WO2005115985A1 - Derives d'aminopyridine utilises comme agonistes selectifs de la dopamine d3 - Google Patents

Derives d'aminopyridine utilises comme agonistes selectifs de la dopamine d3 Download PDF

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Publication number
WO2005115985A1
WO2005115985A1 PCT/IB2005/001554 IB2005001554W WO2005115985A1 WO 2005115985 A1 WO2005115985 A1 WO 2005115985A1 IB 2005001554 W IB2005001554 W IB 2005001554W WO 2005115985 A1 WO2005115985 A1 WO 2005115985A1
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formula
compounds
alkyl
reaction
pyridin
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PCT/IB2005/001554
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English (en)
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Charlotte Moira Norfor Allerton
Andrew Simon Cook
David Hepworth
Duncan Charles Miller
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Pfizer Limited
Pfizer Inc.
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Priority claimed from GB0411891A external-priority patent/GB0411891D0/en
Priority claimed from GB0412463A external-priority patent/GB0412463D0/en
Priority to BRPI0511571-0A priority Critical patent/BRPI0511571A/pt
Priority to AU2005247699A priority patent/AU2005247699A1/en
Priority to EP05747191A priority patent/EP1758862A1/fr
Priority to CA002567935A priority patent/CA2567935C/fr
Priority to JP2007514200A priority patent/JP4198183B2/ja
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to MXPA06013786A priority patent/MXPA06013786A/es
Priority to AP2006003824A priority patent/AP2006003824A0/xx
Priority to EA200601982A priority patent/EA200601982A1/ru
Publication of WO2005115985A1 publication Critical patent/WO2005115985A1/fr
Priority to IL179314A priority patent/IL179314A0/en
Priority to NO20065326A priority patent/NO20065326L/no
Priority to TNP2006000387A priority patent/TNSN06387A1/fr

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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a class of dopamine agonists, more particularly a class of agonists that are selective for D3 over D2.
  • These compounds are useful for the treatment and/or prevention of sexual dysfunction, for example female sexual dysfunction (FSD), in particular female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD; lack of interest in sex), female orgasmic disorder (FOD; inability to achieve orgasm); and male sexual dysfunction, in particular male erectile dysfunction (MED).
  • Male sexual dysfunction as referred to herein is meant to include ejaculatory disorders such as premature ejaculation, anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD; lack of interest in sex).
  • HSDD hypoactive sexual desire disorder
  • HSDD hypoactive sexual desire disorder
  • the present invention provides for compounds of formula (I):
  • R 1 is selected from H and (C C 6 )alkyl
  • R 2 is selected from H and (C C 6 )alkyl
  • R 3 is selected from:
  • substituted phenyl means phenyl substituted with 1 or more substituents each independently selected from (C C 6 )alkyl, halo and OR 7 , each substituent may be the same or different;
  • R and R 2 are H, R 3 is moiety (II), A is 0, R 5 is H or (C-,-C 6 )alkyl, and R 6 is H or (C C 6 )alkyl, then R 4 cannot be n-propyl; and pharmaceutically acceptable salts, solvate, polymorphs and prodrugs thereof.
  • (C ⁇ -C 6 )alkyl may be straight chain or branched.
  • Suitable heteroaryl groups include pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • halo means fluoro, chloro, bromo or iodo.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternatives groups, the selected groups may be the same or different,
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate .
  • malate, maieate, malonate mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
  • Hemisalts of acids may also be formed, for example, hemisulphate.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • the pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • references to compounds of formula I include references to the salts and solvates thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula I.
  • a compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Furthermore, the skilled person will understand that moiety (II) encompasses all stereoisomeric and distereoisomeric forms, in particular:
  • Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof.
  • An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 25 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Certain isotopically-labelled compounds of formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • R 1 is selected from H, methyl and ethyl More preferably R is selected from H and methyl
  • R is H.
  • R 2 is selected from H, methyl and ethyl More preferably R 2 is selected from H and methyl Most preferably R 2 is H.
  • Moieties (Ha) and (lib) are preferred.
  • A is O or CH 2 More preferably A is O
  • R 4 is (C 1 -C 6 )alkyl optionally substituted with a phenyl or a substituted phenyl group. More preferably R 4 is (C ⁇ -C )alkyl optionally substituted with phenyl Even more preferably R 4 is selected from methyl, ethyl, n-propyl or n-butyl Most preferably R 4 is selected from methyl, ethyl, and n-propyl
  • R 5 is selected from H and (C C )alkyl; wherein said (C C 4 )alkyl may be optionally substituted with 1 or 2 OR 7 groups More preferably R 5 is selected from H, methyl and ethyl; wherein said methyl and said ethyl may be optionally substituted with an OR 7 group Most preferably R 5 is selected from H, methyl and ethyl.
  • R 5 is (C C 4 )alkyl optionally substituted with 1 or 2 OR 7 groups More preferably R 5 is selected from methyl and ethyl; wherein said methyl and said ethyl may be optionally substituted with an OR 7 group. Most preferably R 5 is selected from methyl and ethyl.
  • R 6 is selected from H, methyl and ethyl More preferably R 6 is selected from H and methyl Most preferably R 6 is H
  • R 7 is selected from H and (C C 4 )alkyl; wherein said (C C 4 )alkyl is optionally substituted with 1 or 2 phenyl or substituted phenyl groups More preferably R 7 is selected from H, methyl and ethyl; wherein said methyl and said ethyl are optionally substituted with a phenyl group Most preferably R 7 is selected from H and (CH 2 )phenyl
  • R 4 represents (C C 4 )alkyl, optionally substituted by 1 or 2 phenyl, substituted phenyl or heteroaryl groups. More preferably R 4 represents ethyl, propyl or butyl, said groups being optionally substituted by a phenyl group. Most preferably R 4 represents ethyl or propyl, said groups being optionally substituted by a phenyl group.
  • R 8 is selected from H, methyl and methoxy. More preferably R 8 is selected from H and methoxy. Most preferably R 8 is H.
  • R 9 is selected from (C C 4 )alkyl. More preferably R 9 is selected from methyl, ethyl and n-propyl. Most preferably R 9 is n-propyl.
  • R 10 is selected from H and (d-C 3 )alkyl; wherein said (d-C 3 )alkyl may be optionally substituted with 1 or 2 OR 7 or phenyl groups. 5 More preferably R 10 is selected from H and methyl. Most preferably R 10 is H.
  • R 3 is selected from moieties (II) and (III) More preferably R 3 is selected from moieties (lla), (lib), and (III)0 Most preferably R 3 is selected from moieties (lla) and (lib).
  • heteroaryl is a 5 or 6 membered aromatic ring, containing from 1 to 3 heteroatoms, said heteroatom independently selected from O and N; More preferably heteroaryl is a 5 or 6 membered aromatic ring, containing from 1 to 2 nitrogen atoms.
  • compounds (and salts thereof) of the present invention are exemplified herein; more preferred are:
  • the invention additionally comprises the compounds (+)-5-(4- propylmorpholin-2-yl)-1 ,3-thiazol-2-amine and (-)-5-(4-propylmorpholin-2-yl)-1 ,3-thiazol-2-amine (Examples 26 and 27).
  • 5 Compounds of the invention may be prepared, in known manner, in a variety of ways. The routes below illustrate methods of synthesising compounds of formula (I); the skilled man will appreciate that other methods may be equally as practicable.
  • NPG is the 2,5-dimethylpyrrole system [as described in J. Chem. Soc. Perkin Trans. 1, 1984, 2801-2807, and as illustrated by the compound of formula (Via)], may be introduced through reaction of an aminopyridine of formula (V) with 1-2 equivalents of 2,5- hexanedione in toluene at reflux with azeotropic removal of water and an acid catalyst, such as para- toluenesulfonic acid.
  • an aminopyridine of formula (V) with 1-2 equivalents of 2,5- hexanedione in toluene at reflux with azeotropic removal of water and an acid catalyst, such as para- toluenesulfonic acid.
  • Aromatic haiide of formula (VI) may be converted into aldehydes of formula (VII) by, for example, generation of an organometallic reagent from a halogenated pyridine of formula (VI), followed by reaction with a formylating agent such as dimethylformamide or morpholine-4-carbaldehyde.
  • organometallic pyridine derivatives include Grignard (organomagnesium) or organolithium reagents, which may be prepared from the bromide (or iodide) by halogen-metal -exchange.
  • Typical conditions comprise addition of isopropylmagnesium chloride (or butyllithium) to the bromide (VI) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (may require heating in certain cases when isopropylmagnesium chloride is used as the metallating agent) or below (e.g. -78 °C when butyllithium is used) to perform the halogen metal exchange reaction, followed by addition of the formylating agent at 0 °C or lower.
  • anhydrous ethereal solvent such as tetrahydrofuran at room temperature
  • Compounds of formula (VIII) may be prepared by reaction of an aldehyde of formula (VII) with a cyanide source, such as potassium cyanide or trimethylsilylcyanide, or with nitromethane and a base, such as sodium hydroxide, to form an intermediate adduct which may be reduced by treatment with borane, lithium aluminium hydride or hydrogenation in an ethereal solvent.
  • a cyanide source such as potassium cyanide or trimethylsilylcyanide
  • a base such as sodium hydroxide
  • Typical conditions comprise reacting 1.0 equivalents of aldehyde in 1.5 equivalents of 3M HCl with sodium sulfite (1.5 equivalents) followed by potassium cyanide (1.5 equivalents) at room temperature.
  • the resulting cyanohydrin intermediate is then reduced by treatment with 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex of the product.
  • a strong acid to hydrolyse the initially formed boron complex of the product.
  • Compounds of formula (IX) may be prepared from compounds of formula (VIII) by employing standard amide bond forming conditions followed by reduction of the intermediate amide with a hydride reducing agent such as borane or lithium aluminium hydride.
  • a hydride reducing agent such as borane or lithium aluminium hydride.
  • acid chlorides in the presence of a suitable base such as triethylamine or 4- methylmorpholine may be used for the amide forming stage.
  • Typical reaction conditions comprise 1.0 equivalents of amine (VIII), 1.2-2.0 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25°C.
  • Reducing agents such as borane or lithium aluminium hydride can be used for the amide reduction stage.
  • Typical conditions comprise 1.0 equivalents of amide, 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex of the product.
  • the skilled person will be aware that other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.
  • Compounds of formula (IX) can also be made by reductive amination of compounds of formula (VIII) with a suitable aldehyde (1 equivalent or more) in the presence of a hydride reducing agent such as sodium cyanoborohydride ⁇ r sodium triacetoxyborohydride (1 equivalent or more) in an alcoholic solvent such as ethanol at room temperature.
  • a hydride reducing agent such as sodium cyanoborohydride ⁇ r sodium triacetoxyborohydride
  • Compounds of formula (X) may be prepared by reaction of compounds of formula (IX) with chloroacetyl chloride or 2-substituted ⁇ -chloroacyl chlorides (such as 2-chioropropionyl chloride or 2-chlorobutyryl chloride) in the presence of a base such as triethylamine, sodium carbonate or potassium hydroxide.
  • chloroacetyl chloride or 2-substituted ⁇ -chloroacyl chlorides such as 2-chioropropionyl chloride or 2-chlorobutyryl chloride
  • Typical conditions comprise 1.0 equivalents of amine (IX), 1.0-1.3 equivalents of acid chloride, 1.2-2.0 equivalents of triethylamine in dichloromethane at 25°C, the crude reaction mixture is then dissolved in IPA with 1.2-3.0 equivalents of aqueous potassium hydroxide.
  • Compounds of formula (XI) may be prepared by reaction of compounds of formula (X) with reducing agents such as borane or lithium aluminium hydride. Typical conditions comprise 1.0 equivalents of amide (X), 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex.
  • reducing agents such as borane or lithium aluminium hydride.
  • Typical conditions comprise 1.0 equivalents of amide (X), 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex.
  • reducing agents such as borane or lithium aluminium hydride.
  • Typical conditions comprise 1.0 equivalents of amide (X), 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex.
  • the skilled person will be aware that other non-acidic methods are available for breaking the
  • Compounds of formula (I) may be prepared from compounds of formula (XI) by deprotection. The nature of this reaction will depend upon the protecting group selected for use.
  • Typical conditions comprise 1.0 equivalents of compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux
  • Chloroketones of formula (XII) may be formed from halides of formula (VI) via generation of a reactive organometallic intermediate.
  • Suitable organometallic pyridine derivatives include Grignard (organomagnesium) or organolithium reagents, which may be prepared from the bromide (or iodide) by halogen-metal exchange.
  • Chloroketones of formula (XII) may be converted in epoxides of formula (XIII) via- reduction to an intermediate chlorohydrin and base promoted epoxide formation.
  • reaction of (XII) with sodium borohydride (0.3 equivalents or more) in dioxan with subsequent treatment with excess sodium hydroxide solution affords epoxides of formula (XIII).
  • Enantiomerically pure, or enantiomerically enriched epoxides of formula (XIII) may be obtained by employing an asymmetric reducing agent.
  • an asymmetric reducing agent for example, reaction of chloroketones of general formula (XIII) with (-)- ⁇ -chlorodiisopinocampheylborane (1.5 or more equivalents) in tetrahydrofuran at low temperature (e.g -30°C) and subsequent treatment of the intermediate chlorohydrin with sodium hydroxide affords enantiomerically enriched epoxides of formula (XIII).
  • Typical reaction conditions comprise 1 equivalent amino acid ester (XIV), 1 equivalent of acid chloride and 3 equivalents of base in dichloromethane at 25 °C. Examples of compounds of formula (XV) are also commercially available.
  • Reaction Step 12 Amide and ester reduction then N-Boc formation
  • Compounds of the formula (XVI) may be prepared by reacting compounds of the formula (XV) with 5 borane-THF complex, followed by treatment with a strong acid (e.g 5M HCl) to hydrolyse the resulting boron complexes with the product.
  • a strong acid e.g 5M HCl
  • Other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.. This is followed by t-butyloxycarbonyl protection of the formed amine.
  • Typical reaction conditions comprise 1 equivalent of the amide (XV) with 3 equivalents of BH 3 -THF in THF at reflux, cooling, cautious addition of 6M aqueous HCl, and heating to reflux for a further0 6h.
  • Compounds of the formula (XVII) may be prepared by reacting compounds of the formula (XVI) with an organic solution of HCl. Typical reaction conditions comprise 1 equivalent of the carbamate (XVI) and a 1- 10 equivalents of a 4M solution of HCl in dioxan at 25°C. Examples of compounds of formula (XVII) are also commercially available.
  • Compounds of the formula (XVIII) may be prepared by reacting compounds of the formula (XVII) with an ⁇ -halo ketone of formula (XII), if necessary in the presence of a base such as triethylamine or 4- 15 methylmorpholine.
  • Typical conditions comprise 1 equivalent of the aminoalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of a compound of formula (XII) at 65°C.
  • Morpholinol intermediates of formula (XVIII) can be reduced to diols of formula (XIX) by reaction with a hydride reducing agent such as sodium borohydride (1 equivalent or more) in an alcoholic solvent such as ethanol at room temperature.
  • a hydride reducing agent such as sodium borohydride (1 equivalent or more) in an alcoholic solvent such as ethanol at room temperature.
  • Morpholine ring closure 5 Diol compounds of formula (XIX) can be ring-closed to morpholine compounds of formula (XI) using a number of methods. For example treating a dichloromethane solution of (XIX) with excess -concentrated sulfuric acid at room temperature will effect cyclisation. Alternatively, the ring closure may be effected using Mitsunobu-type conditions employing the using of 1.1 0 equivalents of a dialkyl azodicarboxylate reagent, such as diispropyl azodicarboxylate (DIAD), and 1.1 equivalents of triphenylphosphine in an inert solvent such as tetrahydrofuran.
  • a dialkyl azodicarboxylate reagent such as diispropyl azodicarboxylate (DIAD)
  • DIAD diispropyl azodicarboxylate
  • triphenylphosphine in an inert solvent such as tetrahydrofuran
  • a further alternative is to use a sulfonylating agent, such as p-toluenesulfonylimidazole (1 equivalent) in the presence of strong base such as sodium hydride in an inert solvent such as tetrahydrofuran, as described in Org. Lett. 2004, 6(6), 1045-1047.
  • a sulfonylating agent such as p-toluenesulfonylimidazole (1 equivalent) in the presence of strong base such as sodium hydride in an inert solvent such as tetrahydrofuran, as described in Org. Lett. 2004, 6(6), 1045-1047.
  • Compounds of formula (I) may be prepared from compounds of formula (XI) by deprotection. The nature of this reaction will depend upon the protecting group selected for use.
  • Typical conditions comprise 1.0 equivalents of compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux
  • Compounds of formula (XX) may be prepared from compounds of formula (XIX) by deprotection.
  • Typical conditions comprise 1.0 equivalents of compound (XIX) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.
  • Compounds of formula (I) may then be prepared by cyclisation of compounds of formula (XX) by treatment with acid. Typical conditions employ concentrated sulfuric acid and dichloromethane as solvent at room temperature or above. Other methods, such as those described for Reaction Step 16 in scheme 3 may also be used to form the morpholine ring.
  • Scheme 5 describes an alternative method for conversion compounds of formula (XVIIl) into compounds of formula (XI), wherein R 1 , R 2 , R 4 , R 5 and R 6 are as defined above.
  • Compounds of formula (XI) may be formed from compounds of the formula (XVlll) by reaction step 19 - reaction of a compound of formula (XVlll) with an hydride source such as triethylsilane and an acidic or Lewis acidic reagent such as trimethylsilyltriflate.
  • a hydride source such as triethylsilane
  • an acidic or Lewis acidic reagent such as trimethylsilyltriflate.
  • Typical conditions comprise addition of 5 - 10 equivalents of triethylsilane to 1 equivalent of the morpholinol (XVIIl) in dichloromethane at -78 °C followed by addition of 2 equivalents of trimethylsilyltriflate.
  • Compounds of formula (XIX) may be derived by reaction step 20 - reaction of an amine of formula (XVII) with an epoxide of formula (XIII).
  • the reaction is generally conducted in an inert solvent such as toluene or DMSO and at elevated temperature. Typical reaction conditions: involve heating (XIII) and (XVII) together in DMSO at 90 °C.
  • An alternative method for the synthesis of compounds of formula (XVlll) is shown in Scheme 7, wherein
  • Compounds of formula (XVlll) may be prepared by reaction step 21 - reaction of an organometallic reagent generated from a halogenated pyridine compound of formula (VI), with a morpholinone compound of formula (XXI) (see scheme 8).
  • organometallic pyridine derivatives include Grignard (organomagnesium) or organolithium reagents, which may be prepared from the bromide (or iodide) by halogen-metal exchange.
  • Typical conditions comprise addition of isopropylmagnesium chloride (or butyllithium) to the bromide (VI) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (may require heating in certain cases when isopropylmagnesium chloride is used as the metallating agent) or below (e.g. -78 °C when butyllithium is used) to perform the halogen metal exchange reaction, followed by addition of the morpholinone (XXI) at 0 °C or lower.
  • anhydrous ethereal solvent such as tetrahydrofuran at room temperature
  • tetrahydrofuran e.g. -78 °C when butyllithium is used
  • Morpholinone compounds of formula (XXI), wherein R 4 , R 5 and R 6 are as defined above, may be prepared as shown in Scheme 8 (XXII) (XVII) I (22)
  • Morpholinone compounds of formula (XXI) may be prepared by reaction step 22 - the- reaction of an amino alcohol of formula (XVII) with an ⁇ -halo ester compound such as methyl bromoacetate (XXII) in the presence of a base such as triethylamine or 4-methylmorpholine.
  • Typical conditions comprise 1 equivalent of the aminoalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of methyl bromoacetate using toluene as solvent at room temperature or above. In some cases heating with azeotropic removal of methanol is required to achieve a good conversion to the desired product (XXI).
  • An alternative method for the synthesis of epoxides of formula (XIII), wherein R 1 and R 2 are as defined above, is shown in Scheme 9.
  • Compounds of formula (XIII) may be prepared by reaction step 23 - reaction of an aldehyde of formula (VII) with a sulfur ylid reagent such as that generated from trimethylsulfonium iodide and a suitable base.
  • Typical reaction conditions involve: reaction of trimethylsulfonium iodide (1 equivalent) with sodium hydride (1 equivalent) in DMSO at 0 °C followed by addition of the aldehyde (VII) and allowing the reaction to stand at room temperature.
  • Compounds of formula (XIII) may be prepared by reaction step 24 - treatment of an alkene of formula (XXlll) with an oxidising agent such as m-chloroperbenzoic acid, or dimethyldioxirane.
  • Typical reaction conditions comprise: reaction of 1 equivalent of alkene (XXlll) with 1-2 equivalents of m-chioroperbenzoic acid in dichloromethane at room temperature.
  • Alkenes of formula (XXlll), wherein R 1 and R 2 are as defined above, may be prepared .according to scheme 11.
  • Alkene compounds of formula (XXlll) may be prepared from aldehydes of formula (VII) by reaction step 25, a Wittig or similar olefination reaction.
  • Typical reaction conditions involved treating 1 equivalent of aldehyde (VII) with 1-2 equivalents of the ylid generated from the reaction of equal molar quantities of methyl triphenylphosphonium iodide and butyllithium, in tetrahydrofuran and room temperature or below.
  • alkenes of formula (XXlll), wherein R 1 and R 2 are as defined above may be prepared according to scheme 12.
  • Alkene compounds of formula (XXlll) may be prepared by reaction step 26 - a palladium catalysed vinylation reaction using haiide compounds of formula (VI).
  • Typical vinyl sources which may be used for this process include vinyltributylstannane, ethene gas (at high pressure), or a vinyl boronic acid.
  • Many Pd(0) or Pd(ll) catalysts are suitable for this transformation, such as Pd(PPh 3 ) 4 .
  • Typical conditions comprise: reaction of a halogenated pyridine of formula (VI) (1 equivalent) with ethylene gas (at high pressure e.g.
  • a Pd- catalysts such as Pd(OAc) 2 (1.5 mol%), a phosphine ligand such as tri-o-tolylphosphine (5 mol%) and amine base, such as triethylamine (large excess) at elevated temperatures (e.g.80 °C).
  • R 4 group (as defined above) may be introduced into any of several intermediates in the synthetic sequence. This is most conveniently achieved by reaction step 27, a reductive amination procedure. Examples of suitable intermediates for use in such a transformation are shown in Scheme 13, wherein R 1 , R 2 , R 5 and R 6 are as defined above. Other intermediates useful in the preparation of compounds of formula I may be equally as practicable.
  • a typical procedure comprises reacting 1 equivalent of secondary amine (such as (XIX), (XI), or (I), with 1 equivalent of an aldehyde in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature, then addition of 1 equivalent (or more) of sodium triacetoxyborohydride or sodium cyanoborohydride.
  • secondary amine such as (XIX), (XI), or (I)
  • an aldehyde such as tetrahydrofuran or dichloromethane
  • Any suitable nitrogen protecting group may be used (as described in "Protecting Groups in Organic Synthesis” 3 rd Edition T. W. Greene and P.G. Wuts, Wiley-lnterscience, 1999).
  • a common nitrogen protecting group (PC) suitable for use herein is tert-butoxy carbonyl, which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane.
  • a compound of formula (XXIV) may be prepared by reaction step 28 - N-protection.
  • a nitrogen protecting agent such as benzyl chloroformate
  • Typical reaction conditions involve: reaction of 1 equivalent of secondary amine (XIX) with (1 equivalent, or more) of benzyl chloroformate in an inert solvent such as dichloromethane, together with triethylamine (1 equivalent, or more) at room temperature.
  • Ring closure Ring closure of diol (XXIV) to morpholine (XXV) may be accomplished using many of the methods previously described herein, see Reaction Step 16, scheme 3. Particularly suitable in this instance is a Mitsunobu-type ring closure reaction through the action of a dialkyl azodicarboxylate reagent (1.1 equivalent) plus triphenylphosphine (1.1 equivalent) in an inert solvent such as tetrahydrofuran at room temperature.
  • Compounds of formula (l) may be prepared by reaction step 29 - deprotection of morpholine (XXV), under conditions dependent upon the nature of the protecting group used. For example, if benzyloxycarbonyl is used as the protecting group then it may be removed by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon, under hydrogen pressure of 1 atmosphere or greater. If the morpholine nitrogen is protected with a benzyl group it can be deprotected by transfer hydrogenation. Typical conditions involve treating one equivalent of compound of formula (XXV) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as catalyst (10% by weight), at reflux for 3 hours.
  • XXV morpholine
  • Compounds of formula (XVII) may be prepared by reaction step 30, a reductive amination procedure. Typical conditions involve: reaction of 1 equivalent of amino alcohol of formula (XVI) with 1.1 equivalents of an aldehyde in dichloromethane and the presence of dried 4A molecular sieves at room temperature. After filtration and evaporation of the reaction mixture, the residue is redissolved in methanol and reacted with sodium borohydride (2 equivalents or more) at room temperature.
  • the reductive amination can be accomplished in two steps via formation and then reduction of an intermediate amide, in a similar fashion to that described for Reaction Step 4 (Scheme 1) and in Reaction Steps 11 and 12 (scheme 3).
  • XXVI XXVI
  • benzophenone imine in the presence of a suitable base and a metal catalyst, e.g. a Pd complex.
  • Typical reaction conditions involve: reacting chloropyridine (XXVI) (1 equivalent) with benzophenone imine (1.2 equivalents), sodium terf-butoxide (1.4 equivalents), tris(dibenzylideneacetone)dipalladium(0) (1 mol%) and 2,2'-bis(diphenylphosphino)-1.1'-binaphthyl (BINAP) (3 mol%) in toluene at 80 to 120 °C.
  • Compounds of formula (XXVII) may be converted to compounds of formula (I) by hydrogenolysis (using an inert solvent and heterogeneous catalysis such as Pd on carbon at or above 1 atmosphere pressure of hydrogen), or alternatively by treatment with an aqueous acid e.g. 2M HCl in the presence of water and miscible organic solvent such as tetrahydrofuran or dioxan. Transfer hydrogenation may also be used to effect this transformation. Typical conditions involve treating one equivalent of compound of formula (XXVII) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as catalyst (10% by weight), at reflux for 3 hours.
  • Compounds of formula (I) wherein R 1 , R 2 and R 4 are as defined above and R 3 is as defined herein, may be prepared according to scheme 17.
  • Compounds of formula (XXX) may be prepared by reacting compounds of the formula (XXIX) with Zn/Cu couple (or other activated Zn source) with sonication, followed by addition of a 2-chloro-4-iodopyridine and a suitable palladium catalyst and ligand, and heating to 70°C for 18 hours.
  • Typical conditions comprise 1 equivalent of the azetidine (XXIX) with 40 wt% Zn/Cu couple in DMF with sonication at room temperature for 4 hours, followed by addition of 1.05 equivalents of the halogenated pyridine (VI), 0.05 equivalents of tris(dibenzylideneacetone)dipalladium(0) and 0.1 equivalents of tri-o-furylphosphine and heating to 70 °C for 18 hours.
  • Compounds of the formula (XXIX) may be prepared as described in Synlett, 4, 1998, 379.
  • Compounds of formula (XXXI) may be prepared by reacting compounds of the formula (XXX) with a suitable acid, such as HCl or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in the presence of a cation scavenger such as Et 3 SiH.
  • a suitable acid such as HCl or TFA
  • a suitable solvent such as dichloromethane or diethyl ether
  • Et 3 SiH a cation scavenger
  • Typical conditions compose 1 equivalent of the azetidine (XXX) with CH 2 CI 2 saturated with HCl gas at 0 °C then allowing to stand at room temperature overnight.
  • Compounds of formula (XXXIl) may be prepared by reacting compounds of formula (XXXI) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid.
  • Typical conditions comprise reacting 1 equivalent of the azetidine (XXXI) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane at room temperature for 18 hours.
  • Compounds of formula (XXXIl) may be converted to compounds of formula (I) via intermediates (XXXIll). Conversion of (XXXIl) to (XXXIll) may accomplished using benzophenone imine together with a suitable base and a metal catalyst, e.g. a Pd(0) complex.
  • a metal catalyst e.g. a Pd(0) complex.
  • Typical reaction conditions involve: reacting chloropyridine (XXXIl) (1 equivalent) with benzophenone imine (1.2 equivalents), sodium ferf-butoxide (1.4 equivalents), tris(dibenzylideneacetone)dipalladium(0) (1 mol%) and 2,2'-bis(diphenylphosphino)-1.1'- binaphthyl (BINAP) (3 mol%) in toluene at 80 to 120 °C.
  • Compounds of formula (XXXIll) may be converted to compounds of formula (I) either by hydrogenolysis (using an inert solvent and heterogeneous catalysis such as Pd on carbon at or above 1 atmosphere pressure of hydrogen), or by treatment with an aqueous acid in the presence of a water miscible organic solvent such as tetrahydrofuran or dioxan. Transfer hydrogenation may also be used for effect this transformation.
  • Typical conditions involve treating one equivalent of compound of formula (XXVII) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as catalyst (10% by weight), at reflux for 3 hours.
  • Zincate coupling Compounds of formula (XXXIV) may be prepared by reacting compounds of the formula (XXIX) with Zn/Cu couple (or other activated Zn source) with sonication, followed by addition of compounds of the formula (VI) and a suitable palladium catalyst and ligand, and heating to 70°C for 18 hours.
  • Typical conditions comprise 1 equivalent of the azetidine (XXIX) with 40 wt% Zn/Cu couple in DMF with sonication at room temperature for 4 hours, followed by addition of 1.05 equivalents of the halogenated pyridine (VI), 0.05 equivalents of tris(dibenzylideneacetone)dipalladium(0) and 0.1 equivalents of tri-o-furylphosphine and heating to 70 °C for 18 hours.
  • Compounds of the formula (XXIX) may be prepared as described in Synlett, 4, 1998, 379.
  • Compounds of formula (XXXV) may be prepared by reacting compounds of the formula (XXXIV) with a suitable acid, such as HCl or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in the presence of a cation scavenger such as EkSiH Typical conditions comprise 1 equivalent of the azetidine (XXXIV) with CH 2 CI 2 saturated with HCl gas at 0 °C then allowing to stand at room temperature overnight.
  • a suitable acid such as HCl or TFA
  • a suitable solvent such as dichloromethane or diethyl ether
  • Compounds of formula (XXXVl) may be prepared by reacting compounds of formula (XXXV) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid.
  • Typical conditions comprise 1 equivalent of the azetidine (XXXV) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane at room temperature for 18 hours.
  • Compounds of formula (VII) may be converted to nitrile compounds of formula (XXXVIl) by reaction with tosylmethyl isocyanide (TosMic).
  • TosMic tosylmethyl isocyanide
  • Typical conditions involve: treating aldehyde (VII) (1 equivalent) with TosMic (1 equivalent) and potassium fe/f-butoxide (2 equivalents) in ethylene glycol dimethyl ether at -45 °C after a period of 30 minutes methanol is added and the reaction mixture allowed to reach room temperature.
  • Nitriles of formula (XXXVIl) may be converted to amines of formula (XXXVIII) by reduction of the nitrile group. This reduction may be achieved through the action of a hydride reducing agent, such as lithium aluminium hydride, or sodium borohydride in the presence of a transition metal salt, such as NiCI 2 or CoCI 2 . Alternatively the nitrile group may be reduced by hydrogenation with a transition metal catalyst such as Raney Nickel or Pd on carbon.
  • a transition metal catalyst such as Raney Nickel or Pd on carbon.
  • Typical conditions involve: reacting nitrile (XXXVIl) (1 equivalent) with nickel chloride (1 equivalent) in methanol followed by cautious addition of sodium borohydride (3 equivalents or more) at 0 °C.
  • the primary amines (XXXVIII) may be converted to compounds of formula (XXXIX) by a reductive amination procedure, by reaction with an aldehyde and hydride reducing agent such as sodium triacetoxyborohydride or sodium borohydride
  • Typical conditions involve: reacting compounds of formula (XXXVIII) with a suitable aldehyde (1 equivalent or more) in the presence of a hydride reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (1 equivalent or more) in an alcoholic solvent such as ethanol.
  • a hydride reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (1 equivalent or more) in an alcoholic solvent such as ethanol.
  • Compounds of formula (XXXIX) may be converted to compounds of formula I by using a reaction to deprotect the nitrogen of the aminopyridine group (PGN) to liberate the NH 2 in compounds (I).
  • PPN aminopyridine group
  • the nature of this reaction will depend upon the protecting group selected for use. For example, when the 2,5- dimethylpyrrole system is used to protect the aminopyridine group, it may be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalents of compound (XXXIX) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.
  • nitrile compounds of formula (XXXVIl) may be converted into compounds of formula (I) as shown in Scheme 20.
  • the intermediates of formula (XXXVIl) may be reduced e.g. with sodium borohydride and nickel chloride in the presence of an acylating agent, such as a carboxylic acid anhydride to afford amide intermediates of formula (XL).
  • an acylating agent such as a carboxylic acid anhydride
  • Typical conditions involve: reacting nitrile (XXXVIl) (1 equivalent) with nickel chloride (1 equivalent) and a carboxylic acid anhydride (1 equivalents or more) in methanol followed by cautious addition of sodium borohydride (3 equivalents or more) at 0 C C.
  • Amides of general formula (XL) may be reduced to amines using borane or lithium aluminium hydride.
  • Typical conditions comprise 1.0 equivalents of amide (XL), 1.2-3.0 equivalents of borane in THF at reflux followed by heating in strong aqueous acid, such as 5M HCl.
  • the resulting amine intermediates may then be deprotected to give the aminopyridine compounds of formula (I), as previously described in Reaction Step 7.
  • Compounds of formula (XXXVIl) may be prepared by reaction step 39 - reaction of halogenated pyridine (VI) with tributyl(cyanomethyl)stannane and a palladium catalyst according to the procedure described in Chem. Lett 1984, 1511-1512. Typical conditions involve treating 1 equivalent of (VI) with 1.5 equivalents of tributy!(cyanomethyl)stannane, bis(acetonitrile)dichloropalladium(ll) (2.5 mol%) and tri-o-tolylphosphine (5 mol%) in xylene at 120 °C.
  • Compounds of formula (XLII) may be converted to compounds of formula (XXXVIII) by deprotection.
  • the nature of this reaction will depend upon the protecting group selected for use. For example, when benzyloxycarbonyl is used as the protecting group then it may be removed by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon.
  • Typical reaction conditions involve: reacting compounds of formula (XLII) in an alcohol solvent (such as ethanol) with hydrogen (at a pressure of 1 atmosphere of greater) in the presence of a transition metal catalyst such as Pd on carbon.
  • Compounds of formula (XXXIX) may be prepared by reaction step 41 - deoxygenation of a compound of formula (IX) by, for example, hydrogenation (in an inert solvent such as ethanol, in the presence of a transition metal catalyst, such as Pd on carbon in an atmosphere of hydrogen (1 atmosphere or higher)).
  • a hydride source such as triethylsilane in conjunction with a suitable acid may be used (as described in Heterocycles 2003, 1203-1209)
  • Typical reaction conditions involve: -dissolving (IX) in a mixture dichloromethane and trifluoroacetic acid at room temperature and adding 1 (or more) equivalents of triethylsilane.
  • a further method for the production of compounds of formula (XXXVIl) is shown in scheme 24.
  • An aldehyde of formula (VII) is reduced by treatment with a hydride reducing agent such as sodium borohydride in an alcoholic solvent, such as ethanol at room temperature.
  • a hydride reducing agent such as sodium borohydride in an alcoholic solvent, such as ethanol at room temperature.
  • the resulting alcohol can be activated towards nucleophilic displacement by conversion to a group X (generally a haiide or sulfonate ester) to give intermediates of formula (XLIII).
  • Typical conditions involve: reaction of one equivalent of methanesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 °C.
  • Halogenated pyridines or formula (VI) can be converted to methyl ketones of formula (XLIV) by treatment first with butyllithium (or other agent capable of facilitating a halogen metal exchange reaction) and treating the resultant organometallic intermediate with a suitable acetyl source, such as acetylmorpholine or the Weinreb amide derived from acetic acid.
  • a suitable acetyl source such as acetylmorpholine or the Weinreb amide derived from acetic acid.
  • Methyl ketones of formula (XLIV) may be converted into arylacetic acids of formula (XLV) by treatment with sulfur and morpholine.
  • a typical procedure involves: reacting 1 equivalent of methyl ketone (XLIV) with sulfur (2 equivalents) and in excess morpholine at reflux (either neat or in an alcoholic solvent such as ethanol), followed by hydrolysis either in refluxing 2M hydrochloric acid or 2M NaOH.
  • Pyridyl acetic acids of formula (XLV) may be converted to amides of formula (XLVI) by reaction with an amine of formula (XLVII) and a suitable amide coupling reaction, such as by reaction with an acid chloride or anhydride then addition of a suitable amine, or using a peptide coupling reagent such dicylcohexyl carbodiimide. or other carbodiimide reagent.
  • a suitable base such as triethylamine or 4-methylmorpholine may be used for the amide forming stage.
  • Typical reaction conditions comprise conversion of the acid (XLV) to the acid chloride by treatment with oxalyl chloride with a trace of dimethylformamide as catalyst in an inert solvent such as dichloromethane. After evaporation of solvents and excess oxalyl chloride, 1.0 equivalents of amine (XLVII), 1.2-2.0 equivalents of base (preferably triethylamine) are reacted with 1.0 equivalents of the acid chloride in dichloromethane at 25 c C.
  • Amides of general formula (XLVI) may be converted into compounds of formula (XXXIX) by reduction with a hydride reducing agent, such as borane-tetrahyrdrofuran complex.
  • a hydride reducing agent such as borane-tetrahyrdrofuran complex.
  • Typical conditions comprise 1.0 equivalents of amide (XLVI), 1.2-3.0 equivalents of borane in THF at reflux then treatment with a strong acid such as 5M HCl at elevated temperature to hydrolyse the initially formed boron complexes with the product.
  • a strong acid such as 5M HCl
  • Other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.
  • Compouns of formula (XLV) may be prepared according to reaction step 47, hydrolysis.
  • a nitrile of general formula (XXXVIl) is hydrolysed by heating in a strongly acidic or basic aqueous solution. Typical conditions involve heating a compound of formula (XXXVIl) in a 5M HCl solution at reflux.
  • Compounds of formula (XLVIII), wherein R 8 is OMe can be formed from compounds of formula (IX) by reaction step 48 - methylation of alcohol (IX) with a suitable electrophilic methyl source, such as iodomethane.
  • a suitable electrophilic methyl source such as iodomethane.
  • a strong base such as sodium hydride is also required.
  • Typical conditions involve treating 1 equivalent of (IX) with 1.1 (or more) of sodium hydride in an inert solvent such as tetrahydrofuran or dimethylformamide then adding 1 (or more) equivalents of iodomethane at room temperature.
  • Halogenated pyridine compounds of formula (VI) can be readily converted to ketones of formula (XLIX) using methods similar to the formation of methyl ketone compounds of formula (XLIV) (scheme 25). Namely, by treatment first with butyllithium (or other agent capable of facilitating a halogen metal exchange reaction) and treating the resultant organometallic intermediate with a suitable acyl source, such as acylmorpholine or Weinreb amide (both which are readily prepared using methods well-known to the skilled person).
  • a suitable acyl source such as acylmorpholine or Weinreb amide
  • the ketone of formula (XLIX) can then be converted to nitrile (XXXVIl) by reaction with tosylmethyl isocyanide (TosMic).
  • TosMic tosylmethyl isocyanide
  • Typical conditions involve: treating ketone (XLIX) (1 equivalent) with TosMic (1 equivalent) and potassium terf-butoxide (2 equivalents) in ethylene glycol dimethyl ether at -45 °C. After a period of 30 minutes methanol is added and the reaction mixture allowed to reach room temperature.
  • Nitriles of formula (XXXVIl) may subsequently be converted to compounds of formula (I) using 'the procedures previously described in scheme 19.
  • Thioethers of the formula (LI) may be formed by reaction of a compound of formula (XLIII), wherein X is generally a haiide or a sulfonate ester, with a compound of the formula (L) [commercially available or prepared a described in J.Chem.Soc Perkin I, 1987, 111-120] in the presence of a base in an alcoholic solvent.
  • Typical conditions comprise 1.0 equivalents of alkylhalide, 1.0 equivalents of thiol and 1.0-4.0 equivalents of a tertiary amine base such as triethylamine in an alcoholic solvent such as ethanol.
  • Compounds of formula (Lll) may be prepared by reacting compounds of the formula (LI) with a suitable acid, such as HCl or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in the presence of a cation scavenger such as Et 3 SiH Typical conditions comprise adding 1 equivalent of the protected amine (LI) to CH 2 CI 2 saturated with HCl gas at 0 °C then allowing to stand at room temperature overnight.
  • a suitable acid such as HCl or TFA
  • a suitable solvent such as dichloromethane or diethyl ether
  • Compounds of formula (Llll) may be prepared from compounds of formula (Lll) by employing standard amide bond forming conditions followed by reduction of the intermediate amide with a hydride reducing agent such as borane or lithium aluminium hydride.
  • a hydride reducing agent such as borane or lithium aluminium hydride.
  • acid chlorides in the presence of a suitable base such as triethylamine or 4- methylmorpholine may be used for the amide forming stage.
  • Typical reaction conditions comprise 1.0 equivalents of amine (Lll), 1.2-2.0 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25°C.
  • Reducing agents such as borane or lithium aluminium hydride can be used for the amide reduction stage.
  • Typical conditions comprise 1.0 equivalents of amide, 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex of the product.
  • Other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.
  • Compounds of formula (LIV), wherein R 11 is benzyl or (C C 6 )alkyl may be formed by treatment of compounds of formula (Llll) with an alkyl or benzyl chloroformate in an inert solvent such as dichloromethane or diethyl ether in the presence of a base.
  • Typical conditions comprise 1.0 equivalents of the amine (Llll), 1.0 equivalents of an alkylchloroformate such as methylchloroformate and 1.0-3.0 equivalents of a tertiary amine base such as triethylamine in diethyl ether at 25°C.
  • Compounds of the formula (LV) may be formed by treatment of thioether (LIV) with a strong base such as lithium diisopropylamide in an inert solvent such as diethyl ether or THF.
  • a strong base such as lithium diisopropylamide
  • Typical conditions comprise addition of 3.0 equivalents of a strong base such as lithium diisopropylamide to 1.0 equivalents of the thioether (LIV) at a temperature below -50°C in an inert solvent such as THF and allowing to warm to ambient temperature.
  • Compounds of formula (LVI) may be prepared by reaction of compounds of formula (LV) with reducing agents such as borane or lithium aluminium hydride. Typical conditions comprise 1.0 equivalents of amide (LV), 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex. Other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.
  • reducing agents such as borane or lithium aluminium hydride.
  • Typical conditions comprise 1.0 equivalents of amide (LV), 1.2-3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyse the initially formed boron complex.
  • Other non-acidic methods are available for breaking the boron complex e.g. treatment with diethanolamine.
  • Typical conditions comprise 1.0 equivalents of compound (LVI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.
  • Compounds of the formula (LVII) may be formed from compounds of the formula (XXIV), wherein PG' is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl, by selective conversion of the primary hydroxyl group to a group X (generally a haiide or sulfonate ester).
  • Typical conditions involve: reaction of one equivalent of toluenenesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 °C.
  • Compounds of the formula (LVIII) may be formed by from compounds of the formula (LVII), wherein PG' is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl, by reaction with a suitable nucleophile such as thioacetic acid in an inert solvent such as acetonitrile in the presence of a suitable base.
  • a suitable nucleophile such as thioacetic acid in an inert solvent such as acetonitrile in the presence of a suitable base.
  • Typical conditions involve: reaction of one equivalent of compounds of the formula (LVII) with 1.0-2.0 equivalents of thioacetic acid in the presence of 1.0 - 5.0 equivalents of a suitable base such as potassium carbonate in an inert solvent such as acetonitrile and the mixture heated to reflux.
  • Compounds of the formula (LVIII) may be activated towards nucleophilic displacement at the benzylic centre by conversion to a group X (generally a haiide or sulfonate ester). In situ ring closure may then occur to provide compounds of the formula (LIX).
  • Typical conditions involve: reaction of one equivalent of toluenenesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 °C. Evaporation of the solvent followed by redissolution in a higher boiling solvent such as acetonitrile with 0-5.0 equivalents of a suitable base such as potassium carbonate and heating of the mixture to reflux may be necessary to effect the ring closure.
  • Compounds of the formula (LX) may be formed from an alkene of the formula (XXlll) by reacting with N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine and a catalytic amount of an acid such as trifluoroacetic acid in an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or toluene at - 10°C to the reflux temperature of the reaction mixture.
  • an acid such as trifluoroacetic acid
  • an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or toluene
  • Alternative catalysts include anhydrous potassium or cesium fluoride, tetra-n-butylammonium fluoride, trifluoromethanesulfonic acid, trimethylsilyltrifluoromethanesulfonate and iodotrimethylsilane.
  • Typical conditions involve: reaction of 1 equivalent of alkene (XXlll) with 1.5 equivalents of N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine and 0.1 equivalents of trifluoroacetic acid in dichloromethane.
  • Compounds of the formula (LX) may be deprotected to secondary amines of the formula (LXI) by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon, under hydrogen pressure of 1 atmosphere or greater. Alternatively it can be deprotected by transfer hydrogenation. Typical conditions involve treating one equivalent of compound of formula (LX) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as catalyst (10% by weight), at reflux for 3 hours.
  • Compounds of formula (LXII) may be prepared by reacting compounds of formula (LXI) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid.
  • Typical conditions comprise reacting 1 equivalent of the pyrrolidine (LX) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane at room temperature for 18 hours.
  • Typical conditions comprise 1.0 equivalents of compound (LXI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.
  • Compounds of formula (LXIII) may be prepared from compounds of formula (VI) by reaction with 3-pyridyl boranes (or similar boronic acid) in the presence of a suitable base and suitable palladium catalyst.
  • Typical conditions comprise addition of the 3-pyridyl borane to a compound of formula (VI) in toluene/ethanol as solvent, in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate, followed by heating to reflux.
  • 3-pyridyl boranes (or similar boronic acids) are commercially available.
  • Compounds of formula (LXIV) may be prepared from compounds of formula (LXIII) by addition of an alkyl iodide. Typical conditions comprise addition of the alkyl iodide to a compound of formula (LXIII), in a suitable solvent such as acetonitrile and then heating to reflux.
  • Compounds of formula (LXV) may be prepared from compounds of formula (LXIV) by hydrogenation.
  • Typical conditions comprise hydrogenation of a compound of formula (LXIV), at elevated pressure, in a suitable solvent such as ethanol, in the presence of a suitable catalyst such as Pt0 2 .
  • the separated diastereomeric esters may then separately be hydrolysed under standard ester hydrolysis conditions to release chiral alcohols in enantiomerically enriched form.
  • a chiral reagent including enzymes
  • the compounds of the present invention have utility as selective D3 agonists in the treatment of disease states.
  • the present invention provides a class of selective D3 agonists. Serendipitously, these have been found to be efficacious; whilst reducing the side effects associated with unselective prior art compounds.
  • a further aspect of the invention provides a compound of formula (I) for use as a medicament.
  • Compounds of present invention are particularly useful in treating sexual dysfunction, female sexual dysfunction, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder; male erectile dysfunction, hypertension, neurodegeneration, depression, and psychiatric disorders. Accordingly, the present invention provides for, the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of sexual dysfunction.
  • the compounds of the present invention are useful in male sexual dysfunction, particularly male erectile dysfunction.
  • Male erectile dysfunction otherwise known as male erectile disorder, is defined as:
  • Penile erection is a haemodynamic event which is dependent upon the balance of contraction and relaxation of the corpus cavernosal smooth muscle and vasculature of the penis (Lerner ef a/ 1993, J. Urology, 149, 1256-1255).
  • Corpus cavernosal smooth muscle is also referred to herein as corporal smooth muscle or in the plural sense corpus cavemosa. Relaxation of the corpus cavernosal smooth muscle leads to an increased blood flow into the trabecular spaces of the corpus cavemosa, causing them to expand against the surrounding tunica and compress the draining veins. This produces a vast elevation in blood pressure which results in an erection (Naylor, 1998, Br. J. Urology, 81, 424-431).
  • NANC neurotransmitters found in the penis, other than NO, such as calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP).
  • CGRP calcitonin gene related peptide
  • VIP vasoactive intestinal peptide
  • NO nitric oxide
  • NOS nitric oxide synthase
  • sGC soluble guanylate cyclase
  • cGMP intracellular cyclic guanosine 3',5'-monophosphate
  • Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in the reward, emotional and cognitive processes.
  • D3 is an initiator of sexual behaviour.
  • the present invention provides for, the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of erectile dysfunction.
  • the present invention provides for the use of a compound of formula (I) in the preparation of a medicament in combination with a PDE5 inhibitor for the treatment of erectile dysfunction.
  • Suitable PDE5 inhibitors are described herein.
  • the compounds of the present invention are useful in the treatment or prevention of female sexual dysfunction (FSD), particularly female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD; lack of interest in sex), FSAD with concomitant HSDD, and female orgasmic disorder (FOD; inability to achieve orgasm).
  • FSD female sexual dysfunction
  • FSAD female sexual arousal disorder
  • HSDD hypoactive sexual desire disorder
  • FOD female orgasmic disorder
  • FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression.
  • FSD is a collective term for several diverse female sexual disorders (Leiblum, S.R. (1998) - Definition and classification of female sexual disorders. Int. d. Impotence Res., 10, S104-S106; Berman, J.R., Berman, L & Goldstein, I. (1999) - Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options. Urology, 54, 385-391). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems. Several types of disease, medications, injuries or psychological problems can cause FSD. Treatments in development are targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.
  • Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli.
  • Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity.
  • Orgasm is the release of sexual tension that has culminated during arousal.
  • FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm.
  • FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders.
  • the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), in doing so it may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders.
  • Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies.
  • This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.
  • FSAD Female sexual arousal disorder
  • the genitalia do not undergo the engorgement that characterises normal sexual arousal.
  • the vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded.
  • Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis.
  • Other causes result from treatment with diuretics, antihistamines, antidepressants e.g. selective serotonin re-uptake inhibitors (SSRIs) or antihypertensive agents.
  • SSRIs selective serotonin re-uptake inhibitors
  • Sexual pain disorders (includes dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
  • D3 is thought to be an initiator of sexual behaviour.
  • the clitoris is considered to be a homologue of the penis (Levin, R.J. (1991), Exp. Gin. Endocrinol, 98, 61-69); the same mechanism that provides provides an erectile response in the male produces an increase in genital blood flow in the female with an associated effect upon FSD. In addition there are changes in proceptivity and receptivity.
  • a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, more particularly hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder.
  • the compounds of formula (I) are useful in the treatment or prophylaxis of female sexual arousal disorder (FSAD), FSAD with concomitant hypoactive sexual desire disorder, orgasmic disorder, and hypoactive sexual desire disorder, and most preferably in the treatment or prophylaxis of female sexual arousal disorder.
  • FSAD female sexual arousal disorder
  • FSAD with concomitant hypoactive sexual desire disorder, orgasmic disorder, and hypoactive sexual desire disorder and most preferably in the treatment or prophylaxis of female sexual arousal disorder.
  • the compounds of formula (I) are useful in the treatment of a subject with female sexual arousal disorder and concomitant hypoactive sexual desire disorder.
  • DSM Diagnostic and Statistical Manual
  • FSAD Female Sexual Arousal Disorder
  • the arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia.
  • the disturbance causes marked distress and/or interpersonal difficulty.
  • FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post-menopausal (+ hormone replacement therapy (HRT)) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital (UG) disorders.
  • HRT hormone replacement therapy
  • UG urogenital
  • the primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation.
  • the secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.
  • Drug candidates for treating FSAD which are under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to male genitalia.
  • the compounds of the present invention are advantageous by providing a means for restoring a normal sexual arousal response - namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity.
  • the present invention provides a means to restore, or potentiate, the normal sexual arousal response.
  • a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder and female sexual arousal disorder with concomitant hypoactive sexual desire disorder.
  • the genital organs consist of an internal and external group.
  • the internal organs are situated within the pelvis and consist of ovaries, the uterine tubes, uterus and the vagina.
  • the external organs are superficial to the urogenital diaphragm and below the pelvic arch. They comprise the mons pubis, the labia majora and minora pudendi, the clitoris, the vestibule, the bulb of the vestibule, and the greater vestibular glands" (Gray's Anatomy, CD. Clemente, 13 th American Edition).
  • the compounds of the invention find application in the following sub-populations of patients with FSD: the young, the elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy.
  • the compounds of the invention find application in patients with FSD arising from:-
  • Vasculogenic etiologies e.g. cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vascular system.
  • Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery, iii) Hormonal/endocrine etiologies such as dysfunction of the hypothaiarrtic/pituitary/gonadal axis, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism.
  • prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism.
  • the Compounds of the present invention are also useful in the treatment of depression.
  • Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in reward, emotional and cognitive processes.
  • Chronic treatment with several classes of antidepressants are known to increase the expression of D3 in the limbic area, and antidepressant effects of desipramine can be blocked by sulpride (D2/D3 antagonist) when injected to nucleus accumbens (area rich in D3) but not caudate-putamen (area rich in dopamine D2 receptors).
  • sulpride D2/D3 antagonist
  • antidepressant effects were observed preclinical models of depression and in patients treated with pramipexole, a D3-preferring D2/D3 agonist.
  • D3 receptors mediate the anti-depressant activity and that selective D3 receptor agonists represent a new class of antidepressant drugs. Since antidepressants are known to be effective in other psychiatric disorders, D3 agonists would have the potential to treat psychiatric diseases.
  • Suitable conditions include depression (e.g. depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, major depression, child abuse induced depression, post partum depression and grumpy old man syndrome), single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; trichotillomania, kleptomania, attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder; borderline personality disorder; avoidant personality disorder; anxiety disorders such as panic disorder with or without ago
  • anorexia nervosa and bulimia nervosa obesity
  • movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome
  • extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour
  • chemical dependencies and addictions e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol
  • behavioral addictions such as an addiction to gambling
  • ocular disorders such as glaucoma and ischemic retinopathy
  • sleeping disorder cataplexy
  • shock exia
  • the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of depression or psychiatric disorders.
  • Suitable depressive conditions and psychiatric disorders are described above.
  • the invention provides for the use of compounds of formula I in the preparation of a medicament for the treatment of obesity.
  • the compounds of the present invention also have utility in the treatment of neurodegeneration; sources of neurodegeneration include neurotoxin poisoning; vision loss caused by neurodegeneration of the visual pathway, such as by a stroke in the visual pathway eg in retina, optic nerve and/or occipital lobe; epileptic seizures; and from impairment of glucose and/or oxygen supply to the brain.
  • sources of neurodegeneration include neurotoxin poisoning; vision loss caused by neurodegeneration of the visual pathway, such as by a stroke in the visual pathway eg in retina, optic nerve and/or occipital lobe; epileptic seizures; and from impairment of glucose and/or oxygen supply to the brain.
  • Conditions related to neurodegeneration include Restless Leg Syndrome, Huntington's disease, Multiple Sclerosis, mild cognitive impairment, Down's syndrome, stroke, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, delirium, dementia, age-related cognitive decline (ARCD), and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, HIV or AIDS-related dementia, diffuse Lewy body type
  • the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of neurodegeneration.
  • Suitable neurodegenerative conditions are described above.
  • the compounds of the present invention are likely to be efficacious in a number of additional indications.
  • the present invention provides for the use of compounds of formula (I), in the preparation of a medicament for the treatment of hypertension, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (e.g. hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, trichotillomania and chronic paroxysmal hemicrania, headache (associated with vascular disorders).
  • endocrine disorders e.g. hyperprolactinaemia
  • vasospasm particularly in the cerebral vasculature
  • cerebellar ataxia e.g. gastrointestinal tract disorders (involving changes in motility and secretion)
  • premenstrual syndrome e.g. hyperprolactinaemia
  • fibromyalgia syndrome e.g. hyperprolactinaemia
  • Activity at the dopamine D3 receptor may be determined using the methods described in WO 2004/052372. Using this assay, the compounds of the present invention all exhibit a functional potency at D3 receptor expressed as an EC50, lower than 1000nM and a 10 fold selectivity for D3 over D2. Selectivity is calculated as the D2 EC50 value divided by the D3 EC50 value. Where the value of the D2 EC50 was >10000, a.figure of 10000 was used in the calculation.
  • the compound of example 14 has a functional potency at the D3 receptor, expressed as an EC50, of 20 nM, with an Emax (maximal response value) of 98% (relative to the maximal effect of standard agent pramipexole). Against the D2 receptor this compound gave only a 22% response (relative to the maximal effect of pramipexole) at 10OOOnM.
  • Suitable auxiliary active agents for use in the combinations of the present invention include: 1) Naturally occurring or synthetic prostaglandins or esters thereof.
  • Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E ⁇ prostaglandin E 0 , 13, 14 - dihydroprosta glandin E ⁇ prostaglandin E 2, eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in WO-00033825 and/or US 6,037,346 issued on 14th March 2000 all incorporated herein by reference, PGE 0 , PGET, PGA ⁇ PGBL PGF !
  • ⁇ - adrenergic receptor antagonist compounds also known as - adrenoceptors or ⁇ -receptors or ⁇ -blockers.
  • Suitable compounds for use herein include: the ⁇ -adrenergic receptor blockers as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to ⁇ -adrenergic receptors are incorporated herein by reference and include, selective ⁇ adrenoceptor or ⁇ 2 -adrenoceptor blockers and non-selective adrenoceptor blockers, suitable ⁇ r adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine,
  • NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N- hydroxy - L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N- cysteine, diazenium diolates,(NO-1) S-nitroso - N- cysteine
  • potassium channel openers or modulators include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI 2 ;
  • Vasodilator agents include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, , Rec 15/2739, trazodone; 6) Thromboxane A2 agonists;
  • ergot alkaloids are described in US patent 6,037,346 issued on 14th March 2000 and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride;
  • Atrial naturetic factor also known as atrial naturetic peptide
  • B type and C type naturetic factors such as inhibitors or neutral endopeptidase
  • Angiotensin receptor antagonists such as losartan
  • Substrates for NO-synthase such as L-arginine
  • Calcium channel blockers such as amlodipine
  • Antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme are antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme
  • Cholesterol lowering agents such as statins (e.g. atorvastatin/ Lipitor- trade mark) and fibrates;
  • Antiplatelet and antithrombotic agents e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors;
  • Insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide;
  • Acetylcholinesterase inhibitors such as donezipil
  • Steroidal or non-steroidal anti-inflammatory agents such as donezipil
  • Estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists preferably raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8- tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof the preparation of which is detailed in WO 96/21656;
  • a PDE inhibitor more particularly a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably PDE2 or PDE5 inhibitor and most preferably a PDE5 inhibitor (see hereinafter), said inhibitors preferably having an IC50 against the respective enzyme of less than 100nM (with the proviso that PDE 3 and 4 inhibitors are only administered topically or by injection to the penis);
  • Vasoactive intestinal protein VIP
  • VIP mimetic VIP analogue
  • PACAP pituitary adenylate cyclase activating peptide
  • VIP receptor agonist e.g. Ro-125-1553
  • VIP fragment e.g. a ⁇ -adrenoceptor antagonist with VIP combination
  • a melanocortin receptor (particularly of the MC3 or MC4 subtype) agonist or modulator or melanocortin enhance, such as melanotan II, PT-14, PT-141 or compounds claimed in WO- 09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO- 00113112, WO-09954358;
  • a serotonin receptor agonist, antagonist or modulator more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993;
  • a testosterone replacement agent including dehydroandrostendione, testostemone (Tostrelle), dihydrotestosterone or a testosterone implant;
  • Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate i.e. as a combination
  • estrogen and methyl testosterone hormone replacement therapy agent e.g. HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone);
  • a purinergic receptor agonist and/or modulator A purinergic receptor agonist and/or modulator
  • a neurokinin (NK) receptor antagonist including those described in WO-09964008;
  • An opioid receptor agonist, antagonist or modulator preferably agonists for the ORL-1 receptor
  • An agonist, antagonist or modulator for oxytocin receptors preferably a selective oxytocin agonist or modulator
  • a SEP inhibitor for instance a SEPi having an IC 50 at less than 100 nanomolar, more preferably, at less than 50 nanomolar.
  • the SEP inhibitors according to the present invention have greater than 30-fold, more preferably greater than 50-fold selectivity for SEP over neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE).
  • ACE angiotensin converting enzyme
  • the SEPi also has a greater than 100-fold selectivity over endothelin converting enzyme (ECE).
  • PDE5 inhibitors include: 5-[2-ethoxy-5-(4-methyl-1 -piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), particularly sildenafil citrate; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino[2',1 ':6,1]pyrido[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil); 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyi)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1
  • a selective dopamine D4 receptor agonist such as 2-[(4-pyridin-2-ylpiperazin-1-yJ)methyl]-1H- benzimidazole (ABT724).
  • the compounds of formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or0 amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art.
  • compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). >5 Accordingly the present invention provides for a pharmaceutical composition comprising a compound of formula (I), and a pharmaceutically acceptable diluent or carrier.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, 30 so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid- 5 filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or 0 hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, JM (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste- masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the compound of formula I may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula I may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions, and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma ef al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecai, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(d/-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phoriophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, efc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from ... to ... ⁇ g of the compound of formula I.
  • the overall daily dose will typically be in the range ... ⁇ g to ... mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the morpholine from example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 mL) and phenylacetaldehyde (52 ⁇ L, 0.45 mmol) was added dropwise as a solution in tetrahydrofuran (15 mL) over 15 minutes. After the addition was complete, the reaction mixture was allowed to stir at room temperature for 1 h before the addition of sodium triacetoxyborohydride (227 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight (-16 h) and then diluted with saturated sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (100 mL).
  • the material from preparation 10 (410 mg, 1.25 mmol) was dissolved in ethanol (10 mL), 5% Pd on carbon (40 mg) was added and the mixture hydrogenated at room temperature overnight at 1 atmosphere. The mixture was then filtered through a plug of arbocel®, washing the plug with ethanol and the combined filtrates and washings were evaporated to a pale yellow solid.
  • the morpholine ring may be formed by the following conditions to provide a mixture of diastereoisomers " :
  • Example 7b 5-[(5S)-5-Methylmorpholin-2-yl]pyridin-2-amine (diastereomer mixture)
  • the diastereoisomers were separated by HPLC on a Chiralcel AD-H column with a mobile phase of methanokethanol 50:50 and a flow rate of 15ml/min
  • the sample of mixed diastereoisomers was subjected HPLC using a Chiralcel OD-H column, mobile phase was 30:70 IPA Hexane with diethylamine 0.1%, at a flow rate of 20mL/min.
  • This boc-protected morpholine (3.6 g, 9 mmol) was treated with 4M HCl in dioxane (30 mL) and the mixture stirred at room temperature for 4 h. The solvent was then evaporated and the residue treated with 2M sodium hydroxide (100 mL) and extracted with dichloromethane (4 x 100 mL).
  • the diol from preparation 21 (950 mg, 3.7 mmol) was dissolved in dichloromethane (15 mL) and treated with concentrated sulfuric acid (7 mL) at room temperature and the mixture stirred for a further 2 h. The reaction was then quenched the addition of ice, then basified by the dropwise addition of 880 NH 3 until the pH -9. The mixture was then extracted with dichloromethane (4 x 50 mL) and the combined organics dried with magnesium sulfate, filtered and evaporated to provide the title compound as a pale brown oil (700 mg, 79%)
  • racemic morpholine was subjected to HPLC using a Chiralcel OD-H column eluting with acetonitrile. This afforded the two enantiomers.
  • the diol from preparation 29 (200 mg, 0.74 mmol) was dissolved in dichloromethane (4 mL) and treated with concentrated sulfuric acid (2 mL) at room temperature and the mixture stirred for a further 2 h. The reaction was then quenched the cautious addition of water, then basified by the dropwise addition of 880 NH 3 until the pH -9. The mixture was then extracted with dichloromethane (3 x 70 mL) and the combined organics dried with magnesium sulfate, filtered and evaporated.
  • the diol from preparation 24(990mg, 3.9 mmol) was dissolved in dichloromethane (10 mL) and treated with concentrated sulfuric acid at room temperature. The mixture was left stirring for 2 h before being quenched by the addition of ice and the basified by the addition of 880 NH 3 to pH -9. The mixture was then extracted with dichloromethane (3 x 150 mL), the combined organics dried over magnesium sulfate, filtered and the solvents evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/ methanol/ 880 NH 3 (95:5:0.5) to provide the title compound as a mixture of diastereoisomers (470 mg, 51%).
  • the aminopyridine imine from preparation 35 (95mg, 0.267mmol, 1.0eq) was dissolved in EtOH (2ml), 10% Pd/C (10mg) and ammonium formate (168mg, 2.67mmol, 10eq) was added and the mixture heated to a gentle reflux for 3h. Further 10% Pd/C (10mg) and ammonium formate (168mg, 2.67mmol, 10eq) added and the mixture heated to reflux for 48h. The catalyst was filtered off through arbocel, and washed with EtOH. The filtrate was evaporated in vacuo to give a colourless oil. This material was dissolved in THF (5ml), 2M HCl (aq) added and stirred at r.t.
  • the morpholine from preparation 38 (1g, 4.17mmol) was dissolved in CH CI 2 (15ml) and concentrated sulfuric acid (7.5ml) was added. The mixture was stirred at r.t. for 2h, basified by cautious addition of 0.880 NH 3 , and extracted with CH 2 CI 2 (2x200ml), the organics combined, dried over magnesium sulphate, filtered and purified by flash chromatography on silica gel eluting with CH 2 CI 2 :MeOH:NH OH 97:3:1 to give the title compound as a light brown oil (560mg 61%).
  • 2,5-hexanedione (46.2 g, 0.41 mol) was added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 I0 mol) and the reaction heated to reflux for 24 hours under Dean and Stark conditions.
  • para-Toluenesulfonic acid (100 mg) was added and the reaction was refluxed for a further 18 hours. 8 mL of water was removed, so the reaction was cooled to room temperature, washed with water (100 mL) and passed through a plug of silica gel, eluting with toluene.
  • the diol from preparation 8 (5 g, 17.2 mmol) was dissolved in dichloromethane (60 mL) and treated with benzyl chloroformate (2.72 mL, 19 mmol) and triethylamine (2.65mL, 19 mmol). The mixture was stirred overnight (-16 h) before being quenched by the addition of 2M sodium hydroxide (100 mL). The mixture was extracted with dichloromethane (2 x 100 mL) and the combined organic fractions dried (MgS0 ), filtered and evaporated.
  • Morpholine from preparation 9 (680 mg, 1. mmol) was dissolved in ethanol (12 mL) and treated with hydroxylamine hydrochloride (600 mg, 8.4 mmol) and the mixture heated at 80 °C overnight (-16 h). After cooling to room temperature the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane in methanol 0% increasing polarity to 2% to provide the title compound as a purple coloured oil (410 mg, 95%).
  • the crude diol from preparation 12 (10g, ⁇ 25mmol) was dissolved in dichloromethane (150 mL) and treated with di-fert-butyl dicarbonate (5.52 g, 25 mmol) and the mixture stirred at room temperature overnight (-16 h).
  • the reaction mixture was diluted with 10% aqueous K 2 C0 3 solution (200 mL), the organic layer separated and the aqueous layer extracted with dichloromethane (2 x 300 mL). The combined organic, fractions were dried over magnesium sulfate, filtered and evaporated.
  • the diol from preparation 13 (6.2 g, 12.5 mmol) was dissolved in toluene (100 mL) and treated with triphenylphosphine (4 g, 15 mmol) at room temperature.
  • Diisopropylazodicarboxylate (DIAD) (3 mL, 15 mmol) was added dropwise and the mixture allowed to stir overnight (-16 h).
  • the reaction mixture was then diluted with water (200 mL), the organic layer separated and the aqueous layer extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and
  • the morpholinol from preparation 19 (1.95 g, 5.9 mmol) was dissolved in ethanol (25 mL) and water (10 mL) and sodium borohydride (900 mg, 23.6 mmol) was added to the stirred mixture at room temperature. Stirring was maintained overnight (-16 h) before the reaction was quenched by the addition of saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethane (2 x 100 mL). Tfie combined organic fractions were dried over magnesium sulfate, filtered and evaporated.
  • the diol from preparation 20 (1.4 g, 4.22 mmol) was dissolved in ethanol (30 mL) and treated with hydroxylamine hydrochlonde (1.12 g, 16.9 mmol), and the mixture heated to reflux over night (-16 h).
  • the diol from preparation 22 was dissolved in dichloromethane (50 mL) and treated with ethanal (166mL, 29.6 mmol) and NaBH(OAc) 3 (6.3 g, 29.6 mmol) and the mixture stirred at room temperature over night (-16 h).
  • the diol from preparation 23 (142 g, 4.3 mmol) was dissolved in ethanol (50 mL) and treated with hydroxylamine hydrochloride (1.5 g, 21.4 mmol) and the mixture heated to 80 °C overnight (-16 h). After cooling to room temperature, the solvents were evaporated and the residue purified by flash chromatography on silica gel eluting with dichloromethane/ methanol/ 880 NH 3 (919:0.5) to afford the title compound as a light brown oil (990 mg, 91 %).
  • morpholinone from preparation 26 (1.5 g, 9.4 mmol) was added as a solution in THF (10 mL) and the reaction mixture left stirring at -78 °C for 1 h. The reaction was then quenched by the addition of saturated aqueous NH 4 CI solution (100 mL) then extracted with ethyl acetate (80 mL). The organic fraction was dried over magnesium sulphate, filtered and evaporated.
  • the morpholinol from preparation 27 (600 mg, 1.7 mmol) was dissolved in ethanol (6 mL) and water (3 mL) and sodium borohydride (270 mg, 7 mmol) was added to the stirred mixture at room temperature. Stirring was maintained overnight (-16 h) before the reaction was quenched by the addition of saturated aqueous ammonium chloride (100 mL) the basified to pH -9 with 2M NaOH solution and extracted with dichloromethane (2 x 200 mL).
  • the diol from preparation 28 (420 mg, 1.5 mmol) was dissolved in propanol (5 mL) and water (1.5 mL) treated with hydroxylamine hydrochloride (2.2 g, 31.4 mmol) and triethylamine (2.2 mL, 15.7 mmol), and the mixture heated to reflux for 12 h.
  • the diol from preparation 30 (900 mg, 2.6 mmol) was dissolved in ethanol (15 mL) and treated with hydroxylamine hydrochloride (905 mg, 13 mmol) and the mixture heated to 80 ° overnight (-16 h). After cooling to room temperature, the solvents were evaporated and the residue pre-absorbed onto silica gel and purified by flash chromatography on silica gel eluting with a gradient of dichloromethane/ methanol/ 880 NH 3 (95:5:0.5 to 92:8:0.5) to afford the title compound as a light brown oil (330 mg)
  • Zinc dust (127mg, 1.94mmol, 1.1 eq) was dried for 18h at 100°C in vacuo, transferred to a round bottomed flask and heated with a hot air gun under vacuum. The flask was allowed to cool to room temperature and DMF (2ml) and 1 ,2-dibromoethane (12 ⁇ l, 0.141 mmol, 0.08eq) added. The mixture was heated to 70°C for 10 mins, allowed to cool to r.t, and TMSCI (18 ⁇ l, 0.141 mmol, 0.08eq) added dropwise. This mixture was stirred at r.t.
  • 5-Azetidin-3-yl-2-chloropyridine dihydrochloride (131 mg, 0.542mmol LOeq) was partitioned between CH 2 CI 2 (10ml) and K 2 C0 3 (10ml, 10% w/v aq), the layers separated, and the aqueous layer re-extracted with CH 2 CI 2 (10ml). The organic layers were combined, dried (MgS0 4 ), filtered and evaporated to ca 2ml volume. Propionaldehyde (79 ⁇ l, 1084mmol, 2.0eq) and sodium triacetoxyborohydride (230mg, 1084mmol, 2.0eq) were added and the mixture stirred at r.t. for 2.5h.
  • This oil was purified by flash chromatography on silica gel eluting with a gradient on 100% CH 2 CI 2 to 95:5:0.5 CH 2 CI 2 :MeOH:NH 4 OH to give the title compound as a yellow oil (110mg, 66%)
  • the diol from preparation 37 (1.5 g, 5.2 mmol) was dissolved in dichloromethane (25 mL) and treated with acetaldehyde (870 ⁇ L, 15.5 mmol) and sodium triacetoxyborohydride (3.3 g, 15.5 mmol) and the reaction mixture left stirring at room temperature overnight (-16 h).
  • the reaction mixture was diluted with saturated ammonium chloride solution then basified by the addition of 10% aqueous K 2 C0 3 solution, and then extracted with dichloromethane (2 x 150 mL). The combined organics were dried (MgS0 4 ), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol.
  • Ethanolamine (0.24mL, 4 mmol) was added dropwise to a solution of borane.tetrahydrofuran complex (1M solution in tetrahydrofuran, 8 mL, 8 mmol) in tetrahydrofuran (5 mL) cooled to 0 °C over 15 minutes.
  • the mixture was allowed reach room temperature then the chloride from preparation 2 (1 g, 4 mmol) in tetrahydrofuran was added dropwise to the stirred solution.
  • the reaction mixture was then stirred at room temperature for 30 minutes then quenched by the addition of 2M sodium hydroxide (10 mL) and the reaction mixture stirred for a further 1 hour.

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Abstract

Cette invention concerne des composés représentés par la formule (I), qui font partie d'une classe d'agonistes de la dopamine et, plus particulièrement, d'une classe d'agonistes sélectifs pour la dopamine D3 sur D2. Ces composés sont utiles pour le traitement et/ou la prévention des dysfonctionnements sexuels, tels que les dysfonctionnements sexuels chez la femme (FSD), notamment le trouble de l'excitation sexuelle chez la femme (FSAD), la baisse du désir sexuel (HSDD), le trouble orgasmique chez la femme (FOD ; incapacité d'atteindre l'orgasme) ; et les dysfonctionnements sexuels chez l'homme, notamment le trouble de l'érection (MED). Les dysfonctionnements sexuels chez l'homme font référence notamment aux troubles de l'éjaculation, tels que l'éjaculation précoce, l'anorgasmie (incapacité d'atteindre l'orgasme) ou les troubles du désir, tels que la baisse du désir sexuel (HSDD). Ces composés sont également utiles pour traiter les troubles neuropsychiatriques et les troubles neurodégénératifs.
PCT/IB2005/001554 2004-05-27 2005-05-17 Derives d'aminopyridine utilises comme agonistes selectifs de la dopamine d3 WO2005115985A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EA200601982A EA200601982A1 (ru) 2004-05-27 2005-05-17 Производные аминопиридина в качестве селективных агонистов d3 - дофаминовых рецепторов
AP2006003824A AP2006003824A0 (en) 2004-05-27 2005-05-17 Aminopyridine derivatives as selective dopamine D3agonists
MXPA06013786A MXPA06013786A (es) 2004-05-27 2005-05-17 Nuevos derivados de aminopiridina y su uso como farmacos.
AU2005247699A AU2005247699A1 (en) 2004-05-27 2005-05-17 Aminopyridine derivatives as selective dopamine D3 agonists
EP05747191A EP1758862A1 (fr) 2004-05-27 2005-05-17 Derives d'aminopyridine utilises comme agonistes selectifs de la dopamine d3
CA002567935A CA2567935C (fr) 2004-05-27 2005-05-17 Derives d'aminopyridine utilises comme agonistes selectifs de la dopamine d3
JP2007514200A JP4198183B2 (ja) 2004-05-27 2005-05-17 選択的ドーパミンｄ３アゴニストとしてのアミノピリジン誘導体
BRPI0511571-0A BRPI0511571A (pt) 2004-05-27 2005-05-17 derivados de aminopiridina como agonistas de dopamina d3 seletivos
IL179314A IL179314A0 (en) 2004-05-27 2006-11-15 Aminopyridine derivatives as selective dopamine d3 agonists
NO20065326A NO20065326L (no) 2004-05-27 2006-11-20 Aminopyridin-derivater som selektive dopamin D3 agonister
TNP2006000387A TNSN06387A1 (fr) 2004-05-27 2006-11-24 Derives d'aminopyridine utiles comme agonistes de dopamine d3 selectifs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0411891.5 2004-05-27
GB0411891A GB0411891D0 (en) 2004-05-27 2004-05-27 New aminopyridine derivatives and their use as pharmaceuticals
GB0412463A GB0412463D0 (en) 2004-06-03 2004-06-03 New aminopyridine derivatives and their use as pharmaceuticals
GB0412463.2 2004-06-03

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AR (1) AR049548A1 (fr)
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BR (1) BRPI0511571A (fr)
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EA (1) EA200601982A1 (fr)
EC (1) ECSP067029A (fr)
GT (1) GT200500125A (fr)
IL (1) IL179314A0 (fr)
MA (1) MA28607B1 (fr)
MX (1) MXPA06013786A (fr)
NL (1) NL1029139C2 (fr)
NO (1) NO20065326L (fr)
PA (1) PA8635101A1 (fr)
PE (1) PE20060366A1 (fr)
SV (1) SV2005002129A (fr)
TW (1) TW200609216A (fr)
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Cited By (8)

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WO2006082511A1 (fr) * 2005-02-07 2006-08-10 Pfizer Limited Nouvelle forme de sel d'un agoniste de la dopamine
WO2010091808A1 (fr) * 2009-02-13 2010-08-19 Bayer Schering Pharma Aktiengesellschaft Pyrimidines condensées
WO2013003769A2 (fr) 2011-06-30 2013-01-03 Donaldson Company, Inc. Ensembles séparateurs air/huile, composants et procédés
WO2017064488A1 (fr) * 2015-10-13 2017-04-20 Indivior Uk Limited Antagonistes du récepteur d3 de la dopamine ayant un fragment morpholine
WO2020210785A1 (fr) * 2019-04-12 2020-10-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composés agonistes du récepteur d3; procédés de préparation; intermédiaires de ceux-ci; et leurs procédés d'utilisation
US10947218B2 (en) 2016-07-20 2021-03-16 Novartis Ag Aminopyridine derivatives and their use as selective ALK-2 inhibitors
US11723899B2 (en) 2020-06-16 2023-08-15 Incyte Corporation ALK2 inhibitors for the treatment of anemia
US11738026B2 (en) 2019-11-22 2023-08-29 Incyte Corporation Combination therapy comprising an ALK2 inhibitor and a JAK2 inhibitor

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2012011821A (es) * 2010-04-12 2012-11-30 Supernus Pharmaceuticals Inc Metodos para producir sales de viloxazina y polimorfos novedosos de las mismas.

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US5077290A (en) * 1990-10-11 1991-12-31 Merck & Co., Inc. Morpholine derivatives compositions and use
WO2003051370A1 (fr) * 2001-12-18 2003-06-26 Pfizer Limited Agonistes selectifs du recepteur de la dopamine d3 pour traiter les troubles d'ordre sexuel
WO2004052372A1 (fr) * 2002-12-10 2004-06-24 Pfizer Limited Derives de morpholine destines a etre utilises comme agonistes de la dopamine dans le traitement de la dysfonction sexuelle i.a.

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Publication number Priority date Publication date Assignee Title
US5077290A (en) * 1990-10-11 1991-12-31 Merck & Co., Inc. Morpholine derivatives compositions and use
WO2003051370A1 (fr) * 2001-12-18 2003-06-26 Pfizer Limited Agonistes selectifs du recepteur de la dopamine d3 pour traiter les troubles d'ordre sexuel
WO2004052372A1 (fr) * 2002-12-10 2004-06-24 Pfizer Limited Derives de morpholine destines a etre utilises comme agonistes de la dopamine dans le traitement de la dysfonction sexuelle i.a.

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101115737B (zh) * 2005-02-07 2010-12-01 辉瑞有限公司 多巴胺激动剂的盐类形式
US7498329B2 (en) 2005-02-07 2009-03-03 Pfizer Inc. Salt form of dopamine agonist
WO2006082511A1 (fr) * 2005-02-07 2006-08-10 Pfizer Limited Nouvelle forme de sel d'un agoniste de la dopamine
US8957064B2 (en) 2009-02-13 2015-02-17 Bayer Intellectual Property Gmbh Fused pyrimidines
CN102317291B (zh) * 2009-02-13 2015-02-11 拜耳知识产权有限责任公司 稠合嘧啶
WO2010091808A1 (fr) * 2009-02-13 2010-08-19 Bayer Schering Pharma Aktiengesellschaft Pyrimidines condensées
WO2013003769A2 (fr) 2011-06-30 2013-01-03 Donaldson Company, Inc. Ensembles séparateurs air/huile, composants et procédés
WO2017064488A1 (fr) * 2015-10-13 2017-04-20 Indivior Uk Limited Antagonistes du récepteur d3 de la dopamine ayant un fragment morpholine
US10577361B2 (en) 2015-10-13 2020-03-03 Indivior Uk Limited Dopamine D3 receptor antagonists having a morpholine moiety
AU2016338992B2 (en) * 2015-10-13 2020-10-08 Indivior Uk Limited Dopamine D3 receptor antagonists having a morpholine moiety
US10947218B2 (en) 2016-07-20 2021-03-16 Novartis Ag Aminopyridine derivatives and their use as selective ALK-2 inhibitors
WO2020210785A1 (fr) * 2019-04-12 2020-10-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Composés agonistes du récepteur d3; procédés de préparation; intermédiaires de ceux-ci; et leurs procédés d'utilisation
US11738026B2 (en) 2019-11-22 2023-08-29 Incyte Corporation Combination therapy comprising an ALK2 inhibitor and a JAK2 inhibitor
US11723899B2 (en) 2020-06-16 2023-08-15 Incyte Corporation ALK2 inhibitors for the treatment of anemia

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AP2006003824A0 (en) 2006-12-31
NL1029139C2 (nl) 2006-06-19
EP1758862A1 (fr) 2007-03-07
ECSP067029A (es) 2006-12-29
PA8635101A1 (es) 2006-05-16
SV2005002129A (es) 2005-12-13
CA2567935A1 (fr) 2005-12-08
BRPI0511571A (pt) 2008-01-02
MXPA06013786A (es) 2007-01-25
AU2005247699A1 (en) 2005-12-08
JP4198183B2 (ja) 2008-12-17
IL179314A0 (en) 2007-03-08
TW200609216A (en) 2006-03-16
UY28925A1 (es) 2005-12-30
NO20065326L (no) 2006-12-19
JP2008500331A (ja) 2008-01-10
GT200500125A (es) 2006-01-10
NL1029139A1 (nl) 2005-11-30
AR049548A1 (es) 2006-08-16
MA28607B1 (fr) 2007-05-02
PE20060366A1 (es) 2006-05-15
CA2567935C (fr) 2009-10-27
EA200601982A1 (ru) 2007-04-27

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