was added portionwise, allowing the effervescence to subside between additions. The reaction mixture was then stirred overnight at room temperature under argon. Sodium bicarbonate solution was added to the reaction and stirring continued until the effervescence subsided. The organic layer was separated and washed with sodium bicarbonate solution then brine. The organic layer was dried and the solvent removed in vacuo. Examples:
(a) R1NH2 = Piperonylamine
Figure imgf000014_0001
The general procedure was followed using 4-bromobenzaldehyde (13.875g, 75mmol), piperonylamine (22.65g, 18.66ml, 150mmol), acetic acid (9g, 8.58ml, 150mmol) and sodium triacetoxyborohydride (19.08g, 90mmol). The crude product was purified by flash chromatography eluting with 50% ethyl acetate/hexane to give the product as a yellow oil (19.24g, 80.1%). 1H NMR (CDCI3, 250MHz): δ 3.69 (2H, s), 3.73 (2H, s), 5.94 (2H, s), 6.75 (2H, s), 6.84 (1 H, s), 7.21 (2H, d, J=8.3Hz), 7.44 (2H, d, J=8.3Hz). LC-MS - single peak M+H 322, 320.
b) R1 NH2 = Phenethylamine
Figure imgf000014_0002
The general procedure was followed using 4-bromobenzylaldehyde (13.875g, 75mmol), phenethylamine (18.15g, 18.81ml, 150mmol), acetic acid (9g, 8.58ml, 150mmol) and sodium triacetoxyborohydride (19.08g, 90mmol). The crude product was purified by flash chromatography eluting with 50% ethyl acetate/hexane. Mass of pure compound obtained = 17.144g (78.8%). 1H NMR (CDCI3, 250MHz): δ 2.77-2.95 (4H, m), 3.74 (2H, s), 7.13-7.29 (7H, m), 7.38-7.47 (2H, m). LC-MS - shows a single peak, M+H 290, 292.
c) R1NH2 = 2-Phenoxyethylamine
Figure imgf000014_0003
The general procedure was followed using 4-bromobenzaldehyde (3.7g), 2- phenoxyethylamine (5.48g), acetic acid (2.3 ml) and sodium triacetoxyborohydride (5.09g) in DCM (80ml). Purification of the crude product by flash chromatography (ethyl acetate- hexane 1 :1) gave the the purified material (5.11g, 84%). H NMR (CDCI3, 250MHz): δ 3.00 (2H, t), 3.83 (2H, s), 4.09 (2H, t), 6.88-6.98 (3H, m), 7.22-7.31 (4H, m) and 7.45 (2H, m). LC-MS shows a single peak, M+H 306, 308. d) R1NH2 = 2-aminoindan
Figure imgf000015_0001
The general procedure was followed using 4-bromobenzaldehyde (3.7g), 2-aminoindan (5.00g), acetic acid (2.3 ml) and sodium triacetoxyborohydride (5.09g) in DCM (80ml). Purification of the crude product by flash chromatography (ethyl acetate-hexane 2:3) gave the the purified material (5.16g, 85%). 1H NMR (CDCI3, 250MHz): δ 2.79 (2H, dd), 3.17 (2H, dd), 3.65 (1 H, m), 3.81 (2H, s), 7.10-7.25 (6H,m) and 7.44 (2H,m). LC-MS shows a single peak, M+H 302, 304.
e) R1 NH2 = 2-(2-aminoethyl)pyridine
Figure imgf000015_0002
The general procedure was followed using 4-bromobenzaldehyde (3.7g), 2-(2- aminoethyl)pyridine (4.88g), acetic acid (2.3 ml) and sodium triacetoxyborohydride (5.09g) in DCM (80ml). Purification of the crude product by flash chromatography (5% methanol in DCM) gave the the purified material (4.34g, 75%). 1H NMR (CDCI3, 250MHz): δ 3.01 (4H, m), 3.77 (2H, s), 7.09-7.19 (4H, m), 7.41 (2H, m), 7.59 (1 H, dt), 8.53 (1 H, d). LC-MS shows a single peak, M+H 291 , 293.
General Procedure for Alkyl ati on Reactions
Figure imgf000015_0003
A solution of the amine (1 equiv) and 2-bromo-5-bromomethylpyridine [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography.
Examples
a) R1 = phenethyl
The general procedure was followed using 2-bromo-5-bromomethylpyridine (8.7 g) and phenylethylamine (16.7 g) in DMF (250 ml). Silica gel chromatography (4% MeOH in DCM) gave the pure product (10.0 g, 99%). 1H NMR (CDCI3, 400MHz): δ 2.77-2.90 (4H, m), 3.76 (2H, s), 7.18-7.32 (5H, m), 7.45 (1 H, d), 7.52 (1 H, dd), 8.27 (1 H, d). LC-MS - shows a single peak, M+H 291 , 293.
2. Attachment of Amine Templates to Wang Resin.
Activation of Wang Resin
Figure imgf000016_0001
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..
General Procedure for Attachment of Amine Templates
Figure imgf000016_0002
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.
Examples
(a) R1 = Phenethyl, W = CH
The general procedure was followed using 2-pyridyl carbonate resin (5.56g, 7.4 mmol) and N-phenethyl-4-bromobenzylamine (4.29g, 14.8 mmol)) in anhydrous DCM (80ml). Mass of resin obtained = 6.58g. A small sample was cleaved in 20% TFA DCM for 2h. 1H NMR (250MHz, CD3OD): δ 2.96-3.06 (2H, m), 3.22-3.33 (2H, m), 4.21 (2H, s), 7.21- 7.43 (7H, m), 7.60-7.69 (2H, m).
(b) R1 = 3,4-Methylenedioxybenzyl, W = CH
The general procedure was followed using 2-pyridyl carbonate resin (19g, 26.8mmol). and N-(3,4-methylenedioxybenzyl)-4-bromobenzylamine (17.3g, 54 mmol). Mass of resin obtained = 25.03g. A small sample was cleaved in 20% TFA/DCM for 2h. 1H NMR (250MHz, CD3OD): δ 4.15 (2H, s), 4.19 (2H, s), 6.00 (2H, s), 6.86-6.97 (3H, m), 7.39 (2H, d, J=8.6Hz), 7.63 (2H, d, J=8.6Hz).
(c) R1 = 2-Phenoxyethyl, W = CH
The general procedure was followed using 2-pyridyl carbonate resin (5.56g, 7.4 mmol) and N-(2-phenoxyethyl)-4-bromobenzylamine (4.53g, 14.8mmol) in DCM (80ml). Mass of resin obtained = 6.71g. A small sample was cleaved in 20% TFA/DCM for 2h. 1H NMR (250MHz, CD3OD): δ 3.39 (2H, τ, J = 5.0Hz), 4.18 (2H, t, J=5.0Hz), 4.21 (2H, s), 6.90 (3H, m), 7.22 (2H, m), 7.35 (2H, m) and 7.55 (2H, m).
(d) R1 = lndan-2-yl, W = CH
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. The mixture was cooled and the resin was filtered and washed with DCM (x3), THF (x3) and DCM (x3), before drying in vacuo at 40 C Mass of product resin = 6.75g. A small quantity of resin was cleaved with 20% TFA/DCM for 2h. 1H NMR (250MHz, CD3OD): δ 3.17 (2H, δd), 3.50 (2H, dd), 4.11 (1H, m), 4.27 (2H, s), 7.24 (4H, m), 7.45 (2H, m) and 7.64 (2H, m).
(e) R1 = 2-(2-Pyridyl)ethyl, W = CH
The general procedure was followed using 2-pyridyl carbonate resin (5.56g, 7.4 mmol) and N-[2-(2-pyridyl)ethyl]-4-bromobenzylamine (4.31g, 14.8mmol) in DCM (80ml). Mass of resin obtained = 6.61 g. A small quantity of resin was cleaved with 20% TFA/DCM for 2h. 1H NMR (250MHz, CD3OD): δ3.28 (2H, μ), 3.47 (2H, m), 4.27 (2H, s), 7.40-7.53 (4H, m), 7.63 (2H, m), 7.99 (1H, m) and 8.59 (1 H, m).
(f) R1 = Phenethyl, W = N
The general procedure was followed using 2-pyridyl carbonate resin and (6-Bromo- pyridin-3-ylmethyl)-phenethylamine in anhydrous DCM (80ml). Mass of resin obtained = g. A small sample was cleaved in 20% TFA DCM for 2h. LC-MS - shows a single peak, M+H 291 , 293. 1H NMR (400MHz, CD3OD): δ 3.02 (2H, dd), 3.32 (2H, dd), 4.28 (2H, s), 7.26-7.37 (5H, m), 7.72 (1 H, d), 7.82 (1 H, dd), 8.47 (1 H, d).
3. Procedure for Solid Phase Suzuki Reaction.
Figure imgf000017_0001
W = CH, N
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(PPh3)4 (0.15 equiv.) was added followed by 4- formylbenzeneboronic acid (3 equiv.) after about five minutes. Sodium carbonate (6 equiv.) in water (DME:water ratio 9:1) was added and the mixture was heated until gentle reflux was obtained (internal temp. ~75°C). The mixture was stirrred under reflux in an argon atmosphere for 18h and the reaction then allowed to cool. The reaction solution was decanted and the kans rinsed with THF-water (1:1 x2), water (x3) and THF-water. They were then transferred to a kan washer and washed with THF, THF-water (1 :1 x2), water (x2), THF (x3) and DCM (x3). The kans containing resin product were then dried overnight in vacuo at 40°C.
4. Solid Phase Reductive Amination Reactions
Figure imgf000018_0001
General conditions for solid phase reductive aminations reactions.
W = CH, N
Kans containing the resin-bound biphenyl aldehydes (0.035mmol per kan), Na2S04 (5 equiv.) and 1 ,2-dichoroethane (DCE) (1ml per kan) were placed into flasks and vacuum applied and released. The amine R2NH2 (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-H20 (1 :1), H20 and THF-H20 (1 :1). They were then transferred to a kan washer and washed with THF, THF-H20 (1 :1), H20(x2), THF- H20 (1 :1), THF, DMF, THF (x3) and DCM (x3). The kans containing resin product were dried in vacuo at 40°C.
Examples of amines used are: N-(2-aminoethyl)morpholine, 3-(aminomethyl)pyridine, 4- amino-1-benzylpiperidine, N,N-dimethylethylenediamine, 3-methoxyphenethylamine, 3- phenylpropylamine,
1 -(3-aminopropyl)-4-metfιylpiperazine, 2-(aminomethyl)pyridine, 5-methyl-2-
(aminomethyl)pyrazine, 3-amino-1-BOC-piperidine, 2-(aminomethyl)-1-BOC-piperidine and 3-(dimethylamino)propylamine. 5. Further Reactions of Resin Bound Secondary Amines
(a) General procedure for acylation reactions with acid chlorides
Figure imgf000019_0001
W = CH, N
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.
Examples of acid chlorides used are;
Cinnamoyl chloride, thiophene-2-carbonyl chloride
3,4-methylenedioxybenzoyl chloride, 3-phenylpropionyl chloride, trans-2- phenylcyclopropanecarbonyl chloride, cyclopentylacetyl chloride and phenoxyacetyl chloride.
(b) General procedure for reactions with isocyanates
Figure imgf000019_0002
The general procedure for acid chlorides applies except that triethylamine was omitted. An example of an isocyanate used is phenyl isocyanate (R3 = NHPh)
(c) General procedure for reaction with sulfonyl chlorides
The general procedure for acid chlorides applies except that triethylamine was replaced with pyridine (11 equivalents) and 4-dimethylaminopyridine (1 equivalent). An example of a sulfonyl chloride used is is beta-styrylsulfonyl chloride.
(d) General procedure for reaction with carboxylic acids
6. Cleavage of Final Products from the Resin
Figure imgf000020_0001
W = CH, N; X = CO, CONH, S02
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.
Products were analysed by LC/MS and if necessary purified using high throughput preparative HPLC.
Preparation of compounds of the following formula:
Figure imgf000020_0002
1. Solution Phase Alkylation Reactions
Br _—// \ xV) —/ 'Br *- Br— <T' ^ ^~R1
N^ N;
General Procedure for Alkylation Reactions
A solution of the amine (1 equiv) and 2-bromo-5-bromomethylpyridine [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples
a) R1 = dimethylaminoethyl
The general procedure was followed using 2-bromo-5-bromomethylpyridine (3.9 g) and dimethylamino ethylamine (5.5 g) in DMF (100 ml). Silica gel chromatography (4% MeOH in DCM) gave the pure product (0.62 g, 25%). LC-MS - shows a single peak, M+H .
2. Solution Phase Acylation Reactions
R2
H °
^ R1 -→ - R Brr~
N
General procedure for acylation reactions with acid chlorides
A solution of the amine in DCM was treated with pyridine followed by the acid chloride, stirred at room temperature for 3h, diluted with DCM, washed with sat. aq. NaHC03 and dried over MgS04. Concentration to dryness under vacuum gave the desired product.
Examples
a) R1 = dimethylaminoethyl, R2 = cyclopentylethyl
The general procedure was followed using Λ/,-(6-Bromo-pyridin-3-ylmethyl)-Λ/,Λ/-dimethyl- ethane-1 ,2-diamine (200 mg), 3-cyclopentylpropionyl chloride (138 mg), pyridine (0.13 ml) and DCM (10 ml). Preparative HPLC gave the desired product (253 mg, 85%).
b) R1 = dimethylaminoethyl, R2 = phenylethenyl
The general procedure was followed using Λ/'-(6-Bromo-pyridin-3-ylmethyl)-Λ/,Λ/-dimethyl- ethane-1 ,2-diamine (200 mg), cinnamoyl chloride (143 mg), pyridine (0.13 ml) and DCM (10 ml). Preparative HPLC gave the desired product (247 mg, 82%).
3. Solution Phase Suzuki Reactions
Figure imgf000021_0001
General Procedure for Suzuki Coupling Reactions
A stirred solution of the bromopyridine in DME was treated with 4-formylboronic acid and a solution of Na2C03 in water. The mixture was degassed with argon for 30 mins then treated with fresh Pd(PPh3)4 and heated at 80 for 20h. The solvent was removed under vacuum and the residue partitioned between DCM and sat. aq. Na2C03. The organic layer was dried over MgS04, filtered and concentrated to dryness under vacuum.
Examples
a) R1 = dimethylaminoethyl, R2 = cyclopentylethyl
The general procedure was followed using W-(6-Bromo-pyridin-3-ylmethyl)-Λ/'-(3- cyclopentylpropionyl)-Λ/,Λ/-dimethyl-ethane-1 ,2-diamine (110 mg), 4-formylboronic acid (47 mg), Pd(PPh3)4 (17 mg), Na2C03 (92 mg), water (2.5 ml) and DME (7.5 ml). The crude product was purified using HPLC (5% MeOH in DCM) giving the desired product (72 mg, 61%).
b) R1 = dimethylaminoethyl, R2 = phenylethenyl
The general procedure was followed using W-(6-Bromo-pyridin-3-ylmethyl)-A/'-(3- cyclopentylpropionyl)-/V,Λ/-dimethyl-ethane-1,2-diamine (240 mg), 4-formylboronic acid (165 mg), Pd(PPh3)4 (36 mg), Na2C03 (200 mg), water (2.5 ml) and DME (7.5 ml). The crude product was purified using HPLC (5% MeOH in DCM) giving the desired product (140 mg, 55%).
4. Solution Phase Reductive Animation Reactions
Figure imgf000022_0001
General procedure for solution phase reductive amination reactions
A stirred solution of the aldehyde in DCM was treated with the amine followed by acetic acid. The mixture was stirred for 30 mins under argon and then treated with sodium triacetoxyborohydride, and stirred for a further 16 h. The mixture was diluted with DCM and washed with sat. aq. Na2C03. The organic layer was dried over MgS04, filtered and concentrated to dryness under vacuum.
Examples
a) R1 = dimethylaminoethyl, R2 = cyclopentylethyl, R3 = phenethyl
The general procedure was followed using 3-cyclopentyl-N-(2-dimethylamino-ethyl)-N-[6- (4-formyl-phenyl)-pyridin-3-ylmethyl]-propionamide (65 mg), phenethylamine (22 mg), acetic acid (19 mg), sodium triacetoxyborohydride (68 mg), and DCM (10 ml). The residue was purified using HPLC giving the desired product (55 mg, 67%).
b) R1 = dimethylaminoethyl, R2 = phenylethenyl, R3 = phenethyl
The general procedure was followed using (E)-N-(2-Dimethylamino-ethyl)-N-[6-(4-formyl- phenyl)-pyridin-3-ylmethyl]-3-phenyl-acrylamide (140 mg), phenethylamine (50 mg), acetic acid (40 mg), sodium triacetoxyborohydride (144 mg), and DCM (10 ml). The residue was purified using HPLC giving the desired product (7 mg, 4%).
Examples
The following compounds, synthesized by the above methodology, were found to be 5- HT5A antagonists with Ki <400 nM.
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0004
Figure imgf000025_0001
Figure imgf000025_0005
Figure imgf000025_0002
Figure imgf000025_0003
Figure imgf000026_0001
Figure imgf000026_0002
Each compound was analysed by LCMS (215 nm) and consisted of a single peak with the expected MH+ ion corresponding to the mass listed.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: pharmaceutically acceptable salt thereof:
Figure imgf000027_0001
(I) wherein one of Ar^ and Ar2 is phenyl linked in a 1 ,4-relationship, and the other is phenyl linked in a 1 ,4-relationship or a 6 membered heteroaryl ring linked in a 1 ,4-relationship;
R1 is hydrogen, or a group of formula (a):
R4 Y
I x
I
(a)
wherein
X is C=0 or S02; Y is a single bond, -CH2-, -(CH2)2-, -CH=CH-, -CH20-, -OCH2-,
C3_7cycloalkylene or NH; and R4 is optionally substituted phenyl or C3.
7cycloalkyl;
Z is a single bond, -CH2-, -(CH2)2- or -(CH2)3-;
R7 is NR^R9 where R^ and R are independently hydrogen or C<|_βalkyl, 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, -CH2-, -(CH2)2-, -CH2CH20-, or -CH2OCH -; and
E is optionally substituted phenyl, indanyl, methylenedioxyphenyl, or a 5- or 6-membered heteroaryl ring.
2. A compound as claimed in claim 1 , wherein R7 is Me2N-, 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.
3. A compound as claimed in claim 1 or claim 2, wherein one of Ar-| and Ar is phenyl linked in a 1 ,4-relationship, and the other is phenyl linked in a 1 ,4-relationship or pyridyl linked in a 1 ,4-relationship.
4. A compound as claimed in claim 1 , 2 or 3, wherein R4 is phenyl, cyclopentyl or methylenedioxyphenyl.
5. A compound as claimed in any of claims 1-4, wherein Y is a bond, -CH20-, -OCH2- , -(CH2)2-, -CH=CH-, cyclopropyl or NH.
6. A compound as claimed in any of claims 1-5, wherein A is a bond, CH2, (CH2)2 or (CH2)20.
7. A compound as claimed in any of claims 1-6, wherein E is phenyl, pyridyl or methylenedioxyphenyl.
8. A compound as claimed in claim 1 which is any of E1-E40 or a pharmaceutically acceptable salt thereof.
9. 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):
R7 NH2
(II) wherein R7 and Z are as defined for formula (I), and a compound of formula (111):
Figure imgf000028_0001
wherein Ar-j , Ar2, A and E are as defined for formula (l), in the presence of a suitable reducing agent;
and thereafter optionally: • removing any protecting groups, and/or
• converting a compound of formula (I) into another compound of formula (I), and/or
• forming a pharmaceutically acceptable salt.
10. A compound as claimed in any of claims 1-8 or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance.
11. A compound as claimed in any of claims 1-8 or a pharmaceutically acceptable salt thereof for use in the treatment of a CNS disorder.
12. A compound as claimed in claim 11 wherein the disorder is depression, anxiety, a sleep disorder or schizophrenia.
13. A method of treatment of a CNS disorder in a mammal including human, which comprises administering to the sufferer a therapeutically safe and effective amount of a compound as claimed in any of claims 1-8 or a pharmaceutically acceptable salt thereof.
14. A method as claimed in claim 13 wherein the disorder is depression, anxiety, a sleep disorder or schizophrenia.
15. Use of a compound as claimed in any of claims 1-8 or a pharmaceutically acceptable salt thereof in the manufaqture of a medicament for treatment of a CNS disorder.
16. The use as claimed in claim 15, wherein the disorder is depression, anxiety, a sleep disorder or schizophrenia.
17. A pharmaceutical composition, which comprises a compound as claimed in any of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
18. A process for preparing a pharmaceutical composition as defined in claim 17, comprising mixing a compound as defined in any of claims 1-8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
PCT/EP2004/004658 2003-04-29 2004-04-28 Biaryl compounds having activity at the 5ht5a receptor WO2004096771A1 (en)

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