WO2013179049A1 - Spiro derivatives as voltage - gated sodium channel modulators - Google Patents

Spiro derivatives as voltage - gated sodium channel modulators Download PDF

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WO2013179049A1
WO2013179049A1 PCT/GB2013/051446 GB2013051446W WO2013179049A1 WO 2013179049 A1 WO2013179049 A1 WO 2013179049A1 GB 2013051446 W GB2013051446 W GB 2013051446W WO 2013179049 A1 WO2013179049 A1 WO 2013179049A1
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methyl
nonan
compound
phenyl
diazaspiro
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PCT/GB2013/051446
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French (fr)
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Gerard M P GIBLIN
David R Witty
David T Macpherson
Steven J STANWAY
Antoinette Wilson
Laura Gleave
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Convergence Pharmaceuticals Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the invention relates to spiro derivatives, to the use of said derivatives in treating diseases and conditions mediated by modulation of voltage-gated sodium channels, to compositions containing said derivatives and processes for their preparation.
  • Voltage-gated sodium channels are responsible for the initial phase of the action potential, which is a wave of electrical depolarisation usually initiated at the soma of the neuron and propagated along the nerve axon to the terminals. At the terminals, the action potential triggers the influx of calcium and the release of neurotransmitter.
  • Drugs such as lidocaine
  • Other sodium channel blockers such as lamotrigine and carbamazepine are used to treat epilepsy. In the latter case, partial inhibition of voltage-gated sodium channels reduces neuronal excitability and reduces seizure propagation.
  • the voltage-gated sodium channel family is made up of 10 subtypes, four of which are brain specific, NaV1.1 , 1.2, 1.3 and 1.6. Of the other subtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific to cardiac muscle, and NaV1.7, 1.8, and 1.9 are found predominantly in sensory neurons.
  • the hypothesised binding site for state-dependent sodium channel blockers is highly conserved between all the subtypes. As a result, drugs such as lidocaine, lamotrigine and carbamazepine do not distinguish between the subtypes. However, selectivity can be achieved as a result of the different frequencies at which the channels normally operate.
  • Drugs that block voltage-gated sodium channels in a state-dependent manner are also used in the treatment of bipolar disorder, either to reduce symptoms of mania or depression, or as mood stabilisers to prevent the emergence of mood episodes.
  • Clinical and preclinical evidence also suggests that state-dependent sodium channel blockers may help to reduce the symptoms of schizophrenia.
  • lamotrigine has been shown to reduce symptoms of psychosis induced by ketamine in healthy human volunteers, and furthermore, studies in patients suggest that the drug can augment the antipsychotic efficacy of some atypical antipsychotic drugs, such as clozapine or olanzapine. It is hypothesised that efficacy in these psychiatric disorders may result in part from a reduction of excessive glutamate release. The reduction in glutamate release is thought to be a consequence of state- dependent sodium channel inhibition in key brain areas, such as the frontal cortex. However, interaction with voltage-gated calcium channels may also contribute to the efficacy of these drugs.
  • WO 2007/042240 (Glaxo Group Limited) describes a series of quaternary alpha- aminocarboxamide derivatives as modulators of voltage-gated sodium channels.
  • the object of the invention is to identify alternative compounds which modulate
  • the invention provides a compound of formula (I) or a
  • Ring A represents a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring
  • n represents an integer selected from 1 to 4; each R 1 independently represents Ci_ 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, halogen, haloCi_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkoxy, -Z-phenyl, -Z-Het, -CN, -NR 6 R 7 , wherein said Het group represents a 5- or 6-membered aromatic heterocyclic ring or a 4- to 7-membered non- aromatic heterocyclic ring, wherein said phenyl or Het group of R 1 may be optionally substituted by one or more (e.g.
  • R 1 groups represent no more than one -Z-phenyl or one -Z-Het group
  • Z represents a bond or a linker selected from -0-, -CH 2 -, -CH 2 -0- or -0-CH 2 ;
  • R 6 and R 7 independently represent hydrogen or Ci_ 6 alkyl or R 6 and R 7 together with the nitrogen atom to which they are attached join to form a 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring;
  • R 8 represents Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, halogen, haloCi_ 6 alkyl, Ci_ 6 alkoxy, haloCi.
  • n an integer selected from 0 to 4.
  • each R 2 independently represents Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, halogen, haloCi_ 6 alkyl, Ci -6 alkoxy, haloCi. 6 alkoxy, -CN or -NR 6 R 7 ;
  • R 3 represents hydrogen or Ci_ 6 alkyl
  • R 4 represents hydrogen or Ci_ 6 alkyl
  • each R 5 independently represents Ci_ 3 alkyl
  • Y represents -CH 2 - or -(CH 2 ) 2 -;
  • p represents an integer from 0 to 3.
  • 'halo' or 'halogen' refers to fluorine, chlorine, bromine or iodine.
  • 'Ci. 3 alkyl' refers to a linear or branched saturated hydrocarbon group containing from 1 to 3 carbon atoms.
  • 'Ci_ 6 alkyl' refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • 'C 2 . 6 alkenyl' as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond.
  • 'C 2 - 6 alkynyr as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 6 carbon atoms and containing a carbon carbon triple bond.
  • Ci -6 alkoxy' refers to an -0-Ci. 6 alkyl group wherein Ci -6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.
  • 'haloCi. 6 alkyr refers to a Ci -6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi. 6 alkyr therefore includes monohaloCi. 6 alkyl and also polyhaloCi. 6 alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi. 6 alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
  • 'haloCi. 6 alkoxy' as used herein as a group or part of a group refers to a -O-C1. 6 alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen.
  • the term 'haloCi. 6 alkoxy' therefore includes monohaloCi. 6 alkoxy, and also polyhaloCi. 6 alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi. 6 alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
  • 5- or 6-membered aromatic heterocyclic ring means a heterocyclyl group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring.
  • five membered aromatic heterocyclic groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • six membered aromatic heterocyclic groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • non-aromatic heterocyclic ring means a heterocyclyl group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring.
  • non-aromatic embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems.
  • the term "fully saturated” refers to rings where there are no multiple bonds between ring atoms.
  • Particular examples include morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g.
  • preferred non-aromatic heterocyclyl groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N- alkyl piperazines.
  • nitrogen containing non-aromatic heterocyclic ring means a non- aromatic heterocyclyl ring as defined herein wherein the ring must contain at least one ring nitrogen atom.
  • nitrogen-containing non-aromatic heterocyclyl groups include aziridine, morpholine, thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • Ring A represents a phenyl ring. In an alternative embodiment, Ring A represents a 5- or 6-membered aromatic heterocyclic ring. In a further embodiment, Ring A represents a 5-membered aromatic heterocyclic ring such as pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole or tetrazole. In a yet further embodiment, Ring A represents thienyl. In an alternative embodiment, Ring A represents a 6-membered aromatic
  • Ring A represents pyridine or pyrimidine.
  • n represents an integer selected from 1 to 3. In a further embodiment, n represents an integer selected from 1 to 2. In one embodiment, n represents 1. In an alternative embodiment, n represents 2.
  • R 1 independently represents Ci_ 6 alkyl (such as methyl, ethyl or isopropyl), halogen (such as fluorine or chlorine), haloCi_ 6 alkyl (such as CF 3 ), Ci_ 6 alkoxy (such as -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -0-CH(Me) 2 or -0-CH 2 -CH(Me) 2 ), halod-e alkoxy (such as -0-CF 3 , -OCHF 2 or -CH 2 -0-CF 3 ), -Z-aryl (such as -O-phenyl, -0-CH 2 - phenyl or -CH 2 -0-phenyl), -Z-Het or -NR 6 R 7 (such as -N(Me) 2 ) wherein said phenyl groups are optionally substituted by one or more (e.g. 1 , 2
  • R 1 independently represents d-e alkyl (such as methyl, ethyl or isopropyl), halogen (such as fluorine or chlorine), halod-6 alkyl (such as CF 3 ), d-e alkoxy (such as -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -0-CH(Me) 2 or -0-CH 2 -CH(Me) 2 ), halod-e alkoxy (such as -0-CF 3 or -CH 2 -0-CF 3 ), -Z-aryl (such as -O-phenyl, -0-CH 2 -phenyl or - CH 2 -0-phenyl), -NR 6 R 7 (such as -N(Me) 2 ) wherein said phenyl groups are optionally substituted by one or more (e.g. 1 , 2 or 3) R 8 groups such as halogen (e
  • Z represents -0-, -CH 2 -0- or -0-CH 2 .
  • R 6 and R 7 independently represent hydrogen or methyl. In a further embodiment, R 6 and R 7 both represent methyl.
  • R 8 represents halogen (e.g. fluorine or chlorine) or halod-6 alkoxy (e.g. -0-CF 3 ).
  • R 8 represents halogen (e.g. fluorine) or halod-6 alkoxy (e.g. -0-CF 3 ).
  • m represents an integer selected from 0 to 3. In a further embodiment, m represents an integer selected from 0 to 2. In a further embodiment, m represents an integer selected from 0 or 1. In one embodiment, m represents 1. In an alternative embodiment, m represents 0.
  • R 2 independently represents Ci_ 6 alkyl, halogen, haloCi_ 6 alkyl, d -6 alkoxy or haloCi_ 6 alkoxy. In a further embodiment, R 2 independently represents halogen (such as chlorine or fluorine).
  • R 3 represents hydrogen, methyl or ethyl. In a further embodiment, R 3 represents hydrogen or ethyl.
  • R 4 represents hydrogen, methyl or ethyl.
  • R 5 independently represents Ci_ 3 alkyl (such as methyl). In one embodiment, p represents 0 or 1. In one embodiment, p represents 0. In an alternative embodiment, p represents 1. For the avoidance of doubt it should be stated that R 5 may be present at any position on either of the spiro rings.
  • Y represents -CH 2 -. In an alternative embodiment, Y represents - (CH 2 ) 2 -.
  • the compound of formula (I) is:
  • a reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • a-oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • salts consist of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic,
  • naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids is the hydrochloride salt.
  • the compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.
  • the salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • solvates For example, a complex with water is known as a "hydrate”.
  • Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • the invention provides compounds of formula (la)
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, A, X and Y are as defined herein for compounds of formula (I).
  • the invention provides compounds of formula (lb)
  • the invention provides compounds of formula (lc)
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, A, X and Y are as defined herein for compounds of formula (I).
  • the invention rovides compounds of formula (Id)
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, A, X and Y are as defined herein for compounds of formula (I).
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. 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 usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), 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, 125 l and 131 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 sulfur, such as 35 S.
  • hydrogen such as 2 H (D) and 3 H (T)
  • 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, 125 l and 131 l
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P
  • sulfur 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 compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), 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 (D), 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 reagents in place of the non-labeled reagent previously employed.
  • Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the
  • R is an ester substituent, for example, a Ci -7 alkyl group, a C3.12
  • phosphate esters are those derived from phosphoric acid.
  • formula (I) includes within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group.
  • R 2 , R 3 , R 4 , R 5 , m, p, X and Y are as defined herein for compounds of formula (I) and L 1 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S0 2 CF 3 group, with a boronic acid derivative or an aryl-tin derivative of a compound of formula A-(R 1 ) n , wherein A, n and R 1 are as defined herein for compounds of formula (I);
  • a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S0 2 CF 3 group, with a boronic acid derivative or an aryl-tin derivative of a compound of formula A-(R 1 ) n , wherein A, n and R 1 are as defined herein for compounds of formula (I);
  • R 2 , R 3 , R 4 , R 5 , m, p, X and Y are as defined herein for compounds of formula (I), with a compound of formula L 2 -A-(R 1 ) n , wherein A, n and R 1 are as defined herein for compounds of formula (I) and L 2 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S0 2 -CF 3 group;
  • Process (a) typically comprises the use of sodium borohydride in a suitable solvent such as methanol modified by a suitable catalyst such as cobalt chloride.
  • Process (a) may alternatively comprise hydrogenation over a Rainey Nickel catalyst followed by heating in a suitable solvent such as methanol.
  • process (b) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst such as a Palladium catalyst and a suitable base such as potassium carbonate in a suitable solvent such as aqueous 1 ,4-dioxane.
  • a suitable catalyst such as a Palladium catalyst and a suitable base such as potassium carbonate in a suitable solvent such as aqueous 1 ,4-dioxane.
  • process (b) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst such as a palladium tetrakis triphenylphosphine and a suitable base. It is recognised that alternative aryl coupling protocols can be used in place of a Suzuki reaction, for example a Stille coupling.
  • Process (c) typically comprises the Suzuki coupling reaction of a compound of formula (IV) with a compound of formula L 2 -A-(R 1 ) n in the presence of a palladium catalyst such as palladium tetrakis triphenylphosphine in a suitable solvent such as aqueous 1 ,4-dioxane in the presence of a suitable base such as potassium carbonate.
  • a palladium catalyst such as palladium tetrakis triphenylphosphine
  • a suitable solvent such as aqueous 1 ,4-dioxane
  • a suitable base such as potassium carbonate
  • L 3 and L 4 independently represent suitable leaving groups such as a halogen atom (e.g. bromine) or an -O-SO2-CF 3 group and P 1 and P 2 independently represent suitable protecting groups such as Boc.
  • Step (i) typically comprises a Sonigashira coupling catalysed by copper iodide in the presence of palladium tetrakistriphenylphosphine in a solvent system such as toluene and isopropylamine.
  • Step (ii) typically comprises an acid catalysed deprotection reaction catalysed for example by trifluoroacetic acid in a solvent such as dichloromethane.
  • Step (iii) typically comprises a ring closure reaction catalysed by a Lewis acid such as silver triflate in a solvent such as acetonitrile.
  • Step (iv) typically comprises a reduction, for example hydrogenation, over platinum on charcoal in a solvent such as methanol in the presence of an acid modifier such as trifluoroacetic acid.
  • step (v) typically comprises treatment with Boc anhydride in a solvent such as dichloromethane.
  • Step (vi) typically comprises a biaryl coupling such as a Suzuki coupling with a boronic acid derivative of a compound of formula A-(R 1 ) n catalysed by for example palladium
  • tetrakistriphenylphosphine in a solvent system comprising for example 1 ,4-dioxane and water and in the presence of a base such as sodium carbonate.
  • Step (vii) typically comprises deprotonation alpha to the carbonyl group using a hindered base such as lithium hexamethyldisilazide in a solvent such as THF at low temperature, followed by alkylation with bromoacetonitrile.
  • a hindered base such as lithium hexamethyldisilazide
  • a solvent such as THF at low temperature
  • Compounds of formula (II) may be prepared from compounds of formula (ll) p by a suitable deprotection reaction.
  • P 2 represents Boc
  • such deprotection suitably comprises treatment with an acid calalyst such as trifluoroacetic acid in a solvent such as dichloromethane.
  • R 2 , R 4 , m, X and Y are as defined herein for compounds of formula (I) and P 3 represents a suitable protecting group such as Boc.
  • Step (i) typically comprises coupling of a protected phenol carboxaldehyde such as tert- butyldimethylsilyloxybenzene-3-carbaldehyde with a Boc protected 2-amino-N- alkylpyrrolidinone following treatment by sequential treatment with acid and base catalysts in solvents such as dichloromethane and toluene.
  • a protected phenol carboxaldehyde such as tert- butyldimethylsilyloxybenzene-3-carbaldehyde
  • a Boc protected 2-amino-N- alkylpyrrolidinone following treatment by sequential treatment with acid and base catalysts in solvents such as dichloromethane and toluene.
  • Step (ii) typically comprises a 3+2 cycloaddition reaction of the imine with phenyl vinyl sulfone which can typically be effected in the presence of a strong base such as DBU and a transition metal catalyst such as tetrakis(acetonitrile)copper(l) hexafluorophosphate in the presence of an asymmetric copper ligand.
  • a strong base such as DBU
  • a transition metal catalyst such as tetrakis(acetonitrile)copper(l) hexafluorophosphate
  • Step (iii) typically comprises elimination of the resultant bicyclic sulfone to afford the corresponding deprotected phenyl imine, which can be achieved by treatment with a strong base such as potassium tert-butoxide in a solvent such as methyl-THF.
  • Step (iv) typically comprises reduction of the imine which can be achieved using catalytic hydrogenation over a platinum catalyst in a solvent such as acetic acid.
  • Step (v) typically comprises conversion of the phenol to the corresponding
  • trifluoromethanesulfonate ester by treatment with 1 , 1 , 1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methane sulphonamide in a solvent such as dichloromethane in the presence of an organic base such as triethylamine.
  • R 2 , R 4 , m, X and Y are as defined herein for compounds of formula (I).
  • Step (i) typically comprises condensation of an optionally substituted 2-aminopyrrolidinone with an aryl bromo-3-carboxaldehyde in the presence of a dehydrating agent such as magnesium sulfate in a solvent such as dichloromethane.
  • a dehydrating agent such as magnesium sulfate in a solvent such as dichloromethane.
  • Step (ii) typically comprises a 3+2 cycloaddition reaction with phenyl vinyl sulfone catalysed by a transition metal salt such as a silver or copper salt, in the presence of base and optionally a chiral phosphine ligand such as 1-(di(1-naphthenyl)phosphinyl)-2-((4S)-4- (propan-2-yl)-4,5-dihydro-1 ,3-oxazolyl)-ferrocene.
  • a transition metal salt such as a silver or copper salt
  • Step (iii) typically comprises elimination of the phenyl sulfone with a strong base such as potassium tert-butoxide.
  • Step (iv) typically comprises reduction of the imine using a hydride donor such as sodium borohydride in the presence of acid.
  • R 2 , R 4 , m, X and Y are as defined herein for compounds of formula (I) and L 5 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S0 2 - CF 3 group.
  • a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S0 2 - CF 3 group.
  • Step (i) typically comprises reacting a compound of formula (I I l) b with pinacolborane in the presence of a palladium catalyst in a solvent such as toluene.
  • R 1 , n, A, R 2 , m, R 4 , X and Y are as defined herein for compounds of formula (I).
  • Step (i) typically comprises reacting a compound of formula (XIX) with a 3-bromoph ketone in a solvent such as toluene in the presence of a dehydrating agent such as molecular sieves.
  • Step (ii) typically comprises a 3+2 cycloaddition reaction with phenyl vinyl sulfone in the presence of a strong base such as potassium fe butoxide in a solvent such as THF.
  • Step (iii) typically comprises a biaryl coupling such as a Suzuki coupling with a boronic acid catalysed by, for example, palladium ditriphenylphosphine dichloride in a solvent system comprising, for example, dimethoxyethane and water and in the presence of a base such as sodium carbonate.
  • a biaryl coupling such as a Suzuki coupling with a boronic acid catalysed by, for example, palladium ditriphenylphosphine dichloride in a solvent system comprising, for example, dimethoxyethane and water and in the presence of a base such as sodium carbonate.
  • Step (iv) typically comprises the reductive elimination of the phenylsulfonyl group by reaction with an electron donor agent such as sodium amalgam in a mixture of an organic solvent such as THF and a buffered aqueous phase containing, for example, dibasic sodium phosphate.
  • an electron donor agent such as sodium amalgam in a mixture of an organic solvent such as THF and a buffered aqueous phase containing, for example, dibasic sodium phosphate.
  • interconversion includes alkylation of compounds of formula (I) wherein R 4 represents hydrogen to a compound of formula (I) wherein R 4 represents Ci_ 6 alkyl.
  • Such an interconversion reaction typically comprises a suitable base such as sodium hydride to deprotonate the amide followed by treatment with an alkylating agent such as methyl iodide in a solvent such as DMF.
  • One further particular interconversion which may be mentioned includes alkylation of compounds of formula (I) wherein R 3 represents hydrogen to a compound of formula (I) wherein R 3 represents Ci_ 6 alkyl.
  • Such an interconversion reaction typically comprises reductive amination with an aldehyde in the presence of a suitable mild hydride donor agent such as sodium acetoxyborohydride.
  • isomer separation may occur at any suitable stage in the synthetic sequence. It should be stressed that such chiral separation forms a key aspect of the invention and that such separation may be conducted in accordance with the methodology described herein or may be conducted in accordance with known methodology.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO- OCH 2 C 6 H 5 , -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OCiCHafeCeh CeHs, -NH-Bpoc), as a 9- fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2- trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc),
  • protecting groups for amines include toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.
  • tosyl toluenesulphonyl
  • methanesulphonyl methanesulphonyl
  • benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.
  • PMB para-methoxybenzyl
  • THP tetrahydropyranyl
  • a carboxylic acid group may be protected as an ester for example, as: an Ci -7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_ 7 haloalkyl ester (e.g., a Ci -7 trihaloalkyl ester); a triCi- 7 alkylsilyl-Ci- 7 alkyl ester; or a C 5 . 2 o aryl-Ci. 7 alkyl ester (e.g., a benzyl ester; a
  • the compounds will be state-dependent sodium channel inhibitors.
  • the compounds will be subtype NaV1.7 sodium channel state-dependent inhibitors.
  • the compounds will be state-dependent sodium channel inhibitors which have a suitable developability profile on oral administration, for example in terms of exposure (Cmax) and/or bioavailability.
  • the compounds will be sodium channel inhibitors.
  • the compounds will be subtype NaV1.7 sodium channel inhibitors.
  • the compounds will be sodium channel inhibitors which have a suitable developability profile on oral administration, for example in terms of exposure (Cmax) and/or bioavailability.
  • compounds of the invention for use as a medicament, preferably a human medicament.
  • the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing a disease or condition mediated by modulation of voltage-gated sodium channels.
  • compounds of the invention may be useful as analgesics.
  • they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains;
  • neuropathic pain neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • Compounds of the invention may be useful in the treatment of neuropathic pain.
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved.
  • neuropathic pain The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Compounds of the invention may also be useful in the amelioration of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases; lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, non-allergic rhinitis, cough, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
  • the compounds of the invention are useful in the treatment of neuropathic pain or inflammatory pain as described herein.
  • other diseases or conditions that may be mediated by modulation of voltage-gated sodium channels are selected from the list consisting of [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the
  • DSM-IV American Psychiatric Association
  • ICD-10 International Classification of Diseases, 10th Edition
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode
  • Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311)
  • Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major
  • Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, Wth Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and Wth Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): ii) Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grand
  • Amphetamine-Induced Sexual Dysfunction Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder
  • Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine
  • Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Wthdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Wthdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or An
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g.
  • Alzheimer's disease includes primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apn
  • Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as
  • Impulse control disorder including: Intermittent Explosive Disorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31), Pyromania (312.33), Trichotillomania (312.39), Impulse-Control Disorders Not Otherwise Specified (312.3), Binge Eating, Compulsive Buying, Compulsive Sexual Behaviour and Compulsive Hoarding.
  • diseases or conditions that may be mediated by modulation of voltage gated sodium channels are depression or mood disorders
  • diseases or conditions that may be mediated by modulation of voltage gated sodium channels are substance related disorders.
  • diseases or conditions that may be mediated by modulation of voltage gated sodium channels are Bipolar Disorders (including Bipolar I Disorder, Bipolar II Disorder (i.e. Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) or Bipolar Disorder Not Otherwise Specified (296.80)).
  • Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (i.e. Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) or Bipolar Disorder Not Otherwise Specified (296.80)
  • diseases or conditions that may be mediated by modulation of voltage gated sodium channels are Nicotine-Related Disorders such as Nicotine
  • Compounds of the invention may also be useful in the treatment and/or prevention of disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD), sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la
  • Tourette's syndrome ataxias, muscular rigidity (spasticity), and temporomandibular joint dysfunction.
  • Compounds of the invention may also be useful in the treatment of bladder hyperrelexia following bladder inflammation.
  • Compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, motor neuron disease);
  • the compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and
  • Compounds of the invention may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • Compounds of the invention may also be useful in the treatment of tinnitus, and as local anaesthetics.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • each compound may differ from that when the compound is used alone.
  • combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other compounds
  • medicaments indicated to be useful in the treatment or prophylaxis of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine.
  • Such therapeutic agents include for example COX-2 (cyclooxygenase-2) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)-3- (4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO 99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modulators,
  • cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5 J ⁇ agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for example modulators of the NR2B subtype; EP 4 receptor ligands; EP 2 receptor ligands; EP 3 receptor ligands; EP 4 agonists and EP 2 agonists; EP 4 antagonists; EP 2 antagonists and EP 3 antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or Transient Receptor Potential (TRP) ligands; and purinergic receptor ligands, including antagonists at
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • iv) anxiolytics such as anxio
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • iv) anxiolytics such as anxio
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii)
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
  • the compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • norepinephrine reuptake inhibitors such as atomoxetine
  • alpha 2 adrenoceptor agonists such as clonidine
  • antidepressants such as clonidine
  • modafinil modafinil
  • cholinesterase inhibitors such as galantamine and donezepil
  • the compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • alpha adrenoceptor antagonists
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine,
  • thioridazine mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram,
  • escitalopram fluoxetine, paroxetine and sertraline
  • dual serotonin/noradrenaline reuptake inhibitors such as venlafaxine, duloxetine and milnacipran
  • Noradrenaline reuptake inhibitors such as reboxetine
  • tricyclic antidepressants such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine
  • monoamine oxidase inhibitors such as isocarboxazide, moclobemide, phenelzine and tranylcypromine
  • others such as bupropion, mianserin, mirtazapine, nefazodone and trazodone.
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex,
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
  • non-aqueous vehicles which may include edible oils
  • edible oils for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will for example contain from 5-1000 mg of the active ingredient.
  • the dosage as employed for adult human treatment may range from 10 to 3000 mg per day depending on the route and frequency of administration. For oral administration a typical dose may be in the range of 50 to 1500 mg per day, for example 120 to 1000 mg per day.
  • the invention includes the following further aspects.
  • the embodiments described for the first aspect similarly apply to these further aspects.
  • the diseases and conditions described above extend, where appropriate, to these further aspects: i) A compound of the invention for use in treating or preventing a disease or condition mediated by modulation of voltage-gated sodium channels. ii) A method of treatment or prevention of a disease or condition mediated by modulation of voltage-gated sodium channels in a mammal comprising administering an effective amount of a compound of the invention. iii) Use of a compound of the invention in the manufacture of a medicament to treat or prevent a disease or condition mediated by modulation of voltage-gated sodium channels. iv) Use of a compound of the invention to treat or prevent a disease or condition mediated by modulation of voltage-gated sodium channels.
  • the absolute configuration of the stereocentres of the spiro fused compounds prepared from achiral starting materials and resolved chemically or by use of chiral chromatography have been assigned on the basis of NOE 1 H NMR experiments, by determining the relative stereochemistry of adjacent stereocentres, and relating these to chiral intermediates and final compounds which have had their absolute configurations determined by single crystal X-ray crystallography.
  • Some compounds have been assigned using a combination of optical rotation, chiral chromatography elution order and NMR spectroscopy (for determining the relative stereochemistry of adjacent stereocentres) and relating these to chiral intermediates and final compounds which have had their absolute configurations determined by single crystal X-ray crystallography.
  • NMR spectra are typically recorded either on Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm ( ⁇ ) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90°C. When more than one conformer was detected the chemical shifts for the most abundant one is reported.
  • Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks are typically taken also on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM mass spectrometer operating in positive or negative electrospray ionisation mode.
  • Chiral chromatography was typically performed using a ChiralPakTM AD column from Daicel® chiral columns.
  • Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian. The following abbreviations are used herein:
  • Decription 12 (5R)-3-(3-Benzyloxyphenyl)-8-methyl-4,8-diazaspiro[4.4]non-3-en-9-one (D12)
  • the crude product was re-dissolved in 2-methyl-2-butanol (100 ml_), acetic acid (10 ml_, 175 mmol) and Pt 5 wt.% on activated carbon (0.350 g, 1.794 mmol) was added.
  • the reaction mixture was hydrogenated at 55 psi for one day.
  • the reaction mixture was filtered with celite and concentrated.
  • the crude product was passed through an amino- silica cartridge to give (3R,5R)-3-(3-hydroxyphenyl)-8-methyl-4,8-diazaspiro[4.4]nonan-9-one (D13) (1 g); m/z (M+H + ) 247.
  • reaction mixture was subjected to microwave heating in a sealed tube at 120°C for 35 mins.
  • a Stratospheres PL-Thiol MP SPE column was pre-treated with methanol, then the filtered reaction mix passed through the column, washing with methanol.
  • Tetrakis(acetonitrile)copper(l)hexafluorophosphate 46mg, 0.12mmol
  • (2S)-1-[(R)- (dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]-2-(diphenylphosphino)ferrocene 86 mg, 0.12mmol
  • the 2 isomers (D17a, D17b) (4.43g) were combined in THF (99ml) at 0°C under argon and treated with potassium t-butoxide (5.53 g, 49.3 mmol) portionwise (1.5g followed by 1.7g followed by 2.33g at approx 2 minute intervals). The mixture was stirred at 0°C for 30 minutes and acetic acid (3.39 ml, 59.2 mmol) was added dropwise. The mixture was then diluted with methanol and applied directly to SCX resin. The SCX was washed with methanol and then the product was released by elution with 2N ammonia in methanol to give racemic product 2.865 g as an orange gum.
  • the mixture was refluxed for 5 hrs and then cooled and acetic acid (0.13 ml) was added and the product was passed through a SCX column.
  • the column was washed with dioxin/water/methanol and the product was eluted with 2M ammonia in methanol.
  • (S)-2-(3-Bromo-phenyl)-7-ethyl-1 ,7-diaza-spiro[4.4]non-1-en-6-one was prepared in a manner similar to (D18a) in preparation 4, except for starting from 3-amino-1-ethyl-2- pyrrolidinone in place of 3-amino-1-methyl-2-pyrrolidinone and using a ChiralPak AD-H column for the chiral separation step.
  • the reaction mixture was cooled and quenched carefully by the addition of saturated aqueous ammonium chloride.
  • Dichloromethane was added and the mixture stirred for 5 minutes.
  • the organic solution was separated using a hydrophobic frit and the solvent evaporated at reduced pressure.
  • the borane adduct was suspended in 5M hydrochloric acid (8 ml) and heated to 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was basified to ⁇ pH8 by the addition of 2M sodium hydroxide solution.
  • Dichloromethane was added and the mixture stirred for 5 minutes before separation of the organic phase using a hydrophobic frit.
  • the solvent was evaporated and the residue dissolved in methanol and applied to an SCX column.
  • the column was eluted with methanol, followed by 0.5M ammonia in methanol. Basic fractions were combined and concentrated to give the crude products. The products were purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane.
  • Example 141 2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E141 )
  • Diastereoisomer A (E141a), a racemic mixture of (2R,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7- diaza-spiro[4.5]decan-6-one and (2S,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.5]decan-6-one (126 mg, 0.388 mmol, 65% yield); LCMS (5 min method): 1.23min, MH+ 325.12
  • Diastereoisomer B (E141 b), a racemic mixture of (2R,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7- diaza-spiro[4.5]decan-6-one and (2S,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.5]decan-6-one (87 mg, 0.268 mmol, 45% yield); LCMS (5 min method): 1.23 min, MH+ 325.12.
  • Diastereoisomer A (D30a) (406 mg, 0.9326 mmol, 19% yield); NMR (CDCI 3 ) ⁇ 2.25-2.38 (2H, m), 2.49-2.65 (3H, m), 3.33-3.50 (2H, m), 4.04 (1 H, q), 4.48 (1 H, bs), 5.63 (1 H, bs), 7.06 (1 H, t), 7.24 (3H, m), 7.41 (2H, t), 7.54 (1 H, t), 7.73 (1 H, d).
  • Diastereoisomer B (D30b) (470mg, 1.0796mmol, 22% yield); NMR (CDCI 3 ) ⁇ 2.16-2.34 (4H, m), 2.83 (1 H, dd), 3.29-3.49 (2H, m), 4.20 (1 H, q), 4.53 (1 H, d), 6.34 (1 H, bs), 7.1 1 (1 H, t), 7.32-7.45 (7H, m), 7.55 (1 H, m).
  • Diastereoisomer A (D32a), a racemic mixture of (2R,5S)-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one and (2S,5R)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (136mg, 0.4607mmol, 38% yield); NMR (CDCI 3 ) ⁇ 1.65-1.84 (1 H, m), 1.90-2.01 (1 H, m), 2.03-2.15 (1 H, m), 2.17-2.43 (3H, m), 2.56 (1 H, bs), 3.25-3.45 (2H, m), 4.62 (1 H, t), 5.72 (1 H, bs), 7.18 (1 H, t), 7.29-7.39 (2h, m), 7.61 (1 h, s).
  • Diastereoisomer B (D32b), a racemic mixture of (2S,5S)-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one and (2R,5R)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (70mg, 0.237mmol, 20% yield); NMR (CDCI 3 ) ⁇ 1.82-2.08 (2H, m), 2.18-2.35 (5H, m), 3.29- 3.48 (2H, m), 4.25 (1 H, t), 5.65 (1 H, bs), 7.22 (1 H, t), 7.40 (1 H, d), 7.50 (1 H, d), 7.67 (1 H, s).
  • the reaction mixture was cooled and quenched carefully by the addition of saturated aqueous ammonium chloride.
  • Dichloromethane was added and the mixture stirred for 5 minutes.
  • the organic solution was separated using a hydrophobic frit and the solvent evaporated at reduced pressure.
  • the borane adduct was suspended in 5M hydrochloric acid (8 ml) and heated to 90°C for 1 hour. After cooling to room temperature, the reaction mixture was basified to ⁇ pH 8 by the addition of 2M sodium hydroxide solution.
  • Dichloromethane was added and the mixture stirred for 5 minutes before separation of the organic phase using a hydrophobic frit.
  • the solvent was evaporated and the residue dissolved in methanol and applied to an SCX column.
  • the column was eluted with methanol, followed by 0.5M ammonia in methanol. Basic fractions were combined and concentrated to give the crude products. The products were purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane.
  • the compounds of the invention were either tested in a QPatch NaV1.7 assay (referred to in the Table below as QP) or an lonWorks NaV1.7 Assay (referred to in the Table below as IW).
  • HEK293-hNaV1.7 cells were grown in DMEM-F12 + 10% FBS culture media at 37°C. At a confluency of 50-70% cells were dissociated from culture flasks & triturated to ensure unicellular cell suspension; cell density was measured & adjusted to 2-3 x 10 6 cells/ml. Recordings were obtained using QPatch16x.
  • the external solution was (in rtiM): NaCI, 128; KCI, 5; MgCI 2 , 2; CaCI 2 , 2; Glucose, 30; HEPES, 15; pH7.3, 305-315mOsm.
  • V1/2 SSI half-maximal voltage for steady state inactivation
  • Two holding voltages were used to determine test drug inhibition: -90mV, where most of the channels are in a closed state; and V1/2 SSI, where half of the channels are inactivated. Currents were elicited every 10 seconds by stepping to a membrane potential of OmV for 20ms.
  • HEK293-huNaV1.7 cells were grown in DMEM-F12 + 10% FBS culture media at 37°C. At a confluency of 50-70% cells were dissociated from culture flasks and triturated to ensure unicellular cell suspension. Currents were recorded at room temperature (21-23°C) using the lonWorksHT planar array electrophysiology technology (Molecular Devices Corp.). After cell addition a seal test was performed prior to antibiotic (amphotericin) circulation to achieve intracellular access. The intracellular solution contained the following (in rtiM): K-gluconate 100, KCI 40mM, MgCI 2 3.2, EGTA 3, HEPES 5, adjusted to pH 7.3.
  • the external solution contained the following (in rtiM): CaCI 2 0.9, KCI 2.7, KH 2 P0 4 1.1 , MgCI 2 0.5, NaCI 136.9, NaHP0 4 8.
  • Test compounds were applied for 3- 3.5 min.
  • UD block (1-((Drug10/drug1) /(Ctl10/Ctl1))) x100. Data presented here are the negative log of the concentration that caused a 15% inhibition (UD15) of the sodium current (pUD15).

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Abstract

The invention relates to spiro derivatives, to the use of said derivatives in treating diseases and conditions mediated by modulation of voltage-gated sodium channels, to compositions containing said derivatives and processes for their preparation.

Description

SPIRO DERIVATIVES AS VOLTAGE - GATED SODIUM CHANNEL
MODULATORS
FIELD OF THE INVENTION
The invention relates to spiro derivatives, to the use of said derivatives in treating diseases and conditions mediated by modulation of voltage-gated sodium channels, to compositions containing said derivatives and processes for their preparation.
BACKGROUND OF THE INVENTION
Voltage-gated sodium channels are responsible for the initial phase of the action potential, which is a wave of electrical depolarisation usually initiated at the soma of the neuron and propagated along the nerve axon to the terminals. At the terminals, the action potential triggers the influx of calcium and the release of neurotransmitter. Drugs, such as lidocaine, that block voltage-gated sodium channels are used as local anaesthetics. Other sodium channel blockers, such as lamotrigine and carbamazepine are used to treat epilepsy. In the latter case, partial inhibition of voltage-gated sodium channels reduces neuronal excitability and reduces seizure propagation. In the case of local anaesthetics, regional block of sodium channels on sensory neurons prevents the conduction of painful stimuli. A key feature of these drugs is their state-dependent mechanism of action. The drugs are thought to stabilise an inactivated conformation of the channel that is adopted rapidly after the channel opens. This inactivated state provides a refractory period before the channel returns to its resting (closed) state ready to be reactivated. As a result, state-dependent sodium channel blockers inhibit the firing of neurons at high frequency, for example in response to painful stimuli, and will help to prevent repetitive firing during periods of prolonged neuronal depolarisation that might occur, for example, during a seizure. Action potentials triggered at low frequencies, for example in the heart, will not be significantly affected by these drugs, although the safety margin differs in each case, since at high enough concentrations each of these drugs is capable of blocking the resting or open states of the channels.
The voltage-gated sodium channel family is made up of 10 subtypes, four of which are brain specific, NaV1.1 , 1.2, 1.3 and 1.6. Of the other subtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific to cardiac muscle, and NaV1.7, 1.8, and 1.9 are found predominantly in sensory neurons. The hypothesised binding site for state-dependent sodium channel blockers is highly conserved between all the subtypes. As a result, drugs such as lidocaine, lamotrigine and carbamazepine do not distinguish between the subtypes. However, selectivity can be achieved as a result of the different frequencies at which the channels normally operate. Drugs that block voltage-gated sodium channels in a state-dependent manner are also used in the treatment of bipolar disorder, either to reduce symptoms of mania or depression, or as mood stabilisers to prevent the emergence of mood episodes. Clinical and preclinical evidence also suggests that state-dependent sodium channel blockers may help to reduce the symptoms of schizophrenia. For example, lamotrigine has been shown to reduce symptoms of psychosis induced by ketamine in healthy human volunteers, and furthermore, studies in patients suggest that the drug can augment the antipsychotic efficacy of some atypical antipsychotic drugs, such as clozapine or olanzapine. It is hypothesised that efficacy in these psychiatric disorders may result in part from a reduction of excessive glutamate release. The reduction in glutamate release is thought to be a consequence of state- dependent sodium channel inhibition in key brain areas, such as the frontal cortex. However, interaction with voltage-gated calcium channels may also contribute to the efficacy of these drugs.
WO 2007/042240 (Glaxo Group Limited) describes a series of quaternary alpha- aminocarboxamide derivatives as modulators of voltage-gated sodium channels.
The object of the invention is to identify alternative compounds which modulate
voltage-gated sodium channels.
SUMMARY OF THE INVENTION
According to a first aspect, the invention provides a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof:
Figure imgf000003_0001
(I)
wherein:
Ring A represents a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring;
n represents an integer selected from 1 to 4; each R1 independently represents Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, haloCi_6 alkyl, Ci_6 alkoxy, haloCi_6 alkoxy, -Z-phenyl, -Z-Het, -CN, -NR6R7, wherein said Het group represents a 5- or 6-membered aromatic heterocyclic ring or a 4- to 7-membered non- aromatic heterocyclic ring, wherein said phenyl or Het group of R1 may be optionally substituted by one or more (e.g. 1 , 2 or 3) R8 groups and wherein n represents an integer greater than 1 , said R1 groups represent no more than one -Z-phenyl or one -Z-Het group; Z represents a bond or a linker selected from -0-, -CH2-, -CH2-0- or -0-CH2;
R6 and R7 independently represent hydrogen or Ci_6 alkyl or R6 and R7 together with the nitrogen atom to which they are attached join to form a 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring;
R8 represents Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, halogen, haloCi_6 alkyl, Ci_6 alkoxy, haloCi.
6 alkoxy, -CN or -NR6R7;
m represents an integer selected from 0 to 4;
each R2 independently represents Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, halogen, haloCi_6 alkyl, Ci-6 alkoxy, haloCi.6 alkoxy, -CN or -NR6R7;
X represents -N=, -C(H)= or -C(R2)=;
R3 represents hydrogen or Ci_6 alkyl;
R4 represents hydrogen or Ci_6 alkyl;
each R5 independently represents Ci_3 alkyl;
Y represents -CH2- or -(CH2)2-; and
p represents an integer from 0 to 3.
DETAILED DESCRIPTION OF THE INVENTION
The term 'halo' or 'halogen' as used herein refers to fluorine, chlorine, bromine or iodine.
The term 'Ci.3alkyl' as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 3 carbon atoms. The term 'Ci_ 6alkyl' as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
The term 'C2.6alkenyl' as used herein as a group or part of a group refers to a linear or branched hydrocarbon group containing from 2 to 6 carbon atoms and containing a carbon carbon double bond. The term 'C2-6alkynyr as used herein as a group or part of a group refers to a linear or branched hydrocarbon group having from 2 to 6 carbon atoms and containing a carbon carbon triple bond.
The term 'Ci-6alkoxy' as used herein as a group or part of a group refers to an -0-Ci.6alkyl group wherein Ci-6alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.
The term 'haloCi.6alkyr as used herein as a group or part of a group refers to a Ci-6alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term 'haloCi.6alkyr therefore includes monohaloCi.6alkyl and also polyhaloCi. 6alkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi.6alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and the like.
The term 'haloCi.6alkoxy' as used herein as a group or part of a group refers to a -O-C1. 6alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with a halogen. The term 'haloCi.6alkoxy' therefore includes monohaloCi.6alkoxy, and also polyhaloCi.6alkoxy. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi.6alkoxy may have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
The term 5- or 6-membered aromatic heterocyclic ring means a heterocyclyl group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring. Examples of five membered aromatic heterocyclic groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered aromatic heterocyclic groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
The term 4- or 7-membered non-aromatic heterocyclic ring means a heterocyclyl group containing one or more carbon atoms, one or more hydrogen atoms and one or more heteroatoms such as nitrogen, oxygen and sulfur; the carbon and heteroatoms being interconnected to form a ring. The term "non-aromatic" embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems. The terms "unsaturated" and "partially saturated" refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C≡C or N=C bond. The term "fully saturated" refers to rings where there are no multiple bonds between ring atoms. Particular examples include morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl piperazines such as N-methyl piperazine. In general, preferred non-aromatic heterocyclyl groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N- alkyl piperazines.
The term 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring means a non- aromatic heterocyclyl ring as defined herein wherein the ring must contain at least one ring nitrogen atom. Particular examples of nitrogen-containing non-aromatic heterocyclyl groups include aziridine, morpholine, thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole, imidazoline, imidazolidinone, oxazoline, thiazoline, 61-1-1 ,2,5- thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine.
For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.
For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
In one embodiment, Ring A represents a phenyl ring. In an alternative embodiment, Ring A represents a 5- or 6-membered aromatic heterocyclic ring. In a further embodiment, Ring A represents a 5-membered aromatic heterocyclic ring such as pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole or tetrazole. In a yet further embodiment, Ring A represents thienyl. In an alternative embodiment, Ring A represents a 6-membered aromatic
heterocyclic ring such as pyridine, pyrazine, pyridazine, pyrimidine and triazine. In a yet further embodiment, Ring A represents pyridine or pyrimidine.
In one embodiment, n represents an integer selected from 1 to 3. In a further embodiment, n represents an integer selected from 1 to 2. In one embodiment, n represents 1. In an alternative embodiment, n represents 2.
In one embodiment, R1 independently represents Ci_6 alkyl (such as methyl, ethyl or isopropyl), halogen (such as fluorine or chlorine), haloCi_6 alkyl (such as CF3), Ci_6 alkoxy (such as -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -0-CH(Me)2 or -0-CH2-CH(Me)2), halod-e alkoxy (such as -0-CF3, -OCHF2 or -CH2-0-CF3), -Z-aryl (such as -O-phenyl, -0-CH2- phenyl or -CH2-0-phenyl), -Z-Het or -NR6R7 (such as -N(Me)2) wherein said phenyl groups are optionally substituted by one or more (e.g. 1 , 2 or 3) R8 groups such as halogen (e.g. fluorine) or halod-6 alkoxy (e.g. -0-CF3).
In a further embodiment, R1 independently represents d-e alkyl (such as methyl, ethyl or isopropyl), halogen (such as fluorine or chlorine), halod-6 alkyl (such as CF3), d-e alkoxy (such as -O-methyl, -O-ethyl, -O-propyl, -O-butyl, -0-CH(Me)2 or -0-CH2-CH(Me)2), halod-e alkoxy (such as -0-CF3 or -CH2-0-CF3), -Z-aryl (such as -O-phenyl, -0-CH2-phenyl or - CH2-0-phenyl), -NR6R7 (such as -N(Me)2) wherein said phenyl groups are optionally substituted by one or more (e.g. 1 , 2 or 3) R8 groups such as halogen (e.g. fluorine) or haloCi-6 alkoxy (e.g. -0-CF3).
In one embodiment, Z represents -0-, -CH2-0- or -0-CH2.
In one embodiment, R6 and R7 independently represent hydrogen or methyl. In a further embodiment, R6 and R7 both represent methyl.
In one embodiment, R8 represents halogen (e.g. fluorine or chlorine) or halod-6 alkoxy (e.g. -0-CF3).
In one embodiment, R8 represents halogen (e.g. fluorine) or halod-6 alkoxy (e.g. -0-CF3).
In one embodiment, m represents an integer selected from 0 to 3. In a further embodiment, m represents an integer selected from 0 to 2. In a further embodiment, m represents an integer selected from 0 or 1. In one embodiment, m represents 1. In an alternative embodiment, m represents 0.
In one embodiment, R2 independently represents Ci_6 alkyl, halogen, haloCi_6 alkyl, d-6 alkoxy or haloCi_6 alkoxy. In a further embodiment, R2 independently represents halogen (such as chlorine or fluorine).
In one embodiment, X represents -N=. In an alternative embodiment, X represents -C(H)=. In an alternative embodiment, X represents -C(R2)=.
In one embodiment, R3 represents hydrogen, methyl or ethyl. In a further embodiment, R3 represents hydrogen or ethyl.
In one embodiment, R4 represents hydrogen, methyl or ethyl.
When present, R5 independently represents Ci_3 alkyl (such as methyl). In one embodiment, p represents 0 or 1. In one embodiment, p represents 0. In an alternative embodiment, p represents 1. For the avoidance of doubt it should be stated that R5 may be present at any position on either of the spiro rings.
In one embodiment, Y represents -CH2-. In an alternative embodiment, Y represents - (CH2)2-.
In one embodiment, the compound of formula (I) is:
(3R,5R)-3-[6-[4-(Trifluoromethyl)phenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one (E1);
(3R,5R)-8-Methyl-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one
(E2);
(3R,5R)-3-[6-[4-Chlorophenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one (E3);
(3R,5R)-8-Methyl-3-[6-[4-chlorophenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one (E4); (3R,5R)-3-[6-[4-Chlorophenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one (E5);
(3R,5R)-3-[6-[4-Chlorophenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one (E6);
(3R,5R)-8-Methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E7);
(3R,5R)-8-Methyl-3-[3-[2-(trifluoromethoxymethyl)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9- one (E8); (3R,5R)-8-Methyl-3-[3-[2-((3-fluorophenyl)methoxy)-phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one (E9);
(3R,5R)-8-Methyl-3-[3-[2-(((4-trifluoromethoxy)phenoxy)methyl)-phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one (E10);
(3R,5R)-8-Methyl-3-[3-[3-(trifluoromethoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E1 1);
(3R,5R)-8-Methyl-3-[3-[2-methylphenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E12);
(3R,5R)-8-Methyl-3-[3-[4-(phenyloxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E13); (3R,5R)-8-Methyl-3-[3-[4-(ethyloxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E14); (3R,5R)-8-Methyl-3-[3-[2,4-di-(methoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E15);
(3R,5R)-8-Methyl-3-[3-[2-(2-methylprop-1-yloxy)-5-(methyl)phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one (E16);
(3R,5R)-8-Methyl-3-[3-[2-(benzylyloxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E17); (3R,5R)-8-Methyl-3-[3-[2-(but-1-yloxy)-6-(fluoro)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9- one (E18);
(3R,5R)-8-Methyl-3-[3-[2-(prop-1-yloxy)-5-(methyl)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan- 9-one (E19);
(3R,5R)-8-Methyl-3-[3-[2-(prop-2-yloxy)-5-(chloro)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9- one (E20);
(3R,5R)-8-Methyl-3-[3-[2-(prop-1-yloxy)-4-(fluoro)-phenyl]phenyl]-4,8-diazaspiro[4.4]nonan- 9-one (E21);
(3R.5R)- -8- ■Methyl- -3- -[3- ■[3- -(trifluoromethyl)-phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one
(E22);
(3R.5R)- -8- ■Methyl- -3- -[3- [4- -(dimethylamino)-phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one
(E23);
(3R.5R)- -8- ■Methyl- -3- -[3- [2- -(phenoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E24);
(3R.5R)- -8- ■Methyl- -3- -[3- [4- -(trifluoromethyl)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one
(E25);
(3R.5R)- ■8- -Methyl- -3- -[3- [2- -(ethyl)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E26);
(3R.5R)- ■8- -Methyl- -3- -[3- ■[3- -(ethoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E27);
(3R.5R)- -8- -Methyl- -3- -[3- ■[3- -(propoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E28);
(3R.5R)- ■8- -Methyl- -3- -[3- [2- -(methoxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one (E29);
(3R.5R)- ■8- -Methyl- -3- -[3- [2- -(prop-2-yloxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9-one
(E30); (3R,5R)-8-Methyl-3-[3-[2-(2-methylprop-1-yloxy)phenyl]phenyl]-4,8-diazaspiro[4.4]nonan-9- one (E31);
(2S,5S)-2-(2'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E32); (2R,5S)-2-(2'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]-nonan-6-one (E33); (2 ,5 )-2-(2'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E34); (2S,5 )-2-(2'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]-nonan-6-one (E35); (2R,5R)-2-(3'-Ethyl-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E36); (2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E37);
(2S,5S)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E38);
(2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E39);
(2R,5R)-2-(5'-Ethyl-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E40); (2S,5R)-2-(5'-Ethyl-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E41); (2S,5S)-2-(5'-Ethyl-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E42); (2R,5S)-2-(5'-Ethyl-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E43); (2R,5S)-2-(3'-Ethyl-biphenyl-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]-nonan-6-one (E44);
(2S,5S)-7-Methyl-2-(2'-trifluoromethoxy-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E45);
(2S,5R)-7-Methyl-2-(2'-trifluoromethoxy-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E46);
(2R,5S)-7-Methyl-2-(3-pyrimidin-2-yl-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E47);
(2R,5R)-2-(3'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E48); (2R,5R)-2-(3'-Ethyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E49); (2R,5R)-2-(4'-Fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E50); (2R,5R)-2-(2'-lsopropyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E51); (2R,5R)-2-(2',3'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E52); (2S,5R)-2-(2\6'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E53); (2S,5R)-2-(3'-Ethyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E54); (2S,5R)-2-(2',3'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E55); (2S,5S)-2-(4'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E56); (2S,5S)-2-(2',6'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E57); (2S,5R)-2-(3'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one
(E58);
(2S,5R)-7-Methyl-2-(4'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E59);
(2S,5R)-7-Methyl-2-(2'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E60); (2S,5R)-2-(4'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E61); (2S,5R)-7-Methyl-2-(2'-methyl-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E62); (2S,5R)-2-(2'-lsopropyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E63); (2S,5S)-2-(2'-lsopropyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E64); (2S,5R)-2-(3'-Ethyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E65); (2S,5S)-2-(3'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E66); (2S,5S)-2-(2',3'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E67); (2S,5S)-7-Methyl-2-(2'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E68);
(2S,5S)-7-Methyl-2-(4'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E69);
(2S,5S)-7-Methyl-2-(2'-methyl-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E70); (2R,5S)-7-Methyl-2-(3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E71);
(2R,5S)-2-(2'-Ethoxy-4'-fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E72);
(2R,5S)-2-(4'-Fluoro-2'-methyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E73);
(2R,5S)-2-(3',5'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E74); (2R,5S)-2-(2'-Fluoro-3'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E75);
(2R,5S)-2-(2',5'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E76); (2R,5S)-2-(3',5'-Dimethyl-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E77);
(2R,5S)-2-(2'-Fluoro-5'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E78);
(2R,5S)-2-(3',5'-Bis(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one (E79);
(2R,5S)-2-(2',3'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E80); (2R,5S)-2-(2'-Methoxy-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E81); (2R,5S)-2-(2'-Ethoxy-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E82); (2R,5S)-7-Methyl-2-(2'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E83);
(2R,5S)-2-(3'-Ethoxy-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E84); (2R,5S)-2-(2'-lsopropyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E85); (2R,5S)-2-(2',6'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E86); (2R,5S)-7-Methyl-2-(2'-methyl-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E87); (2R,5S)-2-(4'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E88); (2R,5S)-7-Methyl-2-(4'-(trifluoromethyl)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6-one (E89);
(2R,5S)-2-(2'-lsobutoxy-5'-methyl-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one (E90);
(2R,5S)-7-Methyl-2-(2'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-3-yl)-1 ,7-diazaspiro[4.4]nonan-6- one (E91);
(2R,5S)-2-(3'-Fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E92); (2S,5R)-7-Methyl-2-(3-(4-methylthiophen-3-yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (E93); (2R,5R)-7-Methyl-2-(3-(4-methylthiophen-3-yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (E94); (2R,5S)-7-Methyl-2-(3-(4-methylthiophen-3-yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (E95); (2S,5S)-7-Methyl-2-(3-(4-methylthiophen-3-yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (E96); Racemic-cis-2-(2-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E97);
2-(2-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 1 (E98);
2-(2-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 2 (E99);
Racemic-trans-2-(2-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E100);
(2R,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E101); (2S,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E102); (2R,5R)-2-(2',6'-Difluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E103);
Racemic-cis-2-(5-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E104);
Racemic-trans-2-(5-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E105);
2-(5-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 1 (E106);
2-(5-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 2 (E107);
Racemic-cis-2-(4-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E108); Racemic-trans-2-(4-fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E109);
2-(4-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 1 (E110);
2-(4-Fluoro-2'-isobutoxy-5'-methyl-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one - Enantiomer 2 (E111);
Racemic-trans-2-(2',5-difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E1 12);
2-(2',5-Difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one - Enantiomer 1 (E1 13);
2-(2',5-Difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one - Enantiomer 2 (E1 14);
Racemic-cis-2-(2',4-difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E1 15);
(2S,5S)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E116);
(2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E117);
(2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E118);
(2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.5]decan-6-one (E119);
(2S,5R)-7-Ethyl-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E120);
(2R,5R)-7-Ethyl-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E121);
(2R,5S)-7-Ethyl-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E122);
(2S,5S)-7-Ethyl-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E123);
(2R,5R)-2-[6-(2-Fluoro-phenyl)-pyridin-2-yl]-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E124);
(2S,5R)-2-[6-(2-Fluoro-phenyl)-pyridin-2-yl]-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E125);
(2S,5S)-2-[6-(2-Fluoro-phenyl)-pyridin-2-yl]-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E126);
(2R,5S)-2-[6-(2-Fluoro-phenyl)-pyridin-2-yl]-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E127);
(2S,5R)-2-(4,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E128); (2R,5S)-2-(4,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E129); (2R,5R)-2-(4,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E130); (2S,5S)-2-(4,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E131); (2S,5S)-2-(3',5'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E132); (2S,5R)-2-(3',5'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E133); (2R,5R)-2-(3',5'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E134); (2S,5R)-2-(2',4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E135); (2R,5R)-2-(2',4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E136); (2R,5S)-2-(2',4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E137); (2S,5S)-2-(2',4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E138); (2S,5R)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E139); (2R,5R)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]-nonan-6-one (E140); 2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E141);
(2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E142);
(2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E143);
(2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E144);
(2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E145);
(2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E146);
(2S,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E147);
(2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E148);
(2S,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E149); (2R,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E150); (2R,5S)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E151); (2S,5S)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E152); (2R,5S)-2-(3-(3-Fluoropyridin-2-yl)phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E153); (2R,5S)-7-Methyl-2-(3-(3-methylpyridin-2-yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (E154); (2R,5S)-1-Ethyl-2-(2'-fluoro-[1 , 1 '-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E155);
(2S,5S)-1-Ethyl-2-(2'-fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E156);
Racemic-cis-2-(2',5-difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E157); and
Racemic-trans-2-(2',4-difluoro-[1 , T-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (E158);
(2S,5S)-2-(4-Chloro-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E159);
(2R,5S)-2-(4-Chloro-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E160);
(2R,5R)-2-(4-Chloro-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E161); (2S,5R)-2-(4-Chloro-2'-fluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6-one (E162);
(2S,5R)-2-(2'-Fluorobiphenyl-3-yl)-2,7-dimethyl-1 ,7-diazaspiro[4.4]nonan-6-one (E163); (2R,5S)-2-(2'-Fluorobiphenyl-3-yl)-2,7-dimethyl-1 ,7-diazaspiro[4.4]nonan-6-one (E164); (2R,5R)-2-(2'-Fluorobiphenyl-3-yl)-2,7-dimethyl-1 ,7-diazaspiro[4.4]nonan-6-one (E165); (2S,5S)-2-(2'-Fluorobiphenyl-3-yl)-2,7-dimethyl-1 ,7-diazaspiro[4.4]nonan-6-one (E166); or a pharmaceutically acceptable salt or solvate thereof.
A reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof. Hereinafter, compounds and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof as defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".
Many compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.
The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.
One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic,
naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt.
Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).
The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof.
Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.
Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
Also included within the scope of the compound and various salts of the invention are polymorphs thereof.
Compounds of the formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (I).
In one embodiment, the invention provides compounds of formula (la)
Figure imgf000018_0001
(la)
wherein R1 , R2, R3, R4, R5, m, n, p, A, X and Y are as defined herein for compounds of formula (I).
In one embodiment, the invention provides compounds of formula (lb)
Figure imgf000018_0002
(lb) wherein R1 , R2, R3, R4, R5, m, n, p, A, X and Y are as defined herein for compounds of formula (I).
In one embodiment, the invention provides compounds of formula (lc)
Figure imgf000019_0001
(lc)
wherein R1 , R2, R3, R4, R5, m, n, p, A, X and Y are as defined herein for compounds of formula (I).
In one embodiment, the invention rovides compounds of formula (Id)
Figure imgf000019_0002
(Id)
wherein R1 , R2, R3, R4, R5, m, n, p, A, X and Y are as defined herein for compounds of formula (I).
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. 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 usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as 2H (D) and 3H (T), carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l, 125l and 131 l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
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 compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e. 3H (T), and carbon-14, i.e. 14C, 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. 2H (D), 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.
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.
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 reagents in place of the non-labeled reagent previously employed.
Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the
compounds of formula (I) bearing a carboxylic acid group or a hydroxyl group are also embraced by formula (I). Examples of esters are compounds containing the group
-C(=0)OR, wherein R is an ester substituent, for example, a Ci-7 alkyl group, a C3.12
heterocyclyl group, or a C5.i2 aryl group, preferably a Ci-6 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=0)OCH3 , -C(=0)OCH2CH3,
-C(=0)OC(CH3)3, and -C(=0)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=0)R, wherein R is an acyloxy substituent, for example, a Ci-6 alkyl group, a C3_i2 heterocyclyl group, or a C5_i2 aryl group, preferably a Ci-6 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=0)CH3 (acetoxy), -OC(=0)CH2CH3, -OC(=0)C(CH3)3, -OC(=0)Ph, and -OC(=0)CH2Ph. Examples of phosphate esters are those derived from phosphoric acid.
In one embodiment of the invention, formula (I) includes within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group.
According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as herein defined which comprises:
(a) preparing a compound of formula (I) wherein R4 represents hydrogen which comprises conducting a ring closure reaction upon a compound of formula (II):
Figure imgf000021_0001
(II)
or a protected derivative thereof, wherein R1 , R2, R3, R5, m, n, p, A, X and Y are as defined herein for compounds of formula (I);
(b) reacting a compound of formula (III):
Figure imgf000021_0002
(IN)
or a protected derivative thereof, wherein R2, R3, R4, R5, m, p, X and Y are as defined herein for compounds of formula (I) and L1 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S02CF3 group, with a boronic acid derivative or an aryl-tin derivative of a compound of formula A-(R1)n, wherein A, n and R1 are as defined herein for compounds of formula (I);
(c) reacting a compound of formula (IV):
Figure imgf000022_0001
(IV)
or a protected derivative thereof, wherein R2, R3, R4, R5, m, p, X and Y are as defined herein for compounds of formula (I), with a compound of formula L2-A-(R1)n, wherein A, n and R1 are as defined herein for compounds of formula (I) and L2 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S02-CF3 group;
(d) deprotection of a protected derivative of a compound of formula (I);
(e) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and
(f) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).
Process (a) typically comprises the use of sodium borohydride in a suitable solvent such as methanol modified by a suitable catalyst such as cobalt chloride. Process (a) may alternatively comprise hydrogenation over a Rainey Nickel catalyst followed by heating in a suitable solvent such as methanol.
When L1 represents an -0-S02CF3 group, process (b) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst such as a Palladium catalyst and a suitable base such as potassium carbonate in a suitable solvent such as aqueous 1 ,4-dioxane. When L1 represents a halogen atom such as bromine, process (b) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst such as a palladium tetrakis triphenylphosphine and a suitable base. It is recognised that alternative aryl coupling protocols can be used in place of a Suzuki reaction, for example a Stille coupling.
Process (c) typically comprises the Suzuki coupling reaction of a compound of formula (IV) with a compound of formula L2-A-(R1)n in the presence of a palladium catalyst such as palladium tetrakis triphenylphosphine in a suitable solvent such as aqueous 1 ,4-dioxane in the presence of a suitable base such as potassium carbonate.
Compounds of formula (II) wherein p represents 0 may be prepared in accordance with Scheme 1 :
Scheme 1
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
wherein R1 , R2, m, n, A, X and Y are as defined herein for compounds of formula (I), L3 and L4 independently represent suitable leaving groups such as a halogen atom (e.g. bromine) or an -O-SO2-CF3 group and P1 and P2 independently represent suitable protecting groups such as Boc.
Step (i) typically comprises a Sonigashira coupling catalysed by copper iodide in the presence of palladium tetrakistriphenylphosphine in a solvent system such as toluene and isopropylamine.
Step (ii) typically comprises an acid catalysed deprotection reaction catalysed for example by trifluoroacetic acid in a solvent such as dichloromethane.
Step (iii) typically comprises a ring closure reaction catalysed by a Lewis acid such as silver triflate in a solvent such as acetonitrile.
Step (iv) typically comprises a reduction, for example hydrogenation, over platinum on charcoal in a solvent such as methanol in the presence of an acid modifier such as trifluoroacetic acid.
When P2 represents Boc, step (v) typically comprises treatment with Boc anhydride in a solvent such as dichloromethane. Step (vi) typically comprises a biaryl coupling such as a Suzuki coupling with a boronic acid derivative of a compound of formula A-(R1)n catalysed by for example palladium
tetrakistriphenylphosphine in a solvent system comprising for example 1 ,4-dioxane and water and in the presence of a base such as sodium carbonate.
Step (vii) typically comprises deprotonation alpha to the carbonyl group using a hindered base such as lithium hexamethyldisilazide in a solvent such as THF at low temperature, followed by alkylation with bromoacetonitrile.
Compounds of formula (II) may be prepared from compounds of formula (ll)p by a suitable deprotection reaction. For example, when P2 represents Boc, such deprotection suitably comprises treatment with an acid calalyst such as trifluoroacetic acid in a solvent such as dichloromethane.
Compounds of formula (III) wherein p represents 0, R3 represents hydrogen and L1 represents -0-S02CF3 may be prepared in accordance with Scheme 2:
Scheme 2
Figure imgf000027_0001
wherein R2, R4, m, X and Y are as defined herein for compounds of formula (I) and P3 represents a suitable protecting group such as Boc.
Step (i) typically comprises coupling of a protected phenol carboxaldehyde such as tert- butyldimethylsilyloxybenzene-3-carbaldehyde with a Boc protected 2-amino-N- alkylpyrrolidinone following treatment by sequential treatment with acid and base catalysts in solvents such as dichloromethane and toluene. Step (ii) typically comprises a 3+2 cycloaddition reaction of the imine with phenyl vinyl sulfone which can typically be effected in the presence of a strong base such as DBU and a transition metal catalyst such as tetrakis(acetonitrile)copper(l) hexafluorophosphate in the presence of an asymmetric copper ligand.
Step (iii) typically comprises elimination of the resultant bicyclic sulfone to afford the corresponding deprotected phenyl imine, which can be achieved by treatment with a strong base such as potassium tert-butoxide in a solvent such as methyl-THF.
Step (iv) typically comprises reduction of the imine which can be achieved using catalytic hydrogenation over a platinum catalyst in a solvent such as acetic acid.
Step (v) typically comprises conversion of the phenol to the corresponding
trifluoromethanesulfonate ester by treatment with 1 , 1 , 1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methane sulphonamide in a solvent such as dichloromethane in the presence of an organic base such as triethylamine.
Compounds of formula (III) wherein R3 represents hydrogen and L1 represents a halogen atom such as bromine may be prepared in accordance with Scheme 3:
Scheme 3
Figure imgf000029_0001
wherein R2, R4, m, X and Y are as defined herein for compounds of formula (I).
Step (i) typically comprises condensation of an optionally substituted 2-aminopyrrolidinone with an aryl bromo-3-carboxaldehyde in the presence of a dehydrating agent such as magnesium sulfate in a solvent such as dichloromethane.
Step (ii) typically comprises a 3+2 cycloaddition reaction with phenyl vinyl sulfone catalysed by a transition metal salt such as a silver or copper salt, in the presence of base and optionally a chiral phosphine ligand such as 1-(di(1-naphthenyl)phosphinyl)-2-((4S)-4- (propan-2-yl)-4,5-dihydro-1 ,3-oxazolyl)-ferrocene.
Step (iii) typically comprises elimination of the phenyl sulfone with a strong base such as potassium tert-butoxide. Step (iv) typically comprises reduction of the imine using a hydride donor such as sodium borohydride in the presence of acid.
Compounds of formula (IV) wherein p represents 0 and R3 represents hydrogen may be prepared in accordance with Scheme 4:
Scheme 4
Figure imgf000030_0001
wherein R2, R4, m, X and Y are as defined herein for compounds of formula (I) and L5 represents a suitable leaving group such as a halogen atom (e.g. bromine) or an -0-S02- CF3 group.
Step (i) typically comprises reacting a compound of formula (I I l)b with pinacolborane in the presence of a palladium catalyst in a solvent such as toluene.
Compounds of formula (I) wherein R3 represents hydrogen, p represents 1 , R5 represents Ci-3 alkyl and is located germinal to the pyrrolidine nitrogen, may be prepared according to Scheme 5:
Scheme 5
Figure imgf000031_0001
Figure imgf000031_0002
wherein R1 , n, A, R2, m, R4, X and Y are as defined herein for compounds of formula (I).
Step (i) typically comprises reacting a compound of formula (XIX) with a 3-bromoph ketone in a solvent such as toluene in the presence of a dehydrating agent such as molecular sieves. Step (ii) typically comprises a 3+2 cycloaddition reaction with phenyl vinyl sulfone in the presence of a strong base such as potassium fe butoxide in a solvent such as THF.
Step (iii) typically comprises a biaryl coupling such as a Suzuki coupling with a boronic acid catalysed by, for example, palladium ditriphenylphosphine dichloride in a solvent system comprising, for example, dimethoxyethane and water and in the presence of a base such as sodium carbonate.
Step (iv) typically comprises the reductive elimination of the phenylsulfonyl group by reaction with an electron donor agent such as sodium amalgam in a mixture of an organic solvent such as THF and a buffered aqueous phase containing, for example, dibasic sodium phosphate.
Compounds of formula (V), (VI), (XIII), (XIV) and (XIX) are either known or may be prepared in accordance with known methodology.
A wide range of well known functional group interconversions for process (e) are known by a person skilled in the art for converting a precursor compound to a compound of formula (I) and are described in Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992. For example possible metal catalysed functionalisations such as using organo- tin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1 , Edited by Ei-ichi Negishi, Wley, ISBN 0-471-31506-0].
If appropriate, the reactions previously described in Scheme 1-4 are followed or preceded by one or more reactions known to the skilled of the art and are performed in an appropriate order to achieve the requisite substitutions on R1 , R2, R3 and R4, defined above to afford other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include:
protection of reactive functions,
deprotection of reactive functions,
halogenation,
dehalogenation,
dealkylation,
alkylation of amine, aniline, alcohol and phenol, Mitsunobu reaction on hydroxyl groups,
cycloaddition reactions on appropriate groups,
reduction of nitro, esters, cyano, aldehydes,
transition metal-catalyzed coupling reactions,
acylation,
sulfonylation/introduction of sulfonyl groups,
saponification/hydrolysis of esters groups,
amidification or transesterification of ester groups,
esterification or amidification of carboxylic groups,
halogen exchange,
nucleophilic substitution with amine, thiol or alcohol,
reductive amination,
oxime formation on carbonyl and hydroxylamine groups,
S-oxidation,
N-oxidation,
salification.
One particular interconversion which may be mentioned includes alkylation of compounds of formula (I) wherein R4 represents hydrogen to a compound of formula (I) wherein R4 represents Ci_6 alkyl. Such an interconversion reaction typically comprises a suitable base such as sodium hydride to deprotonate the amide followed by treatment with an alkylating agent such as methyl iodide in a solvent such as DMF.
One further particular interconversion which may be mentioned includes alkylation of compounds of formula (I) wherein R3 represents hydrogen to a compound of formula (I) wherein R3 represents Ci_6 alkyl. Such an interconversion reaction typically comprises reductive amination with an aldehyde in the presence of a suitable mild hydride donor agent such as sodium acetoxyborohydride.
It is recognised that the sequence of reactions involving aryl coupling and reduction may be varied. It is also recognised that a wide range of palladium based catalysts are suitable for conducting aryl coupling reactions.
It may also be recognised that isomer separation may occur at any suitable stage in the synthetic sequence. It should be stressed that such chiral separation forms a key aspect of the invention and that such separation may be conducted in accordance with the methodology described herein or may be conducted in accordance with known methodology.
In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=0)R), for example, as: a t-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH3).
An aldehyde or ketone group may be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is treated with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyl carbamate (-NHCO- OCH2C6H5, -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); a 2- biphenyl-2-propyl carbamate (-NHCO-OCiCHafeCeh CeHs, -NH-Bpoc), as a 9- fluorenylmethyl carbamate (-NH-Fmoc), as a 6-nitroveratryl carbamate (-NH-Nvoc), as a 2- trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulphonyl)ethyl carbamate (-NH-Psec).
Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.
A carboxylic acid group may be protected as an ester for example, as: an Ci-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_7 haloalkyl ester (e.g., a Ci-7 trihaloalkyl ester); a triCi-7 alkylsilyl-Ci-7alkyl ester; or a C5.2o aryl-Ci.7 alkyl ester (e.g., a benzyl ester; a
nitrobenzyl ester; para-methoxybenzyl ester.. As discussed hereinabove, it is believed that compounds of the invention may be useful for the treatment of diseases and conditions mediated by modulation of voltage-gated sodium channels.
In one embodiment, the compounds will be state-dependent sodium channel inhibitors.
In another embodiment, the compounds will be subtype NaV1.7 sodium channel state- dependent inhibitors.
In another embodiment, the compounds will be state-dependent sodium channel inhibitors which have a suitable developability profile on oral administration, for example in terms of exposure (Cmax) and/or bioavailability.
In one embodiment, the compounds will be sodium channel inhibitors.
In another embodiment, the compounds will be subtype NaV1.7 sodium channel inhibitors.
In another embodiment, the compounds will be sodium channel inhibitors which have a suitable developability profile on oral administration, for example in terms of exposure (Cmax) and/or bioavailability.
According to a further aspect of the invention, there is provided compounds of the invention for use as a medicament, preferably a human medicament.
According to a further aspect the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing a disease or condition mediated by modulation of voltage-gated sodium channels.
In one particular embodiment, compounds of the invention may be useful as analgesics. For example they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains;
neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
Compounds of the invention may be useful in the treatment of neuropathic pain.
Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
Compounds of the invention may also be useful in the amelioration of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases; lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, non-allergic rhinitis, cough, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g. Crohn's disease, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); other conditions with an inflammatory component such as migraine, multiple sclerosis, myocardial ischemia.
In one embodiment, the compounds of the invention are useful in the treatment of neuropathic pain or inflammatory pain as described herein. Without wishing to be bound by theory, other diseases or conditions that may be mediated by modulation of voltage-gated sodium channels are selected from the list consisting of [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the
American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10)]: i) Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major
Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, Wth Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and Wth Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): ii) Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and Wth Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9). iii) Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01) and Panic Disorder with Agoraphobia (300.21); Agoraphobia;
Agoraphobia Wthout History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood- Injection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00): iv) Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance- Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Wthdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine- Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0),
Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder,
Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,
Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine- Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant- Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine- Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid- Induced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or
Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine
Intoxication Delirium, Phencydidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Wthdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Wthdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-,
Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic- Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related
Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide: v) Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: vi) Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome: vi) Eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50): vii) Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism). viii) Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit
/Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder
Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not
Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as
Tourette's Disorder (307.23): ix) Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9): and x) Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9). xi) Impulse control disorder" including: Intermittent Explosive Disorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31), Pyromania (312.33), Trichotillomania (312.39), Impulse-Control Disorders Not Otherwise Specified (312.3), Binge Eating, Compulsive Buying, Compulsive Sexual Behaviour and Compulsive Hoarding.
In another embodiment, diseases or conditions that may be mediated by modulation of voltage gated sodium channels are depression or mood disorders
In another embodiment, diseases or conditions that may be mediated by modulation of voltage gated sodium channels are substance related disorders.
In a further embodiment, diseases or conditions that may be mediated by modulation of voltage gated sodium channels are Bipolar Disorders (including Bipolar I Disorder, Bipolar II Disorder (i.e. Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) or Bipolar Disorder Not Otherwise Specified (296.80)).
In a still further embodiment, diseases or conditions that may be mediated by modulation of voltage gated sodium channels are Nicotine-Related Disorders such as Nicotine
Dependence (305.1), Nicotine Withdrawal (292.0) or Nicotine-Related Disorder Not
Otherwise Specified (292.9). Compounds of the invention may also be useful in the treatment and/or prevention of disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD), sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la
Tourette's syndrome), ataxias, muscular rigidity (spasticity), and temporomandibular joint dysfunction.
Compounds of the invention may also be useful in the treatment of bladder hyperrelexia following bladder inflammation.
Compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, motor neuron disease); The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and
neuroinflamation.
Compounds of the invention may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
Compounds of the invention may also be useful in the treatment of tinnitus, and as local anaesthetics.
The compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.
Appropriate doses will be readily appreciated by those skilled in the art. It will be
appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a
combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical
composition.
When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the
formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
When used in the treatment or prophylaxis of pain, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other
medicaments indicated to be useful in the treatment or prophylaxis of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine. Such therapeutic agents include for example COX-2 (cyclooxygenase-2) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)-3- (4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO 99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modulators, such as glycine receptor antagonists or memantine; ligands for the α2δ- subunit of voltage gated calcium channels, such as gabapentin, pregabalin and solzira; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs;
cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5 J^ agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for example modulators of the NR2B subtype; EP4 receptor ligands; EP2 receptor ligands; EP3 receptor ligands; EP4 agonists and EP2 agonists; EP4 antagonists; EP2 antagonists and EP3 antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or Transient Receptor Potential (TRP) ligands; and purinergic receptor ligands, including antagonists at P2X3, P2X2 3, P2X4, P2X7 or P2X4 7; KCNQ/Kv7 channel openers, such as retigabine; additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US 5,633,272, US 5,466,823, US 6,310,099 and US 6,291 ,523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO 99/12930, WO 00/26216, WO 00/52008, WO 00/38311 , WO 01/58881 and WO 02/18374.
The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
The compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
The compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii)
antidepressants.
The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants. The compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
The compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
The compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
The compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
The compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and
progesterones.
The compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
The compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline. The compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine
formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
The compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
The compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
The compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine,
thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram,
escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone). Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex,
carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
It will be appreciated that references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
The compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
According to a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). The carrier, diluent and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1 % by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will for example contain from 5-1000 mg of the active ingredient. The dosage as employed for adult human treatment may range from 10 to 3000 mg per day depending on the route and frequency of administration. For oral administration a typical dose may be in the range of 50 to 1500 mg per day, for example 120 to 1000 mg per day.
It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by
conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
It will be appreciated that the invention includes the following further aspects. The embodiments described for the first aspect similarly apply to these further aspects. The diseases and conditions described above extend, where appropriate, to these further aspects: i) A compound of the invention for use in treating or preventing a disease or condition mediated by modulation of voltage-gated sodium channels. ii) A method of treatment or prevention of a disease or condition mediated by modulation of voltage-gated sodium channels in a mammal comprising administering an effective amount of a compound of the invention. iii) Use of a compound of the invention in the manufacture of a medicament to treat or prevent a disease or condition mediated by modulation of voltage-gated sodium channels. iv) Use of a compound of the invention to treat or prevent a disease or condition mediated by modulation of voltage-gated sodium channels.
Examples
The invention is illustrated by the Examples described below.
In the procedures that follow, after each starting material, reference to a Description or Example by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.
Certain Examples described hereinafter have been prepared as a first step from
stereochemically pure methyl 5-oxo-L-prolinate or ethyl 5-oxo-D-prolinate, for example 99% ee. The stereochemistry of the compounds of subsequent Descriptions and Examples have been assigned on the assumption that the pure configuration of 5-oxo-prolinate is
maintained throughout any subsequent reaction conditions.
Where reference is made to the use of a "similar" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.
The absolute configuration of the stereocentres of the spiro fused compounds prepared from achiral starting materials and resolved chemically or by use of chiral chromatography have been assigned on the basis of NOE 1 H NMR experiments, by determining the relative stereochemistry of adjacent stereocentres, and relating these to chiral intermediates and final compounds which have had their absolute configurations determined by single crystal X-ray crystallography. Some compounds have been assigned using a combination of optical rotation, chiral chromatography elution order and NMR spectroscopy (for determining the relative stereochemistry of adjacent stereocentres) and relating these to chiral intermediates and final compounds which have had their absolute configurations determined by single crystal X-ray crystallography.
It will be apparent to the skilled person that absolute configurations can only be definitively characterised by specific analytical determinations such as X-ray crystallography.
Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada), or using Lexichem's automatic chemical naming software (OpenEye Scientific Software Inc. Santa Fe, New Mexico, USA).
Proton Magnetic Resonance (NMR) spectra are typically recorded either on Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm (δ) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90°C. When more than one conformer was detected the chemical shifts for the most abundant one is reported.
HPLC analysis indicated by Rt(HPLC): x min, was performed on an Agilent 1100 series instrument using a Luna 3u C18(2) 100A (50x2.0mm) column (mobile phase: 100% [water + 0.05% TFA] to 95% [acetonitrile + 0.05% TFA] in 8min, flux = 1 ml/min, detection wavelength 220nm.
Mass spectra (MS) are typically taken on a 4 II triple quadrupole Mass Spectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode or on an Agilent LC/MSD 1100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode coupled with HPLC instrument Agilent 1100 Series [LC/MS - ES (+):analysis performed on a Supelcosil ABZ +Plus (33x4.6 mm, 3μηι) (mobile phase: 100% [water +0.1 % HC02H] for 1 min, then from 100% [water +0.1 % HC02H] to 5% [water +0.1 % HC02H] and 95% [CH3CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min; LC/MS - ES (-):analysis performed on a Supelcosil ABZ +Plus (33x4.6 mm, 3μηι) (mobile phase: 100% [water +0.05% NH3] for 1 min, then from 100% [water +0.05% NH3 to 5% [water +0.05% NH3] and 95% [CH3CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min]. In the mass spectra only one peak in the molecular ion cluster is reported.
Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks are typically taken also on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM mass spectrometer operating in positive or negative electrospray ionisation mode. [LC/MS - ES (+/-): analyses performed using an AcquityTM UPLC BEH C18 column (50 x 21 mm, 1.7 μηι particle size), column temperature 40 °C (mobile phase: A-water + 0.1 % HCOOH / B - MeCN + 0.075% HCOOH, Flow rate: 1.0 mL/min, Gradient: t=0 min 3% B, t=0.05 min 6% B, t= 0.57 min 70% B, t=1.4 min 99% B, t=1.45 min 3% B)]. The usage of this methodology is indicated by "UPLC" in the analytic characterization of the described compounds.
For reactions involving microwave irradiation, a Personal Chemistry Emrys™ Optimizer or Biotage Initiator was used.
Chiral chromatography was typically performed using a ChiralPak™ AD column from Daicel® chiral columns.
Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.
SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian. The eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
In a number of preparations, purification was performed using either Biotage manual flash chromatography (Flash+) or automatic flash chromatography (Horizon) systems. All these instruments work with Biotage Silica cartridges.
SPE-Si cartridges are silica solid phase extraction columns supplied by Varian. The following abbreviations are used herein:
Boc benzyloxycarbonyl
Dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
DBU 1 ,8-Diazabicyclo (5.4. Ojundec-7-Ene
DCM Dichloromethane
DMF Dimethylformamide
THF Tetrahydrofuran
EtOAc Ethyl Acetate
Preparation 1
Description 1 : Methyl (2S)-5-(6-bromo-2-pyridyl)-2-(tert-butoxycarbonylamino)pent-4- ynoate (D1 )
A flask was charged with 2,6-dibromopyridine (21.9 g, 92.4 mmol), palladium
tetrakistriphenylphosphine (1.8 g, 1.54 mmol), copper iodide (0.3 g, 1.54 mmol),
diisopropylamine (12.5 ml), and toluene (100 ml). A solution of methyl (2S)-2-(tert- butoxycarbonylamino)pent-4-ynoate [FluoroChem] (7.0 g, 30.8 mmol) in toluene (50 ml) was added with stirring and the mixture stirred for 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution, diluted with water and extracted with ethyl acetate. The organic phase was dried with sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (cyclohexane - ethyl acetate), to give methyl (2S)-5-(6-bromo-2-pyridyl)-2-(tert-butoxycarbonylamino)pent-4-ynoate (D1) (8.55 g); NMR 400 MHz (CD3CI3) δ 1.47 (9H, s), 3.0 (2H, br.s), 3.80 (3H, s), 4.6 (1 H, br.s), 5.4 (1 H, br.s), 7.35 (1 H, d), 7.43 (1 H, d), 7.50 (1 H, dd).
Description 2: Methyl (2S)-2-amino-5-(6-bromo-2-pyridyl)pent-4-ynoate (D2)
To a stirred solution of methyl (2S)-5-(6-bromo-2-pyridyl)-2-(tert-butoxycarbonylamino)pent- 4-ynoate (D1) in dry dichloromethane (80 ml) at 0°C was added trifluoroacetic acid (18 ml) and the mixture stirred for 3 hours. The solvent was evaporated and the residue passed through a 70 g SCX column to give methyl (2S)-2-amino-5-(6-bromo-2-pyridyl)pent-4-ynoate (D2) (5.5 g); NMR 400 MHz (CDCI3) δ 1.7 (2H, br.s), 2.86 (1 H, dd), 2.93 (1 H, dd), 3.78 (1 H, d), 3.79 (3H, s), 7.38 (1 H, d), 7.43 (1 H, d), 7.50 (1 H, dd).
Description 3: Methyl (2S)-5-(6-bromo-2-pyridyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D3)
To a solution of methyl (2S)-2-amino-5-(6-bromo-2-pyridyl)pent-4-ynoate (D2) (600 mg, 2.3 mmol) in dry acetonitrile (125 ml) was added with stirring, silver trifluoromethanesulfonate (600 mg, 2.3 mmol) and the mixture stirred for 16 hours then heated to 50 °C for four hours. The solvent was evaporated and the residue diluted with dichloromethane, filtered and further extracted, then the organic solution evaporated to give methyl (2S)-5-(6-bromo-2- pyridyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D3) as a solid 5.4 g.
Description 4: Methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-2-carboxylate (D4)
To a solution of methyl (2S)-5-(6-bromo-2-pyridyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D3) (1.3 g, 4.6 mmol) in methanol (200 mol) was added 5% platinum on carbon (0.4 g) and trifluoroacetic acid (350μΙ, 4.6 mmol) and the mixture hydrogenated at 2 atmospheres of hydrogen for 40 minutes. A further 0.2 g of catalyst was added and hydrogenation continued for 40 minutes at 2 atmospheres. A further 0.2 g of catalyst was added and hydrogenation continued for 40 minutes at 2 atmospheres. The mixture was filtered and evaporated then passed through an SCX column, to afford methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-2- carboxylate (D4) as a crude material used directly in the next step.
Description 5: 0-1 -Tert-butyl O-2-methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-1 ,2- dicarboxylate (D5)
To a solution of methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-2-carboxylate (D4) (2.27 g, 7.96 mmol) in dichloromethane (50 ml) was added dropwise with stirring, a solution of di-tert- butyl dicarbonate (1.90 g, 8.7 mmol) in dichloromethane (25 ml). The reaction was monitored by HPLC and when no starting material remained, the solvent was evaporated and the residue purified by flash chromatography (cyclohexane - ethyl acetate) to give 0-1- tert-butyl O-2-methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-1 ,2-dicarboxylate (D5) as a white solid (1.9 g); NMR 400 MHz (CDCI3) δ 1.22, 1.44 (9H, 2 x s), 1.90-2.44 (4H, m), 3.79, 3.81 (3H, 2 x s), 4.39, 4.50 (1 H, 2 x dd), 4.90, 5.08 (1 H, 2 x dd), 7.30-7.37 (1 H, m), 7.52-7.57 (1 H, m), 7.89, 8.03 (1 H, 2 x d).
Description 6: 0-1 -Tert-butyl-0-2-methyl (2S,5R)-5-[6-[4-(trifluoromethyl)phenyl]-2- pyridyl]pyrrolidine-1 ,2-dicarboxylate (D6)
0-1-Tert-butyl-0-2-methyl (2S,5R)-5-(6-bromo-2-pyridyl)pyrrolidine-1 ,2-dicarboxylate (D5) (1.50 g, 3.9 mmol), palladium tetrakistriphenylphosphene (0.45 g, 0.39 mmol), sodium carbonate (2.07 g, 19.5 mmol) and 4-trifluoromethylphenylboronic acid (1.11 g, 5.85 mmol) were degassed and stirred in a mixture of 1 ,4-dioxane (30 ml) and water (15 ml) at 80°C for one hour. The mixture was cooled and diluted with water then extracted with ethyl acetate. The organic phase was evaporated and the residue purified by flash chromatography (cyclohexane - ethyl acetate) to afford 0-1-tert-butyl-0-2-methyl (2S,5R)-5-[6-[4- (trifluoromethyl)phenyl]-2-pyridyl]pyrrolidine-1 ,2-dicarboxylate (D6) as a white solid (1.6 g).
Description 7: 0-1 -Tert-butyl-0-2-methyl (2R,5R)-2-(cyanomethyl)-5-[6-[4- (trifluoromethyl)phenyl]-2-pyridyl]pyrrolidine-1 ,2-dicarboxylate (D7)
To a stirred solution of 0-1-tert-butyl-0-2-methyl (2S,5R)-5-[6-[4-(trifluoromethyl)phenyl]-2- pyridyl]pyrrolidine-1 ,2-dicarboxylate (D6) (400 mg 0.89 mmol) in dry THF (9 ml) at -78°C was added dropwise a solution of lithium hexamethyldisilazide (0.9M in toluene, 1.09ml, 0.98 mmol). Once the addition was completed the temperature allowed to warm to -30 °C over 30 minutes. The mixture was re-cooled to -78°C and bromoacetonitrile (119.95 μΙ, 1.07 mmol) added and the mixture stirred at -78°C for 1 hour. The mixture was quenched by addition of excess saturated aqueous ammonium chloride solution, diluted further with water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, evaporated and purified by flash chromatography (cyclohexane - ethyl acetate) to afford O- 1-tert-butyl-0-2-methyl (2R,5R)-2-(cyanomethyl)-5-[6-[4-(trifluoromethyl)phenyl]-2- pyridyl]pyrrolidine-1 ,2-dicarboxylate (D7) (230 mg) as an oil; m/z (M+H+) 490.1).
Description 8: Tert-butyl (3R,5R)-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonane-4-carboxylate (D8)
To a stirred solution of 0-1-tert-butyl-0-2-methyl (2R,5R)-2-(cyanomethyl)-5-[6-[4- (trifluoromethyl)phenyl]-2-pyridyl]pyrrolidine-1 ,2-dicarboxylate (D7) (280 mg, 0.57 mmol) in dry methanol (10 ml) was added cobalt chloride hexahydrate (270 mg, 1.14 mmol) and the mixture stirred to form a violet solution. The mixture was cooled to 0°C and sodium borohydride (215 mg, 5.7 mmol) added portionwise. The mixture was stirred for 20 minutes, then quenched by addition of excess ammonium chloride, the methanol evaporated, the residue diluted with water and extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and evaporated and the residue purified by flash chromatography (cyclohexane - ethyl acetate) to afford tert-butyl (3R,5R)-9-oxo-3-[6-[4- (trifluoromethyl)phenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonane-4-carboxylate (D8) as a brown solid (95 mg).
Description 9: tert-butyl (3R,5R)-8-methyl-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2- pyridyl]-4,8-diazaspiro[4.4]nonane-4-carboxylate (D9)
To a solution of tert-butyl (3R,5R)-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonane-4-carboxylate (D8) (50 mg, 0.1 1 mmol), in dry DMF (1 ml) was added sodium hydride (60% oil dispersion, 5 mg, 0.13 mmol), and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (11 μΙ, 0.165mmol) was added and the stirred reaction mixture monitored by thin layer chromatography until complete. The mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate, the organic phase washed with brine three times, dried over sodium sulphate and evaporated to give tert-butyl (3R,5R)-8-methyl-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonane-4-carboxylate (D9) as a white solid (53 mg); m/z (M+H+) 476.14.
Example 1 : (3R,5R)-3-[6-[4-(Trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonan-9-one hyd
Figure imgf000056_0001
To a solution of tert-butyl (3R,5R)-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonane-4-carboxylate (D8) (46mg) in dichloromethane (2ml) was added trifluoroacetic acid dropwise and the mixture stirred for 3 hours. The solvent was evaporated and the residue purified by eluting through an SCX cartridge. The resulting material was dissolved in diethyl ether (2ml) and was stirred with 1 M HCI in diethyl ether to give a suspension from which the ether was decanted. This gave (3R,5R)-3-[6-[4- (trifluoromethyl)phenyl]-2-pyridyl]-4,8-diazaspiro[4.4]nonan-9-one hydrochloride as a white solid (E1); m/z (M+H+) 362.11 ; NMR 400 MHz (DMSO-d6) δ 2.07-2.37 (4H, m), 2.49-2.84 (2H, m), 3.21-3.44 (2H, m), 5.01-5.14 (1 H, m), 7.59 (1 H, d), 7.83 (2H, d), 8.04 (1 H, t), 8.10 (1 H, d), 8.44 (1 H, d), 8.38-8.51 (1 H, m), 8.73-8.95 (1 H, br.s), 10.74 (1 H, br.s)
Example 2: (3R,5R)-8-Methyl-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonan-9-one hydrochloride (E2)
To a stirred solution of tert-butyl (3R,5R)-8-methyl-9-oxo-3-[6-[4-(trifluoromethyl)phenyl]-2- pyridyl]-4,8-diazaspiro[4.4]nonane-4-carboxylate (D9) (53 mg, 1.1 mmol) in dry
dichloromethane (2 ml) trifluoroacetic acid (0.5 ml), was added dropwise and
the mixture stirred for 3h at room temperature. The solvent was evaporated and the residue filtered through an SCX cartridge to give a white solid (40 mg). This was dissolved in diethyl ether and treated with hydrochloric acid (1 M in diethyl ether, 0.12 ml) to give a precipitate which was isolated: (3R,5R)-8-methyl-3-[6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-4,8- diazaspiro[4.4]nonan-9-one hydrochloride (E2) as a white solid (40 mg); m/z (M+H+) 376.14; NMR 400 MHz (DMSO-d6) δ 2.12-2.28 (2H, m), 2.29-2.39 (2H, m), 2.54-2.73 (2H, m), 2.84 (3H, s), 3.34-3.51 (2H, m), 5.1 1 (1 H, m), 7.61 (1 H, d), 7.89 (2H, d), 8.08 (1 H, t), 8.14 (1 H, d),8.47 (2H, d), 8.94 (1 H br.s), 10.74 (1 H, br.s).
The following compounds were prepared by routes described in Preparation 1 using alternative boronic acids in the Suzuki coupling step and other modifications noted.
Figure imgf000057_0002
Figure imgf000058_0001
Preparation 2
Description 10: 1 -Methyl-3-[((1 E)-{3-[(phenylmethyl)oxy]phenyl}methylidene)amino]-2- pyrrolidinone (D10)
Under a dry nitrogen atmosphere, to a solution of 1 , 1-dimethylethyl (1-methyl-2-oxo-3- pyrrolidinyl) carbamate [Sigma-Aldrich] (2.62 g, 12.25 mmol) in dichloromethane (40 mL), methanesulfonic acid (2.019 mL, 31.1 mmol) was added in quarterly additions at such a rate as to maintain a reaction temperature below 30°C. Between each addition, the solution was allowed to stir for at least 20 min. After the last addition was completed, the reaction mixture was heated to 35°C for 1 hr. The solution was cooled to 0°C and then N- ethyldiisopropylamine (2.69 g, 36.8 mmol) was added at a rate to maintain a reaction temperature below 30°C. Upon completion of this addition, K2C03 (1.953 g, 14.13 mmol) and 3-[(phenylmethyl)-oxy]benzaldehyde [Sigma-Aldrich] (2.0 g, 9.42 mmol) were added and the mixture stirred at 25 °C for 18 hrs. The reaction mixture was partitioned between dichloromethane and water, dried and concentrated to give a crude product which was crystallised from diethyl ether to give 1-methyl-3-[((1 E)-{3-
[(phenylmethyl)oxy]phenyl}methylidene)-amino]-2-pyrrolidinone (D10) (1.7 g); 1 H NMR (DMSO-d6) 400MHz δ 2.13 (1 H, br.dd), 2.38 (1 H, br.dd), 2.79 (3H, s), 3.33-3.39 (1 H, m), 3.44-5.50 (1 H, m), 4.06 (1 H, t), 5.14 (2H, s), 7.13 (1 H, d), 7.33-7.48 (8H, m), 8.35 (1 H, s).
Description 11 : (5S,7S,8S)-7-(Benzenesulfonyl)-8-(3-benzyloxyphenyl)-3-methyl-3,9- diazaspiro[4.4]nonan-4-one (D11)
Anhydrous THF (10 ml) was added to a dry, oxygen-free vessel and this reactor placed under vacuum and backfilled with N2 three times. 1-(di(1-naphthalenyl)phosphinyl)-2-((4S)-4- (propan-2-yl)-4,5-dihydro-1 ,3-oxazolyl)-ferrocene (0.3 eq.) and tetrakis(acetonitrile)copper(l) hexafluorophosphate (0.073 g, 0.195 mmol) were then added. The reactor was placed under vacuum and backfilled with N2 three times. The mixture was stirred for 1 hr at room temperature. During this time and in a different vessel, a solution of 1-methyl-3-[((1 E)-{3- [(phenylmethyl)oxy]phenyl} methylidene)amino]-2-pyrrolidinone (D10) (2 g, 6.49 mmol) was made in THF (20 ml_) and degassed then added to the first reaction mixture and ethenyl phenyl sulfone (1.636 g, 9.73 mmol) was added. Then the reaction mixture was cooled to - 15°C and DBU (0.098 ml, 0.649 mmol) was added. The mixture was stirred at -15°C for 16 hrs and stirred at 15°C for a further 4 hrs. The solvent was evaporated the residue passed down an SCX cartridge to give (5S,7S,8S)-7-(benzenesulfonyl)-8-(3-benzyloxyphenyl)-3- methyl-3,9-diazaspiro[4.4]nonan-4-one (D11); m/z (M+H+) 477.
Decription 12: (5R)-3-(3-Benzyloxyphenyl)-8-methyl-4,8-diazaspiro[4.4]non-3-en-9-one (D12)
To a solution of (5S,7S,8S)-7-(benzenesulfonyl)-8-(3-benzyloxyphenyl)-3-methyl-3,9- diazaspiro[4.4]nonan-4-one (D11)(2.9 g, 6.08 mmol) in 2-methyl THF (20 ml_) at 10-15°C under N2, solid KOtBu (0.5 eq.) was added. After the exotherm has subsided, the another portion of KOtBu (0.5 eq.) was added. After the exotherm has subsided, the remaining KOtBu (3.0 eq.) was then added and the solution is heated to 30°C. The mixture was allowed to stir for 1.5 hrs then evaporated and the residue partitioned between EtOAc and water. The ethyl acetate layer was evaporated to give (5R)-3-(3-benzyloxyphenyl)-8-methyl- 4,8-diazaspiro[4.4]non-3-en-9-one (D12) which was used in next step without further purification; m/z (M+H+) 335.
Description 13: (3R,5R)-3-(3-Hydroxyphenyl)-8-methyl-4,8-diazaspiro[4.4]nonan-9-one (D13)
To a solution of (5R)-3-(3-benzyloxyphenyl)-8-methyl-4,8-diazaspiro[4.4]non-3-en-9-one (D12) (2 g, 5.98 mmol) in 2-methyl-2-butanol (100 ml_, 5.98 mmol), acetic acid (10 ml_, 175 mmol) and palladium on carbon (0.382 g, 3.59 mmol) were added. The mixture was hydrogenated at 55psi for 6 days. The reaction mixture was filtered through celite and concentrated. The crude product was re-dissolved in 2-methyl-2-butanol (100 ml_), acetic acid (10 ml_, 175 mmol) and Pt 5 wt.% on activated carbon (0.350 g, 1.794 mmol) was added. The reaction mixture was hydrogenated at 55 psi for one day. The reaction mixture was filtered with celite and concentrated. The crude product was passed through an amino- silica cartridge to give (3R,5R)-3-(3-hydroxyphenyl)-8-methyl-4,8-diazaspiro[4.4]nonan-9-one (D13) (1 g); m/z (M+H+) 247.
Description 14: 3-[(2R,5R)-7-Methyl-6-oxo-1 ,7-diazaspiro[4.4]non-2-yl]phenyl trifluoromethane sulfonate (D14)
To a solution of (3R,5R)-3-(3-hydroxyphenyl)-8-methyl-4,8-diazaspiro[4.4]nonan-9-one (D13) (1.1 g,4.47 mmol) in dichloromethane (DCM) (15 ml_) at 0°C, 1 , 1 , 1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methanesulfonamide (1.755 g, 4.91 mmol) was added, then Et3N (0.934 ml_, 6.70 mmol) was added dropwise. After addition, the reaction mixture was stirred at 25 °C for 16 hrs. The solvent was evaporated and the residue purified by combiflash chromatography to get desired product 3-[(2R,5R)-7-methyl-6-oxo-1 ,7-diazaspiro[4.4]non-2- yl]phenyl trifluoromethanesulfonate (D14) 1.1 g; m/z (M+H+ 379).
Example 7: (3R,5R)-8-Methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one trifluoroacetic acid salt (E7)
Figure imgf000060_0001
In a microwave vial, to a solution of 3-[(2R,5R)-7-methyl-6-oxo-1 ,7-diazaspiro[4.4]non-2- yl]phenyl trifluoromethanesulfonate (D14) (30.0 mg, 0.079 mmol) in 1 ,4-dioxane (1.5 ml) and water (0.500 ml) was added 2-trifluoromethoxyphenylboronic acid (45.45 mg, 0.16 mmol) and potassium carbonate (54.8 mg, 0.396 mmol). The solution was degassed for 5 minutes. PdCI2(dppf) (5.80 mg, 7.93, 7.9 μηιοΙ) was added and the resulting solution was heated in a microwave at 100°C for 10 minutes. The solution was filtered and evaporated and the residue purified by reverse phase chromatography then treated with excess trifluoroacetic acid and evaporated to afford (3R,5R)-8-methyl-3-[3-[2-(trifluoromethoxy)phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one trifluoroacetic acid salt (E7); m/z (M+H+) 391 ; 1 H NMR (CD3OD) 400MHz δ 2.25-2.38 (1 H, m), 2.45-2.60 (4H, m), 2.70-2.80 (1 H, m), 2.96 (3H, s), 3.49-3.59 (2H, m), 4.91 (1 H, dd), 7.44-7.61 (6H, m), 7.74-7.79 (2H, m).
The following compounds were prepared by routes described in Preparation 2 using alternative boronic acids in the Suzuki coupling step and other modifications noted.
Figure imgf000061_0001
Preparation 3
Description 15: 1,1 -Dimethylethyl (2R,5R)-7-methyl-6-oxo-2-(3-
{[(trifluoromethyl)sulfonyl]-oxy}phenyl)-1 ,7-diazaspiro[4.4]nonane-1 -carboxylate (D15)
To a solution of 3-[(2R,5R)-7-methyl-6-oxo-1 ,7-diazaspiro[4.4]non-2-yl]phenyl
trifluoromethane sulfonate (D14) (2.5 g, 6.61 mmol) in tetrahydrofuran (100 ml_), bis(1 , 1- dimethylethyl) dicarbonate (5.77 g, 26.4 mmol) and Et3N (3.68 mL, 26.4 mmol) were added. The reaction mixture was stirred at 25 °C for 48 hrs. The solvent was evaporated under the reduced pressure to get crude product. It was purified using a combiflash, 120 g silica gel column, solvent: Hexane/EtOAc over 40 minutes to afford 1 , 1-dimethylethyl (2R,5R)-7- methyl-6-oxo-2-(3-{[(trifluoromethyl)sulfonyl]-oxy}phenyl)-1 ,7-diazaspiro[4.4]nonane-1- carboxylate (D15) 2.5 g; m/z (M+H+) 479.
Example 9: (3R,5R)-8-Methyl-3-[3-[2-((3-fluorophenyl)methoxy)-phenyl]phenyl]-4,8- diazaspiro[4.4]nonan-9-one (E9)
Figure imgf000062_0001
To a solution of 1 , 1-dimethylethyl (2R,5R)-7-methyl-6-oxo-2-(3-{[(trifluoromethyl)sulfonyl]- oxy}phenyl)-1 ,7-diazaspiro[4.4]nonane-1-carboxylate (D15) (30 mg, 0.063 mmol) in a mixture of 1 ,4-dioxane (1.5 ml_) and water (0.5 ml_), 2-(((3-fluorophenyl)methoxy)- phenylboronic acid (0.075mmol), K2C03 (14.4 mg, 0.103 mmol), LiCI (4.65 mg, 0.110 mmol) and Pd(PPh3)4 (5.8mg, 5.02 μηιοΙ) were added. The reaction mixture was subjected to microwave heating in a sealed tube at 120°C for 35 mins. A Stratospheres PL-Thiol MP SPE column was pre-treated with methanol, then the filtered reaction mix passed through the column, washing with methanol. The eluent was concentrated and purified by chromatography to give an intermediate which was deprotected using 4M HCI in dioxane, and the concentrated mixture passed through a 500 mg aminated silica column to afford (3R,5R)-8-methyl-3-[3-[2-((3-fluorophenyl)methoxy)-phenyl]phenyl]-4,8-diazaspiro[4.4]- nonan-9-one (E9); m/z (M+H+) 431 ; 1 H NMR 400 MHz (CD3OD) δ 1-89-2.25 (6H, m), 2.89 (3H, s), 3.37-3.40, (2H, m), 4.23 (1 H, dd), 5.08 (2H, s), 6.98-7.14 (5H, m), 7.28-7.46 (6H, m), 7.71 (1 H, d).
The following compounds were prepared by routes described in Preparation 3 using alternative boronic acids in the Suzuki coupling step and other modifications noted.
Figure imgf000062_0002
E11 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[3- 391 as catalyst in
(trifluoromethoxy)phenyl] Suzuki, no phenyl]-4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E12 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2-methylphenyl]phenyl]- 321 as catalyst in
4,8- Suzuki, no
I diazaspiro[4.4]nonan-9- LiCI;
one TFA salt subsequent formation of TFA salt
E13 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[4- 399 as catalyst in
(phenyloxy)phenyl]phen Suzuki, no yl]-4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E14 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[4- 351 as catalyst in
(ethyloxy)phenyl]phenyl] Suzuki, no -4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E15 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2,4-di- 367 as catalyst in
(methoxy)phenyl]phenyl] Suzuki, no
-4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
Figure imgf000064_0001
E21 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2-(prop-1-yloxy)-4- 383 as catalyst in (fluoro)-phenyl]phenyl]- Suzuki, no 4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E22 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[3-(trifluoromethyl)- 375 as catalyst in phenyl]phenyl]-4,8- Suzuki, no
I diazaspiro[4.4]nonan-9- LiCI;
one TFA salt subsequent formation of TFA salt
E23 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[4-(dimethylamino)- 350 as catalyst in phenyl]phenyl]-4,8- Suzuki, no diazaspiro[4.4]nonan-9- LiCI;
one TFA salt subsequent formation of TFA salt
E24 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2- 399 as catalyst in
(phenoxy)phenyl]phenyl] Suzuki, no -4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E25 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[4- 375 as catalyst in
(trifluoromethyl)phenyl]p Suzuki, no henyl]-4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt E26 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2-(ethyl)phenyl]phenyl]- 335 as catalyst in
4,8- Suzuki, no diazaspiro[4.4]nonan-9- LiCI;
one TFA salt subsequent formation of
TFA salt
E27 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[3- 351 as catalyst in
(ethoxy)phenyl]phenyl]- Suzuki, no
4,8- LiCI;
IL diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E28 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[3- 365 as catalyst in
(propoxy)phenyl]phenyl]- Suzuki, no
4,8- LiCI;
diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E29 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2- 337 as catalyst in
(methoxy)phenyl]phenyl] Suzuki, no
-4,8- LiCI;
L¾. IJ diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
E30 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2-(prop-2- 365 as catalyst in yloxy)phenyl]phenyl]- Suzuki, no
4,8- LiCI;
L¾. diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt E31 (3R,5R)-8-Methyl-3-[3- M+H+ PdCI2.(dppf)
[2-(2-methylprop-1- 379 as catalyst in yloxy)phenyl]phenyl]- Suzuki, no
4,8- LiCI;
L¾. IJ diazaspiro[4.4]nonan-9- subsequent one TFA salt formation of
TFA salt
Preparation 4
Description 16: (E)-3-((3-Bromobenzylidene)amino)-1 -methylpyrrolidin-2-one (D16)
A solution of 3-amino-1-methyl-2-pyrrolidinone (0.622 g, 5.45 mmol) in dichloromethane (5 ml) was treated with 3-bromobenzaldehyde (0.916 g, 4.95 mmol) followed by magnesium sulphate (1.192 g, 9.90 mmol). The mixture was stirred at room temperature overnight and then the mixture was diluted with dichloromethane and washed with water (2 x) and brine and then dried (MgS04) and evaporated to give a yellow oil (1.398 g); NMR δΗ (CDCI3) 2.25-2.40 (1 H, m), 2.45-2.55 (1 H, m), 2.94 (3H, s), 3.40-3.45 (1 H, m), 3.55-3.65 (1 H, m), 4.08 (1 H, dd), 7.25-7.30 (1 H, m), 7.55-7.60 (1 H, m), 7.64 (1 H, d), 8.08 (1 H, s), 8.36 (1 H, s).
Description 17: 2-(3-Bromophenyl)-7-methyl-3-(phenylsulfonyl)-1 ,7- diazospiro[4.4]nonan-6-one (D17a, D17b)
A mixture of (E)-3-((3-bromobenzylidene)amino)-1-methylpyrrolidin-2-one (D16) (3.468 g, 12.34 mmol) and phenyl vinyl sulphone (3.455 g, 20.54 mmol) in acetonitrile (35 ml) was treated with silver acetate (3.09 g, 18.50 mmol) and DBU (1.859 ml, 12.34 mmol) and the mixture was stirred in the dark for 1 hour. The mixture was then filtered through Celite and the solvent was evaporated. Chromatography on silica gel (elution with 40-100% ethyl acetate in isohexane) gave 2 fractions: Isomer 1 (D17a) 3.260g, LC-MS: MH+ = 449/451 , C2oH2i BrN203S requires 448/450; Isomer 2 (D17b) 1.174g, LC-MS: MH+ = 449/451 , C2oH2i BrN203S requires 448/450.
Description 17 (alternative chiral method; D17c)
Tetrakis(acetonitrile)copper(l)hexafluorophosphate (46mg, 0.12mmol) and (2S)-1-[(R)- (dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]-2-(diphenylphosphino)ferrocene (86 mg, 0.12mmol) were combined in toluene (5ml) and stirred for 30 minutes in the dark. A solution of (E)-3-((3-bromobenzylidene)amino)-1-methylpyrrolidin-2-one (D16) (700mg, 2.49mmol) in toluene (10ml) was added, followed by triethylamine (62μΙ, 0.45mmol). The reaction mixture was cooled in an ice bath and a solution of phenyl vinyl sulphone (418mg, 2.49mmol) in toluene (4ml) was added. The reaction was allowed to warm to room temperature and stirred for 6 days. Acetic acid (30μΙ) was added and the reaction mixture concentrated at reduced pressure. The residue was dissolved in methanol and applied to an SCX column. The column was eluted with methanol followed by 0.5M ammonia in methanol. Basic fractions were combined and concentrated and then the residue was purified by silica gel chromatography eluting with 20-100% ethyl acetate in iso-hexane to yield (5R,7R,8R)-7- (benzenesulfonyl)-8-(3-bromophenyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (D17c) (736 mg, 66%).
MS: (ES/+) MH+ 449, 451. C20H21 BrN2O3S requires 448, 450.
Description 18: (S)-2-(3-Bromophenyl)-7-methyl-1 ,7-diazospiro[4.4]non-1 -en-6-one and (R)-2-(3-bromophenyl)-7-methyl-1 ,7-diazospiro[4.4]non-1 -en-6-one (D18a, D18b)
The 2 isomers (D17a, D17b) (4.43g) were combined in THF (99ml) at 0°C under argon and treated with potassium t-butoxide (5.53 g, 49.3 mmol) portionwise (1.5g followed by 1.7g followed by 2.33g at approx 2 minute intervals). The mixture was stirred at 0°C for 30 minutes and acetic acid (3.39 ml, 59.2 mmol) was added dropwise. The mixture was then diluted with methanol and applied directly to SCX resin. The SCX was washed with methanol and then the product was released by elution with 2N ammonia in methanol to give racemic product 2.865 g as an orange gum. This was separated by preparative chiral HPLC (ChiralPak AD, elution with 40% ethanol/ 60% heptane) to give fast isomer (D18a) 1.119 g and slow isomer (D18b)1.113 g; (D18a): (chiral HPLC) (S-isomer), LC-MS: MH+ = 307/309, Ci4H15BrN02 requires 306/308; (D18b): (chiral HPLC), (ft-isomer), LC-MS: MH+ = 307/309, Ci4H15BrN02 requires 306/308
Description 19: (2 ?,5S)-2-(3-Bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one and (2S,5S)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D19a, D19b)
A solution of (S)-2-(3-bromophenyl)-7-methyl-1 ,7-diazospiro[4.4]non-1-en-6-one (D18a) (1.117 g, 3.64 mmol) in ethanol (36 ml) was treated with c.HCI (1.8 ml, 59.2 mmol) and sodium cyanoborohydride (686 mg, 10.92 mmol) and the mixture was stirred at room temperature for 20 minutes. Saturated NaHC03 solution was added to adjust the pH to 5 and then water was added to give a clear solution. This solution was passed through an SCX column to trap the product which was then eluted with 2N ammonia in methanol. The eluent containing the product was concentrated and then chromatographed on silica gel (elution with 50-100% ethyl acetate in isohexane) to give (2f?,5S)-2-(3-bromophenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one (149 mg) (D19a) (eluted first) and (2S,5S)-2-(3- bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D19b) (930mg) (eluted second); (D19a): (2R, 5S-isomer), LC-MS: MH+ = 309/31 1 , Ci4H17BrN02 requires 308/310; (D19b): (2S, 5S-isomer), LC-MS: MH+ = 309/31 1 , C14H17BrN02 requires 308/310 - the absolute stereochemistry of this product was determined by x-ray crystallography.
Description 20: (2S,5 ?)-2-(3-Bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D20a) and (2 ?,5 ?)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D20b).
Treatment of solution of (R)-2-(3-bromophenyl)-7-methyl-1 ,7-diazospiro[4.4]non-1 -en-6-one (D18b) (1 .109 g, 3.61 mmol) in ethanol (36 ml) with cHCI (1.8 ml, 59.2 mmol) and sodium cyanoborohydride (535 mg, 8.51 mmol) in a similar manner to that described above followed by work up and chromatography gave (2S,5f?)-2-(3-bromophenyl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (D20a) (136mg) (eluted first) and (2ft,5ft)-2-(3-bromophenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D20b) (849 mg) (eluted second); (D20a): (2S, 5R- isomer), LC-MS: MH+ = 309/31 1 , Ci4H17BrN02 requires 308/310; (D20b): (2R, 5ft-isomer), LC-MS: MH+ = 309/31 1 , Ci4H17BrN02 requires 308/310
Description 21 : 3-Ethyl-2-fluorobenzeneboronic acid (D21 )
To a 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.8457 mL, 0.8457 mmol) in tetrahydrofuran (1 mL) at -78 °C was added n-butyl lithium (0.3383 mL, 0.8457 mmol). The mixture was stirred at -78 °C over 15mins. 1 -Ethyl-2-fluorobenzene (100 mg, 0.8054 mmol) was added to the solution and the mixture stirred over 2hrs. Triisopropylborate (302.95 mg, 1 .6108 mmol) was added and the mixture allowed to warm to room temp and stirred over 2hrs. The reaction mixture was quenched with water (1 ml) and acidified with 2M aqueous hydrochloric acid (2 mL). The mixture was extracted into ethyl acetate and the extracts were dried over magnesium sulphate, filtered and evaporated to yield a brown solid. Column chromatography (5-100% ethyl acetate / iso-hexane) yielded the title compound (D21 ) as a white solid (69 mg, 0.4108 mmol, 51 % yield).
NMR (CDCIa) δ 1 .31 (3H, t), 2.79 (2H, q), 7.22 (1 H, t), 7.46 (1 H, t), 8.03 (1 H, t).
Description 22: 5-Ethyl-2-fluorobenzeneboronic acid (D22)
The title compound was prepared in a similar manner to (D21 ) starting from 4- ethylfluorobenzene to yield the title compound as a yellow solid; NM R (CDCI3) δ 1 .32 (3H, t), 2.73 (2H, q), 7.06 (1 H, t), 7.40 (1 H, m), 7.97 (1 H, m). Example 32: (2S,5S)-2-(2'-Fluoro-[1 ,1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one hyd
Figure imgf000070_0001
A mixture of (2S,5S)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D19b) (150 mg, 0.485 mmol) and (2-fluorophenyl)boronic acid (136 mg, 0.970 mmol) and potassium carbonate (201 mg, 1.454 mmol) in 1 ,4-dioxane (3 ml) and water (1 ml) was degassed with argon bubbling and tetrakis(triphenylphosphine)palladium (0) (28 mg, 0.024 mmol) was added. The mixture was refluxed for 5 hrs and then cooled and acetic acid (0.13 ml) was added and the product was passed through a SCX column. The column was washed with dioxin/water/methanol and the product was eluted with 2M ammonia in methanol. The solvent was removed and the product was chromatographed on silica gel (elution with 50-100% ethyl acetate in isohexane) to give the title compound (140mg); LC- MS: MH+ = 325 C20H21 FN2O requires 324; NMR δΗ (CDCI3) 1.80-1.90 (1 H, m), 2.05-2.35 (6H, m), 2.90 (3H, s), 3.30-3.40 (2H, m). 4.30 (1 H, dd), 7.10-7.35 (3H, m), 7.40-7.50 (3H, m), 7.55-7.58 (1 H, m), 7.60 (1 H, s). The product was dissolved in DCM and treated with 1 M HCl in diethyl ether (0.47ml). The solvents were evaporated and the solid was triturated with diethyl ether and dried in a vacuum oven to give the hydrochloride salt (155 mg); LC-MS: MH+ = 325 C20H21 FN2O requires 324
Example 33: (2R,5S)-2-(2'-Fluoro-[1 ,1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]- nonan-6-one hydrochloride (E3
Figure imgf000070_0002
In a similar fashion, a mixture of (2R,5S)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4] nonan-6-one (D19a) (79.7mg, 0.258 mmol) and (2-fluorophenyl)boronic acid (72.1 mg, 0.516 mmol) and potassium carbonate (107 mg, 0.774 mmol) and
tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.04 mmol) in 1 ,4-dioxane (1.5 ml) and water (0.5 ml) were reacted together and worked up and purified as above to give the title compound (E33) 60.1 mg; LC-MS: MH+ = 325 C20H21 FN2O requires 324; NMR δΗ (CDCI3) 1.77-1.95 (2H, m), 2.00-2.07 (1 H, m), 2.10-2.20 (2H, m), 2.35-2.43 (1 H, m), 2.50 (1 H, broad s), 2.89 (3H, s), 3.22-3.32 (2H, m). 4.68 (1 H, dd), 7.10-7.22 (2H, m), 7.26-7.34 (1 H, m), 7.36-7.50 (4H, m), 7.59 (1 H, s). This was converted to the hydrochloride salt (63 mg) as above; LC-MS: MH+ = 325 C20H21 FN2O requires 324.
Example 34: (2 ?,5 ?)-2-(2'-Fluoro-[1 ,1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one hyd
Figure imgf000071_0001
In a similar fashion, a mixture of (2f?,5f?)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]- nonan-6-one (D20b) (150 mg, 0.485 mmol) and (2-fluorophenyl)boronic acid (136 mg, 0.972 mmol) and potassium carbonate (201 mg, 1.454 mmol) and tetrakis(triphenylphosphine)- palladium (0) (28 mg, 0.024 mmol) in 1 ,4-dioxane (3 ml) and water (1.5 ml) were reacted together and worked up as above. Purification by MDAP gave the title compound (E34) 140 mg; LC-MS: MH+ = 325 C20H21 FN2O requires 324; NMR δΗ (CDCI3) 1.80-1.90 (1 H, m), 2.05- 2.35 (6H, m), 2.91 (3H, s), 3.28-3.38 (2H, m). 4.30 (1 H, dd), 7.10-7.35 (3H, m), 7.40-7.50 (3H, m), 7.55-7.58 (1 H, m), 7.60 (1 H, s). This product was converted to the hydrochloride salt as above; LC-MS: MH+ = 325 C20H21 FN2O requires 324.
Example 35: (2S,5 ?)-2-(2'-Fluoro-[1 ,1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]- nonan-6-one hydrochloride (E35)
Figure imgf000072_0001
In a similar fashion, a mixture of (2S,5f?)-2-(3-bromophenyl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (D20a)(65 mg, 0.210 mmol) and (2-fluorophenyl)boronic acid (58.8 mg, 0.420 mmol) and potassium carbonate (87 mg, 0.629 mmol) and
tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.104 mmol) in 1 ,4-dioxane (1.5 ml) and water (0.5 ml) were reacted together and worked up as above and purified by MDAP to give the title compound (E35) 56.9 mg; LC-MS: MH+ = 325 C20H21 FN2O requires 324; NMR δΗ (CDCIa) 1.77-1.95 (2H, m), 2.00-2.08 (1 H, m), 2.10-2.20 (2H, m), 2.30-2.50 (2H, m), 2.89 (3H, s), 3.22-3.31 (2H, m). 4.68 (1 H, dd), 7.10-7.22 (2H, m), 7.26-7.33 (1 H, m), 7.36-7.48 (4H, m), 7.59 (1 H, s). This product was converted to the hydrochloride salt as above; LC- MS: MH+ = 325 C20H21 FN2O requires 324.
The following compounds were prepared using alternative boronic acids in the Suzuki coupling step by the route described in Preparation 4 with other modifications noted. The preparation of non-commercial boronic acids D21 and D22 is recorded above.
Example Structure Name Analysis Modification
E36 (2R,5R)-2-(3'-Ethyl-2'- MH+ Reducing
fluoro-biphenyl-3-yl)-7- (ES) agent: LiBH4 (as methyl-1 ,7-diaza- 353.12 in E105
spiro[4.4]nonan-6-one Preparation 5) hydrochloride
E37 (2S,5R)-2-(2'-Fluoro- MH+ Reducing
biphenyl-3-yl)-7-methyl- (ES) agent: LiBH4
1 ,7-diaza- 353.12 (Preparation 5) spiro[4.5]decan-6-one
hydrochloride
Figure imgf000072_0002
E38 (2S,5S)-2-(2'-Fluoro- MH+ Reducing
biphenyl-3-yl)-7-methyl- (ES) agent: LiBH4
1 ,7-diaza- 353.1 1 (Preparation 5) spiro[4.5]decan-6-one
hydrochloride
E39 (2R,5S)-2-(2'-Fluoro- MH+ Reducing
biphenyl-3-yl)-7-methyl- (ES) agent: LiBH4
1 ,7-diaza- 353.14 (Preparation 5) spiro[4.5]decan-6-one
hydrochloride
E40 (2R,5R)-2-(5'-Ethyl-2'- MH+ Reducing
fluoro-biphenyl-3-yl)-7- (ES) agent: LiBH4 methyl-1 ,7-diaza- 353.14 (Preparation 5) spiro[4.4]nonan-6-one
hydrochloride
E41 (2S,5R)-2-(5'-Ethyl-2'- MH+ Reducing
fluoro-biphenyl-3-yl)-7- (ES) agent: LiBH4 methyl-1 ,7-diaza- 353.14 (Preparation 5) spiro[4.4]nonan-6-one
hydrochloride
E42 (2S,5S)-2-(5'-Ethyl-2'- MH+ Reducing
fluoro-biphenyl-3-yl)-7- (ES) agent: LiBH4 methyl-1 ,7-diaza- 353.15 (Preparation 5) spiro[4.4]nonan-6-one
hydrochloride
E43 (2R,5S)-2-(5'-Ethyl-2'- MH+ Reducing
fluoro-biphenyl-3-yl)-7- (ES) agent: LiBH4 methyl-1 ,7-diaza- 353.12 (Preparation 5) spiro[4.4]nonan-6-one
hydrochloride
Figure imgf000073_0001
Figure imgf000074_0001
one hydrochloride
Figure imgf000075_0001
one hydrochloride
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
one hydrochloride
Figure imgf000079_0001
one hydrochloride
Figure imgf000080_0001
Figure imgf000081_0001
one hydrochloride
Figure imgf000082_0001
(ES) of E97 by prep
41 1 chiral HPLC
E100 Racemic-trans-2-(2- MH+ Use 3-bromo-2- fluoro-2'-isobutoxy-5'- (ES) fluorobenzaldeh methyl-[1 , 1 '-biphenyl]- 41 1 yde; Imine
A 3-yl)-7-methyl-1 ,7- reduced with
diazaspiro[4.4]nonan-6- NaBH(OAc)3, one HCI in THF
Preparation 5
A variation of the route described in Preparation 4 in which the Suzuki coupling was performed on the imine prior to reduction.
Description 23: (S)-2-(3-Bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1 -en- 6-one (D23)
(S)-2-(3-Bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1-en-6-one (D23) was prepared in a manner similar to (D18a) in Preparation 4, except for starting from 3-bromo-2- fluorobenzaldehyde in place of 3-bromobenzaldehyde and using a ChiralPak AD-H column for the chiral separation step.
Description 24: (S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1 - en-6-one (D24)
To a solution of (S)-2-(3-Bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1 -en-Bone (D23) (409 mg, 1.33 mmol) in 1 ,2-dimethoxyethane (10ml_) and water (3 mL) was added 2-fluorophenylboronic acid (186.29 mg, 1.33 mmol) and sodium carbonate (423.36 mg, 3.99 mmol). The reaction mixture was degassed with nitrogen and then treated with
bis(triphenylphosphine)palladium (II) dichloride (46.73 mg, 0.0700 mmol). The reaction was heated in the microwave at 120 °C for 1 hour and then diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re-extracted with
dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane to give the title compound (D24) (372 mg); MS: (ES/+) MH+ 341. C20H18F2N2O requires 340.
An Alternative Suzuki coupling method is described in D25-D26 Description 25: (S)-2-(3-Bromo-phenyl)-7-ethyl-1 ,7-diaza-spiro[4.4]non-1 -en-6-one (D25)
(S)-2-(3-Bromo-phenyl)-7-ethyl-1 ,7-diaza-spiro[4.4]non-1-en-6-one (D25) was prepared in a manner similar to (D18a) in preparation 4, except for starting from 3-amino-1-ethyl-2- pyrrolidinone in place of 3-amino-1-methyl-2-pyrrolidinone and using a ChiralPak AD-H column for the chiral separation step.
Description 26: (S)-7-Ethyl-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]non-1 -en-Bone (D26)
A solution of (S)-2-(3-Bromo-phenyl)-7-ethyl-1 ,7-diaza-spiro[4.4]non-1-en-6-one (D25) (227. mg, 0.7100 mmol), 2-fluorophenylboronic acid (148.32 mg, 1.06 mmol) and potassium carbonate (293.02 mg, 2.12 mmol) in 1 ,4-dioxane (5 ml_) and water (1 ml_) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (40.81 mg, 0.0400 mmol) was added and the mixture stirred at 90°C over 3hrs. The reaction mixture was allowed to cool, then filtered over kieselguhr and evaporated. The residues were partitioned between
dichloromethane and sat. aq. sodium bicarbonate and separated using a hydrophobic frit. The organic phase was evaporated to yield a brown gum. Column chromatography (10- 100% ethyl acetate in iso-hexane) yielded the title compound (D26) as a brown gum (235 mg, 0.7194 mmol, 99.54% yield); NMR (CDCI3) δ 1.20 (3H, t), 1.83-1.98 (1 H, m), 2.07-2.21 (1 H, m), 2.38-2.50 (1 H, m), 2.51-2.62 (1 H, m), 3.05-3.19 (1 H, m), 3.25-3.52 (4H, m), 3.60- 3.70 (1 H, m), 7.1 1-7.26 (2H, m), 7.29-7.40 (1 H, m), 7.43-7.53 (2H, m), 7.59-7.67 (1 H, m), 7.87 (1 H, d), 8.03 (1 H, s).
Examples 101 , 102 (2R,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza- spiro[4.4]nonan-6-one (E101 ) and (2S,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7- diaza-spiro[4.4]nonan-6-one E102)
Figure imgf000084_0001
To a solution of (S)-2-(2,2'-difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1-en-6- one (D24) (370 mg, 1.0871 mmol) in THF (15 ml_) cooled in an ice bath was added concentrated hydrochloric acid (100 μΙ), followed by the portionwise addition of lithium borohydride (71.028 mg, 3.2612 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and then stirred for 1 hour. A further aliquot of lithium borohydride (72 mg) was added and the reaction stirred for a further 16 hours at room temperature. The reaction mixture was cooled and quenched carefully by the addition of saturated aqueous ammonium chloride. Dichloromethane was added and the mixture stirred for 5 minutes. The organic solution was separated using a hydrophobic frit and the solvent evaporated at reduced pressure. The borane adduct was suspended in 5M hydrochloric acid (8 ml) and heated to 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was basified to ~pH8 by the addition of 2M sodium hydroxide solution. Dichloromethane was added and the mixture stirred for 5 minutes before separation of the organic phase using a hydrophobic frit. The solvent was evaporated and the residue dissolved in methanol and applied to an SCX column. The column was eluted with methanol, followed by 0.5M ammonia in methanol. Basic fractions were combined and concentrated to give the crude products. The products were purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane. Faster isomer, (2R,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E101) (230mg, 62%); NMR (CDCI3) δ 1.71-1.96 (2H, m), 1.97-2.26 (3H, m), 2.44-2.69 (2H, m), 2.92 (3H, s), 3.29-3.34 (2H, m), 4.93-4.98 (1 H, m), 7.14-7.29 (4H, m), 7.35-7.42 (2H, m), 7.69-7.71 (1 H, m).
MS: (ES/+) MH+ 343. C20H20F2N2O requires 342.
Slower isomer, (2S,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E102) (56mg, 15%). NMR (CDCI3) δ 1.81-1.88 (1 H, m), 1.99-2.08 (1 H, m), 2.14-2.41 (4H, m), 2.95 (3H, s), 3.31-3.38 (2H, m), 4.68-4.71 (1 H, m), 7.14-7.30 (4H, m), 7.34-7.41 (2H, m), 7.88-7.94 (2H, m).
MS: (ES/+) MH+ 343. C20H20F2N2O requires 342.
Example 101 hydrochloride salt (2R,5S)-2-(2,2'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7- diaza-spiro[4.4]nonan-6-one hydrochloride
Figure imgf000085_0001
To a solution of (2R,5S)-2-(2,2'-difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E101) (220 mg, 0.60 mmol) in dichloromethane (5m L) was added 1 M hydrogen chloride in diethyl ether (1.90 ml_, 1.90 mmol). The reaction mixture was stirred at room temperature under nitrogen for 30 minutes and then concentrated at reduced pressure to give the title compound (230 mg, 94%); MS: (ES/+) MH+ 343. C20H20F2N2O requires 342.
The following compounds were prepared by Procedure 5 using alternative boronic acids and final stage imine reduction, with the modifications noted. Racemic analogues were prepared from racemic imine.
Figure imgf000086_0001
E105 by prep chiral HPLC
E107 Enantiomer 2 of E105 MH+ (ES) From
41 1 separation of
E105 by prep chiral HPLC
E108 Racemic-cis-2-(4- MH+ (ES) Use 2-fluoro- fluoro-2'-isobutoxy-5'- 41 1 5- methyl-[1 , 1 '-biphenyl]- bromobenzal
3-yl)-7-methyl-1 ,7- dehyde; diazaspiro[4.4]nonan- Imine
6-one reduced with
Pt02/H2
E109 Racemic-trans-2-(4- MH+ (ES) Use 2-fluoro- fluoro-2'-isobutoxy-5'- 41 1 5- methyl-[1 , 1 '-biphenyl]- bromobenzal
XXX 3-yl)-7-methyl-1 ,7- dehyde;
diazaspiro[4.4]nonan- Imine
6-one reduced with
NaBH(OAc)3, HCI in THF
E110 Enantiomer 1 of E109 MH+ (ES) From
41 1 separation of
E109 by prep chiral HPLC
E111 Enantiomer 2 of E109 MH+ (ES) From
41 1 separation of
E109 by prep chiral HPLC
Figure imgf000088_0001
E117 (2R,5S)-2-(2'-Fluoro- MH+ (ES) Use 3-amino- biphenyl-3-yl)-7- 339.1 1-ethyl-2- methyl-1 ,7-diaza- pyrrolidinone spiro[4.5]decan-6-one in place of hydrochloride (D18a)
Reduction using
NaBH(OAc)3
(preparation
6)
E118 (2R,5R)-2-(2'-Fluoro- MH+ (ES) Use 3-amino- biphenyl-3-yl)-7- 339.1 1-ethyl-2- methyl-1 ,7-diaza- pyrrolidinone spiro[4.5]decan-6-one in place of hydrochloride (D18a)
Figure imgf000089_0001
Reduction using
NaBH(OAc)3
(preparation
6)
E119 (2S,5R)-2-(2'-Fluoro- MH+ (ES) Use 3-amino- biphenyl-3-yl)-7- 339.1 1-ethyl-2- methyl-1 ,7-diaza- pyrrolidinone spiro[4.5]decan-6-one in place of hydrochloride (D18a)
Figure imgf000089_0002
Reduction using
NaBH(OAc)3
(preparation
6)
E120 (2S,5R)-7-Ethyl-2-(2'- MH+ (ES) Used
fluoro-biphenyl-3-yl)- 339.1 alternative
1 ,7-diaza- Suzuki spiro[4.4]nonan-6-one conditions of
Figure imgf000089_0003
hydrochloride D25-D26 E121 (2R,5R)-7-Ethyl-2-(2'- MH+ (ES) Used
fluoro-biphenyl-3-yl)- 339.1 alternative
1 ,7-diaza- Suzuki spiro[4.4]nonan-6-one conditions of hydrochloride D25-D26
E122 (2R,5S)-7-Ethyl-2-(2'- MH+ (ES) Used
fluoro-biphenyl-3-yl)- 339.1 alternative
1 ,7-diaza- Suzuki spiro[4.4]nonan-6-one conditions of hydrochloride D25-D26
E123 (2S,5S)-7-Ethyl-2-(2'- MH+ (ES) Used
fluoro-biphenyl-3-yl)- 339.1 alternative
1 ,7-diaza- Suzuki spiro[4.4]nonan-6-one conditions of hydrochloride D25-D26
E124 (2R,5R)-2-[6-(2- MS (ES) Use 2- Fluoro-phenyl)- M+H+ 326 bromo- pyridin-2-yl]-7-methyl- pyridine-6-
Figure imgf000090_0001
1 ,7-diaza- carboxaldehy spiro[4.4]nonan-6-one de in place of hydrochloride 3- bromobenzal dehyde
E125 (2S,5R)-2-[6-(2- MS (ES) Use 2- N Fluoro-phenyl)- M+H+ 326 bromo-
Figure imgf000090_0002
pyridin-2-yl]-7-methyl- pyridine-6- x // HCI 1 ,7-diaza- carboxaldehy spiro[4.4]nonan-6-one de in place of hydrochloride 3- bromobenzal dehyde
Figure imgf000091_0001
Figure imgf000092_0001
6-one hydrochloride E137 (2R,5S)-2-(2',4'- MH+ (ES)
U ■γ H o / Difluoro-biphenyl-3- 343
|j F yl)-7-methyl-1 ,7- .Hci
diaza-spiro[4.4]nonan-
F
6-one hydrochloride
E138 (2S,5S)-2-(2',4'- MH+ (ES)
Difluoro-biphenyl-3- 343
yl)-7-methyl-1 ,7- diaza-spiro[4.4]nonan-
6-one hydrochloride
E139 (2S,5R)-2-(2,2'- MH+ (ES) Use 2-fluoro-
Difluoro-biphenyl-3- 343 3- yl)-7-methyl-1 ,7- bromobenzal
Figure imgf000093_0001
diaza-spiro[4.4]nonan- dehyde in 6-one hydrochloride place of 3- bromobenzal dehyde
E140 (2R,5R)-2-(2,2'- MH+ (ES) Use 2-fluoro-
Difluoro-biphenyl-3- 343 3- yl)-7-methyl-1 ,7- bromobenzal
Figure imgf000093_0002
diaza-spiro[4.4]- dehyde in nonan-6-one place of 3- hydrochloride bromobenzal dehyde
E157 Racemic-cis-2-(2',5- MH+ (ES) Use 5-fluoro- difluoro-[1 , 1 '- 343 5- biphenyl]-3-yl)-7- bromobenzal methyl-1 ,7- dehyde in diazaspiro[4.4]nonan- place of 3-
6-one bromobenzal dehyde; Imine reduced with Pt02/H2 E158 I CO Racemic-trans-2-(2',4- MH+ (ES) Use 2-fluoro- difluoro-[1 , 1 '- 343 5- biphenyl]-3-yl)-7- bromobenzal methyl-1 ,7- dehyde in diazaspiro[4.4]nonan- place of 3-
6-one bromobenzal dehyde;
Imine
reduced with
NaBH(OAc)3,
HCI in THF
Preparation 6
Description 27: 2-(3-Bromo-phenyl)-1 ,7-diaza-spiro[4.5]dec-1 -en-6-one (D27)
The title compound was prepared in a manner similar to the procedure for (D16) in
Preparation 4, but using 3-amino-piperidin-2-one as starting material in place of 3-amino-1- methyl-2-pyrrolidinone.
Description 28: 2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]dec-1 -en-6-one (D28)
To a solution of 2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.5]dec-1-en-6-one (D27) (400 mg, 1.3 mmol) in water (3ml_) and 1 ,2-dimethoxyethane (10ml_) was added sodium carbonate (414.04 mg, 3.91 mmol) and 2-fluorophenylboronic acid (182.19 mg, 1.3 mmol). The reaction mixture was degassed with nitrogen and then treated with
bis(triphenylphosphine)palladium(ll)dichloride (45.7 mg, 0.0700 mmol). The reaction was heated in a microwave at 120 °C for 1 hour. The reaction mixture was diluted with dichloromethane and passed over a hydrophobic frit. The filtrate was evaporated to give a yellow gum. Column chromatography (0-10% methanol in dichloromethane) yielded the title compound (368 mg, 1.1415 mmol, 87% yield) as a clear oil which solidified on standing to give (D28);
LCMS (5 min method): 1.73min, MH+ 323.2
Example 141 : 2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E141 )
Figure imgf000095_0001
To a solution of 2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]dec-1-en-6-one (D28) (194 mg, 0.6000 mmol) in 1 M aq. hydrochloric acid (12.04 mL, 12.04 mmol) and tetrahydrofuran (24 mL) at -10°C was added sodium triacetoxyborohydride (2550.8 mg, 12.04 mmol) portionwise. The solution was stirred at -10°C over 7hrs. The reaction mixture was concentrated to remove tetrahydrofuran. The remaining material was basified with sat. aq. sodium carbonate and extracted into dichloromethane. The extracts were passed over a hydrophobic frit and evaporated to yield a light brown gum. Column chromatography (2% methanol in dichloromethane) yielded two diastereoisomers.
Diastereoisomer A (E141a), a racemic mixture of (2R,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7- diaza-spiro[4.5]decan-6-one and (2S,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.5]decan-6-one (126 mg, 0.388 mmol, 65% yield); LCMS (5 min method): 1.23min, MH+ 325.12
Diastereoisomer B (E141 b), a racemic mixture of (2R,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7- diaza-spiro[4.5]decan-6-one and (2S,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.5]decan-6-one (87 mg, 0.268 mmol, 45% yield); LCMS (5 min method): 1.23 min, MH+ 325.12.
Example 142: (2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E142)
Figure imgf000095_0002
A racemic mixture of (2R,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one and (2S,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E141a) was separated by chiral prep-HPLC (AD-H, 30:70 ethanol:heptane, 20min) to give the title compound
(E142):
Fast isomer, (2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E142);
NMR (CDCI3) δ 1.76-2.02 (6H, m), 2.21-2.44 (2H, m), 2.45-2.91 (1 H, bs), 3.26-3.42 (2H, m), 4.73 (1 H, t), 6.26 (1 H, s), 7.10-7.26 (2H, m), 7.27-7.36 (1 H, m), 7.38-7.52 (4H, m), 7.63 (1 H, s); LCMS (5min method) 1.21 min, MH+ 325.2.
Example 142 hydrochloride salt: (2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.5]decan-6-one hydrochloride E142)
Figure imgf000096_0001
To a solution of (2R,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E142) (40mg, 0.120mmol) in dichloromethane (1 ml_) was added a 1 M solution of hydrogen chloride in diethyl ether (2ml_). The mixture was stirred at room temperature over 1 hr. Evaporation of the solvents yielded the title compound as a pale yellow solid (43 mg, 0.120 mmol, 100%); LCMS (5 min method) 1.25min, MH+ 325.2
Examples 143, 144 (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E143) and (2S,5R)-2-(2'-Fl [4.5]decan-6-one (E144)
Figure imgf000096_0002
A racemic mixture of (2R,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one and (2S,5R)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E141 b) was separated by chiral prep-HPLC (AD-H, 30:70 ethanol:heptane, 20min) to give the title compounds. Fast isomer, (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E143) NMR (CDCIs) δ 1.79-2.12 (6H, m), 2.20-2.44 (2H, m), 2.56-2.82 (1 H, bs), 3.27-3.47 (2H, m), 4.23 (1 H, q), 6.19 (1 H, s), 7.09-7.26 (2H, m), 7.27-7.37 (1 H, m), 7.38-7.60 (4H, m), 7.63-7.71 (1 H, s); LCMS (5 min method) 1.25 min, MH+ 325.2
Slow isomer, (2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.5]decan-6-one (E144) NMR (CDCI3) δ 1.79-2.12 (6H, m), 2.20-2.44 (2H, m), 2.56-2.82 (1 H, bs), 3.27-3.47 (2H, m), 4.23 (1 H, q), 6.19 (1 H, s), 7.09-7.26 (2H, m), 7.27-7.37 (1 H, m), 7.38-7.60 (4H, m), 7.63-7.71 (1 H, s) LCMS (5 min method) 1 .25 min, MH+ 325.2
The following compounds were prepared by the route described in Preparation 6
Figure imgf000097_0001
Preparation 7
Description 29: 3-{[1 -(3-Bromo-phenyl)-methylidene]-amino}-pyrrolidin-2-one (D29)
To a solution of 3-aminopyrrolidin-2-one (500 mg, 4.994 mmol) in DCM (8 ml_) was added magnesium sulphate (1378.3 mg, 1 1.486 mmol) followed by 3-bromobenzaldehyde (923.99 mg,4.994 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and filtrate evaporated to yield 3-{[1 -(3-Bromo-phenyl)-methylidene]- amino}-pyrrolidin-2-one (D29) (1 .276 g, 4.7769 mmol, 95% yield) as a yellow solid.
NMR (CDCIs) δ 2.39-2.63 (2H, m), 3.46 (1 H , m), 3.61 (1 H , m), 4.07 (1 H, t), 6.39 (1 H, bs), 7.28 (1 H, t), 7.57 (1 H, d), 7.67 (1 H , d), 8.00 (1 H, s), 8.36 (1 H, s).
Description 30: 3-Benzenesulfonyl-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6- one (D30)
To a solution of 3-{[1 -(3-bromo-phenyl)-methylidene]-amino}-pyrrolidin-2-one (D29) (1.276 g, 4.7769 mmol) in acetonitrile (30 ml_) was added phenyl vinyl sulfone (1.3338 g ,7.9296 mmol), silver acetate (1 .196 g, 7.1653 mmol) and finally DBU (0.7272 g, 4.7769 mmol). The mixture was stirred at room temperature over 1 hr. The mixture (now a light brown colour) was filtered through kieselguhr and the filtrate was evaporated to yield a brown solid. Column chromatography (EtOAc) yielded two diastereoisomers as yellow solids.
Diastereoisomer A (D30a) (406 mg, 0.9326 mmol, 19% yield); NMR (CDCI3) δ 2.25-2.38 (2H, m), 2.49-2.65 (3H, m), 3.33-3.50 (2H, m), 4.04 (1 H, q), 4.48 (1 H, bs), 5.63 (1 H, bs), 7.06 (1 H, t), 7.24 (3H, m), 7.41 (2H, t), 7.54 (1 H, t), 7.73 (1 H, d).
Diastereoisomer B (D30b) (470mg, 1.0796mmol, 22% yield); NMR (CDCI3) δ 2.16-2.34 (4H, m), 2.83 (1 H, dd), 3.29-3.49 (2H, m), 4.20 (1 H, q), 4.53 (1 H, d), 6.34 (1 H, bs), 7.1 1 (1 H, t), 7.32-7.45 (7H, m), 7.55 (1 H, m).
Description 31 : 2-(3-Bromo-phenyl)-1 ,7-diaza-spiro[4.4]non-1 -en-6-one (D31 )
To a solution of 3-benzenesulfonyl-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (406 mg, 0.9326 mmol) (D30a) in tetrahydrofuran (10 ml_) cooled to 0 °C was added a 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.8653 mL, 1.8653 mmol). The reaction mixture was stirred over 1 hr. The reaction mixture was treated with acetic acid (1.5 mL), filtered and the filtrate evaporated to a dark brown oil. Column chromatography (0-5% methanol in ethyl acetate) yielded 2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]non-1-en-6-one (D31) (137 mg, 0.4673 mmol, 50% yield) as a yellow solid; NMR (CDCI3) δ 1.86-2.01 (1 H, m), 2.16-2.32 (1 H, m), 2.45-2.65 (2H, m), 2.98-3.14 (1 H, m), 3.17-3.34 (1 H, m), 3.38-3.48 (1 H, m), 3.63-3.76 (1 H, m), 6.22 (1 H, bs), 7.29 (1 H, t), 7.58 (1 H, d), 7.76 (1 H, d), 8.07 (1 H, s).
Isomeric 3-benzenesulfonyl-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (D30b) was reacted in a similar manner to 3-benzenesulfonyl-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one (D30a) to yield additional 2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]non- 1-en-6-one (D31)
Description 32: 2-(3-Bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (D32)
To a solution of 2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]non-1-en-6-one (D31) (356 mg,
1.2144 mmol) in tetrahydrofuran (4 mL) cooled to 0°C was added cone. HCI (0.4000 mL) followed by lithium borohydride (79.349 mg,3.6432 mmol) portionwise. The mixture was stirred at room temperature over 1 hr. A further portion of lithium borohydride (79.349 mg,
3.6432 mmol) was added and the mixture stirred at room temperature overnight. Reaction mixture quenched with saturated aqueous ammonium chloride, extracted with
dichloromethane and the phases separated with a hydrophobic frit. The combined organics were evaporated to give a white solid. The solid was suspended in 50% aq. hydrochloric acid (6 mL) and stirred at 90°C over 1.5 hrs. The reaction mixture was cooled and basified with 2M aq. sodium hydroxide , and extracted into dichloromethane. The extract was dried by passing over a hydrophobic frit and the filtrate was evaporated to yield a tan gum.
Column chromatography (0-10% methanol in dichloromethane) yielded two
diastereoisomers.
Diastereoisomer A (D32a), a racemic mixture of (2R,5S)-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one and (2S,5R)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (136mg, 0.4607mmol, 38% yield); NMR (CDCI3) δ 1.65-1.84 (1 H, m), 1.90-2.01 (1 H, m), 2.03-2.15 (1 H, m), 2.17-2.43 (3H, m), 2.56 (1 H, bs), 3.25-3.45 (2H, m), 4.62 (1 H, t), 5.72 (1 H, bs), 7.18 (1 H, t), 7.29-7.39 (2h, m), 7.61 (1 h, s).
Diastereoisomer B (D32b), a racemic mixture of (2S,5S)-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one and (2R,5R)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (70mg, 0.237mmol, 20% yield); NMR (CDCI3) δ 1.82-2.08 (2H, m), 2.18-2.35 (5H, m), 3.29- 3.48 (2H, m), 4.25 (1 H, t), 5.65 (1 H, bs), 7.22 (1 H, t), 7.40 (1 H, d), 7.50 (1 H, d), 7.67 (1 H, s).
Example 145, 146 (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E145) and (2S,5R)-2-(2'- .4]nonan-6-one (E146)
Figure imgf000099_0001
A solution of a racemic mixture of (2R,5S)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6- one and (2S,5R)-2-(3-bromo-phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one (D32a) (136 mg, 0.4607 mmol) in 1 ,4-dioxane (3 ml_) was added to 2-fluorophenylboronic acid (96.692 mg, 0.6910 mmol) and potassium carbonate (191.02 mg, 1.3821 mmol) and water (1 ml_) followed by tetrakis(triphenylphosphine)palladium (26.605 mg, 0.0230 mmol). The mixture was stirred at 90°C over 3 hrs. The reaction mixture was concentrated by removal of 1 ,4- dioxane. The residues were partitioned between water and dichloromethane. The phases were separated and the organic phase was dried by passing over a hydrophobic frit and evaporated to yield a yellow gum. Column chromatography (0-10% methanol in
dichloromethane) yielded a white solid. Chiral prep-HPLC (AD-H, 30:70 ethanol:heptane 20min) yielded two enantiomers as clear gums.
Fast isomer, (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E145) (36 mg, 0.1 16 mmol, 23% yield); NMR (CDCI3) δ 1.79-2.50 (7H, m), 3.24-3.34 (2H, m), 4.72 (1 H, t), 5.61-6.09 (1 H, bs), 7.11-7.27 (2H, m), 7.29-7.37 (1 H, m), 7.40-7.52 (4H, m), 7.62 (1 H, s); LCMS (10 min method) 2.93min, MH+ 311.13
Slow isomer, (2S,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E146) (35 mg, 0.1 13 mmol, 23% yield); NMR (CDCI3) δ 1.79-2.50 (7H, m), 3.24-3.34 (2H, m), 4.72 (1 H, t), 5.61-6.09 (1 H, bs), 7.11-7.27 (2H, m), 7.29-7.37 (1 H, m), 7.40-7.52 (4H, m), 7.62 (1 H, s); LCMS (10 min method) 2.93 min, MH+ 311.13
Example 147, 148 (2S,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E147) and (2R,5R)-2-(2'-Fluoro-bi henyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E148)
Figure imgf000100_0001
Prepared in a similar manner to (E145, E146) from a racemic mixture of (2S,5S)-2-(3-bromo- phenyl)-1 ,7-diaza-spiro[4.4]nonan-6-one and (2R,5R)-2-(3-bromo-phenyl)-1 ,7-diaza- spiro[4.4]nonan-6-one (D32b) to give the title compounds as clear gums.
Fast isomer, (2S,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E147)
NMR (CDCIa) δ 1.85-1.99 (1 H, m), 2.01-2.17 (1 H, m), 2.20-2.40 (5H, m), 3.28-3.48 (2H, m),
4.34 (1 H, t), 5.74 (1 H, bs), 7.11-7.26 (2H, m), 7.29-7.38 (1 H, m), 7.41-7.52 (3H, m), 7.54-
7.61 (1 H, m), 7.68 (1 H, s); LCMS (10 min method) 3.21 min, MH+ 31 1.14.
Slow isomer, (2R,5R)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E148)
NMR (CDCI3) δ 1.85-1.99 (1 H, m), 2.01-2.17 (1 H, m), 2.20-2.40 (5H, m), 3.28-3.48 (2H, m),
4.34 (1 H, t), 5.74 (1 H, bs), 7.11-7.26 (2H, m), 7.29-7.38 (1 H, m), 7.41-7.52 (3H, m), 7.54-
7.61 (1 H, m), 7.68 (1 H, s); LCMS (10 min method) 3.21 min, MH+ 31 1.14.
Example 145 hydrochloride salt: (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.4]nonan-6-one hydrochloride E145)
Figure imgf000100_0002
To a solution of (2R,5S)-2-(2'-Fluoro-biphenyl-3-yl)-1 ,7-diaza-spiro[4.4]nonan-6-one (E145) (36 mg, 0.1 16 mmol) in dichloromethane (1 mL) was added a 1 M solution of hydrogen chloride in diethyl ether (2 mL). The mixture was stirred at room temperature over 1 hr. Evaporation of the solvents yielded (2R,5S)-2-(2'-fluoro-biphenyl-3-yl)-1 ,7-diaza- spiro[4.4]nonan-6-one hydrochloride as a pale yellow solid (40 mg, 0.116 mmol, 100%); NMR (d6-DMSO) δ 2.12-2.47 (5H, m), 3.22-3.45 (3H, m), 4.98 (1 H, bs), 7.28-7.40 (2H, m), 7.42-7.53 (1 H, m), 7.56-7.67 (4H, m), 7.74 (1 H, s), 8.52 (1 H, s), 9.48 (1 H, s), 10.17 (1 H, s); LCMS (5 min method) 1.15 min, MH+ 311.1.
The following compounds were prepared by the route described in Preparation 7
Figure imgf000101_0001
Preparation 8
Description 33: 3-{[1 -(5-Bromo-2-fluoro-phenyl)-meth-(E)-ylidene]-amino}-1 -methyl- pyrrolidin-2-one (D33)
The title compound was prepared in a manner similar to the procedure for (D16) in
Preparation 4 but using 2-fluoro-5-bromobenzaldehyde in place of 3-bromobenzaldehyde.
Description 34: 3-(2-Benzenesulfonyl-ethyl)-3-{[1 -(5-bromo-2-fluoro-phenyl)-meth-(E)- ylidene]-amino}-1 -methyl-pyrrolidin-2-one (D34)
To a mixture of 3-{[1-(5-bromo-2-fluoro-phenyl)-meth-(E)-ylidene]-amino}-1-methyl- pyrrolidin-2-one (D33) (9.62g, 32.2mmol) and phenyl vinyl sulphone (8.4g, 50.0mmol) in acetonitrile (100ml) was added DBU (4.5ml, 29.9mmol) and silver acetate (7.3g, 43.7mmol). The reaction mixture was stirred in the dark for 1.5 hours and then filtered through a pad of celite. The celite was washed with ethyl acetate and then the filtrate evaporated at reduced pressure. The product was purified by silica gel chromatography eluting with 70% ethyl acetate in iso-hexane to yield the title compound (D34) (10.02g, 67%); NMR (CDCI3) δ 2.19- 2.32 (4H, m), 2.92 (3H, s), 3.12-3.22 (1 H, m), 3.28-3.34 (2H, m), 3.52-3.63 (1 H, m), 6.95- 7.01 (1 H, m), 7.49-7.68 (4H, m), 7.91-7.94 (2H, m), 8.02-8.05 (1 H, m), 8.44 (1 H, s); MS: (ES/+) MH+ 467, 469. C20H20BrFN2O3S requires 466, 468.
Description 35: 2-(5-Bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1 -en-6- one D35
To a solution of 3-(2-benzenesulfonyl-ethyl)-3-{[1-(5-bromo-2-fluoro-phenyl)-meth-(E)- ylidene]-amino}-1-methyl-pyrrolidin-2-one (D34) (1 g, 2.1397 mmol) in THF (20 mL) at 0°C was added 1 M potassium tert-butoxide in THF (4.2794 mL, 4.2794 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 0°C for 30 minutes and then quenched by the addition of acetic acid (0.2445 mL, 4.2794 mmol). The reaction mixture was filtered, washed with dichloromethane and the filtrate concentrated at reduced pressure. To a solution of 3- (2-benzenesulfonyl-ethyl)-3-{[1-(5-bromo-2-fluoro-phenyl)-meth-(E)-ylidene]-amino}-1- methyl-pyrrolidin-2-one (8.8 g, 18.83 mmol) in THF (150 mL) at 0°C was added 1 M potassium tert-butoxide in THF (37.659 mL, 37.659 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 0°C for 30 minutes and then quenched by the addition of acetic acid (2.152 mL,37.659 mmol). The reaction mixture was filtered and the filtrate concentrated at reduced pressure. The crude products from the above experiments were combined and purified by silica gel chromatography eluting with 10-100% ethyl acetate in iso-hexane to give the title compound (D35) (4.63 g, 68%); MS: (ES/+) MH+ 325, 327.
C14H14BrFN20 requires 324, 326.
2-(5-Bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1-en-6-one was separated by chiral HPLC in a manner similar to the procedure in Preparation 4, except using a ChiralPak AD-H column into (R)-enantiomer (D35a) and (S)-enantiomer (D35b).
Description 36: (R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1 - en-6-one (D36)
To a solution of (R)-2-(5-bromo-2-fluoro-phenyl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1-en-6- one (D35a) (420 mg, 1.29 mmol) in water (3 mL) and 1 ,2-dimethoxyethane (10 mL) was added sodium carbonate (411.51 mg, 3.88 mmol) and (4-fluorophenyl)boronic acid (198.79 mg, 1.42 mmol). The reaction mixture was degassed with nitrogen and then treated with bis(triphenylphosphine)-palladium (II) dichloride (45.42 mg, 0.0600 mmol). The reaction was heated in the microwave at 120°C for 1 hour. The reaction mixture was diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re- extracted with dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography eluting with 30-100% ethyl acetate in iso-hexane to give the title compound (D36) (431 mg); MS: (ES/+) MH+ 341. C20H18BrF2N2O requires 340.
Example 149, 150 (2S,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza- spiro[4.4]nonan-6-one (E149) and (2R,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7- diaza-spiro[4.4]nonan-6-one (E150)
Figure imgf000103_0001
To a solution of (R)-2-(4,4'-difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]non-1-en-6- one (D36)(428 mg, 1.2575 mmol) in THF (15 ml_) cooled in an ice bath was added concentrated hydrochloric acid (100 μΙ), followed by the portionwise addition of lithium borohydride (82.162 mg, 3.7724 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and then stirred for 1 hour. A further aliquot of lithium borohydride (82 mg) was added and the reaction stirred for a further 16 hours at room temperature. The reaction mixture was cooled and quenched carefully by the addition of saturated aqueous ammonium chloride. Dichloromethane was added and the mixture stirred for 5 minutes. The organic solution was separated using a hydrophobic frit and the solvent evaporated at reduced pressure. The borane adduct was suspended in 5M hydrochloric acid (8 ml) and heated to 90°C for 1 hour. After cooling to room temperature, the reaction mixture was basified to ~pH 8 by the addition of 2M sodium hydroxide solution. Dichloromethane was added and the mixture stirred for 5 minutes before separation of the organic phase using a hydrophobic frit. The solvent was evaporated and the residue dissolved in methanol and applied to an SCX column. The column was eluted with methanol, followed by 0.5M ammonia in methanol. Basic fractions were combined and concentrated to give the crude products. The products were purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane. Faster isomer, (2S,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E149) (229mg, 53%); NMR (CDCI3) δ 1.72-1.94 (2H, m), 2.00-2.25 (3H, m), 2.50-2.57 (1 H, m), 2.65 (1 H, br s), 2.94 (3H, s), 3.29-3.33 (2H, m), 4.91-4.96 (1 H, m), 7.03-7.15 (3H, m), 7.33-7.38 (1 H, m), 7.49-7.54 (2H, m), 7.81-7.84 (1 H, m); MS: (ES/+) MH+ 343.
C20H20F2N2O requires 342.
Slower isomer, (2R,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E150) (105mg, 24%); NMR (CDCI3) δ 1.80-1.89 (1 H, m), 1.96-2.07 (1 H, m), 2.14-2.24 (3H, m), 2.31-2.40 (2H, m), 2.94 (3H, s), 3.31-3.38 (2H, m), 4.61-4.66 (1 H, m), 7.05-7.15 (3H, m), 7.37-7.41 (1 H, m), 7.55-7.60 (2H, m), 8.01-8.04 (1 H, m); MS: (ES/+) MH+ 343. C20H20F2N2O requires 342.
Example 149 hydrochloride salt: (2S,5R)-2-(4,4'-Difluoro-biphenyl-3-yl)-7-methyl-1 ,7- diaza-spiro[4.4]nonan-6-one hydrochloride (E149)
Figure imgf000104_0001
To a solution of (2S,5R)-2-(4,4'-difluoro-biphenyl-3-yl)-7-methyl-1 ,7-diaza-spiro[4.4]nonan-6- one (E149) (226. mg, 0.6600mmol) in dichloromethane (5m L) was added 1 M hydrogen chloride in diethyl ether (3.3ml_, 3.3mmol). The reaction mixture was stirred at room temperature under nitrogen for 30 minutes and then concentrated at reduced pressure to give the title compound (249mg, 99%).
MS: (ES/+) MH+ 343. C20H20F2N2O requires 342.
The following compounds were prepared by the route described in Preparation 8
Figure imgf000104_0002
Figure imgf000105_0001
Preparation 9
Description 37: (2R,5S)-7-Methyl-2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one (D37)
A mixture of (2f?,5S)-2-(3-bromophenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one (D19a) (400 mg, 1.29 mmol) and bis(pinacolato)diboron (395 mg, 1.55 mmol), Pd(dppf)CI2 (106 mg, 0.13 mmol) and potassium acetate (637 mg, 6.5 mmol) in 1 ,4-dioxane (20 ml) was heated to reflux under nitrogen overnight. After cooling, the solvent was evaporated and the product was chromatographed on silica gel (elution with 1 :1 petroleum ether/ethyl acetate) to give the title compound (D37) (300 mg); LCMS: MH+ = 357
Example 153 (2R,5S)-2-(3-(3-Fluoropyridin-2-yl)phenyl)-7-methyl-1,7- diazaspiro[4.4]nonan-6-one hydrochloride (E153)
Figure imgf000106_0001
A mixture of (2R,5S)-7-methyl-2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,7- diazaspiro[4.4]nonan-6-one (D37) (150 mg, 0.42 mmol), 2-bromo-3-fluoropyridine (272 mg, 1.26 mmol), Pd(dppf)CI2 (33 mg, 0.042 mmol) and potassium carbonate (1.26 ml of 1 M solution, 1.26 mmol) in 1 ,4-dioxane (10 ml) was heated to reflux under nitrogen overnight. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel (1 :1 to 1 :2 petroleum ether/ethyl acetate) to give the title compound (40 mg). This product was dissolved in methanol (10 ml) and treated with 1 M HCI (0.12 ml). The solvent was evaporated and the residue purified by preparative HPLC to give the HCI salt; LC-MS: MH+ = 326 C19H20FN3O requires 325; NMR δΗ (d-6 DMSO) 2.20-2.70 (6H, m), 2.86 (3H, s), 3.41-3.46 (2H, m). 5.00 (1 H, m), 7.54-7.72 (3H, m), 7.88-7.99 (2H, m), 8.09 (1 H, s), 8.60 (1 H, s), 9.50 (1 H, broad), 10.35 (1 H, broad).
Example 154 (2R,5S)-7-Methyl-2-(3-(3-methylpyridin-2-yl)phenyl)-1 ,7- diazaspiro[4.4]nonan-6-one hyd
Figure imgf000106_0002
The title compound was prepared in a similar manner to that used in Preparation 9 but using 2-bromo-3-methylpyridine in the Suzuki reaction; LCMS: MH+ = 322
Example 155: (2R,5S)-1 -Ethyl-2-(2'-fluoro-[1 ,1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E155)
Figure imgf000106_0003
A solution of (2S,5 )-2-(2'-fluoro-[1 , 1'-biphenyl]-3-yl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one (E35) in ethanol (0.1 ml) and 1 ,2-dichloroethane (0.5 ml) was treated with acetaldehyde (7.69μΙ_, 0.083 mmol) and sodium triacetoxyborohydride (28 mg, 0.132 mmol) and then acetic acid (4.77 μΙ_, 0.083 mmol) were added. After stirring for 30 mins, saturated sodium bicarbonate solution was added and the product was extracted into dichloromethane. The solution was dried with magnesium sulphate and evaporated. Purification by MDAP gave title compound (E155); NMR δΗ (CDCI3) 0.80 (3H, t), 1.60-1.70 (1 H, m, partially masked by water), 1.90-2.00 (1 H, m), 2.05-2.20(2H, m), 2.25-2.35 (1 H, m), 2.55-2.80 (3H, m), 2.85 (3H, s). 3.25-3.40 (2H, m), 4.35 (1 H, dd), 7.10-7.50 (7H, m), 7.55 (1 H, s).
Example 156: (2S,5S)-1 -Ethyl-2-(2'-fluoro-[1 ,1 '-biphenyl]-3-yl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one (E156)
Figure imgf000107_0001
The title compound was prepared in a similar manner to Example 155.
LC-MS MH+ = 353
The following compounds were prepared by the procedure of Preparation 5 using alternative aldehydes, with the modifications noted.
Figure imgf000107_0002
E161 (2R,5R)-2-(4-Chloro- MH+ (ES) Use 6-chloro- HCI salt 2'-fluoro-biphenyl-3- 359, 361 3-bromo- yl)-7-methyl-1 ,7-diaza- benzaldehyde spiro[4.4]nonan-6-one
hydrochloride
HCI
E162 (2S,5R)-2-(4-Chloro- MH+ (ES) Use 6-chloro- HCI salt 2'-fluoro-biphenyl-3- 359, 361 3-bromo- yl)-7-methyl-1 ,7-diaza- benzaldehyde spiro[4.4]nonan-6-one
hydrochloride
HCI
Preparation 10
Description 38: 3-[(E)-1 -(3-Bromophenyl)ethylideneamino]-1 -methyl-pyrrolidin-2-one (D38)
A mixture of 3-amino-1-methyl-pyrrolidin-2-one (1000 mg, 8.7604mmol) and 3'- bromoacetophenone (2615.5 mg, 13.141 mmol) with Molecular Sieves (2 g) in Toluene (30 ml_) was heated at 80 °C for 10 days. The reaction was filtered and the solvent evaporated to afford a crude oil. This was purified using a Biotage SP4 equipped with a 50g SNAP cartridge, eluting with 100% EtOAc to afford the 3-[(E)-1-(3-bromophenyl)ethylideneamino]- 1-methyl-pyrrolidin-2-one (825 mg, 2.7949mmol, 31.9% yield) as a pale yellow oil contaminated with approximately 10% of the starting acetophenone.
NMR δΗ (CDCIa) 2.26-2.52 (2H, m), 2.41 (3H, s) 2.92 (3H, s), 3.39-3.47 (1 H, m), 3.58 (1 H, dt), 4.51 (1 H, t), 7.52, 7.73 (2 x d, 2H), 8.01 (1 H, s).
Description 39: 7-(Benzenesulfonyl)-8-(3-bromophenyl)-3,8-dimethyl-3,9- diazaspiro[4.4]nonan-4-one (D39a), (D39b)
Potassium fe butoxide 1.0M in THF (0.75 ml_, 0.7500 mmol) was added dropwise to a solution of the 3-[(E)-1-(3-bromophenyl)ethylideneamino]-1-methyl-pyrrolidin-2-one (D38) (200. mg, 0.6800mmol) and phenyl vinyl sulfone (136.77 mg, 0.8100 mmol) in THF (10 ml_) at 0 °C and the reaction was stirred for 3 hours. The reaction was quenched by the addition of satd. aq. NH4CI and then EtOAc was added. The phases were separated and the organic layer was dried (Na2S04) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with a 25g SNAP cartridge, eluting with 50 to 100% EtOAc. 7- (benzenesulfonyl)-8-(3-bromophenyl)-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one was isolated as two diastereomers:
Faster eluting component: (D39a) (106 mg, 0.2287 mmol, 33.8% yield): NMR δΗ (CDCI3) 1.51-1.62 (1 H, m), 1.73 (1 H, dd), 1.89-1.99 (1 H, m), 1.96 (3H, m), 2.59 (1 H, t), 2.75 (1 H, br.s), 2.91 (3H, s); 3.04-3.13 (1 H, m), 3.24 (1 H, dt), 3.90 (1 H, dd), 7.22 (1 H, t), 7.77 (1 H, d), 7.53-7.68 (3H, m), 7.86 (1 H, d), 7.92 (2H, d), 8.03 (1 H, t).
Slower eluting component:(D39b) (62 mg, 0.1338 mmol, 19.7% yield): NMR δΗ (CDCI3) 1.79 (3H, s), 2.24-2.38 (2H, m), 2.48 (1 H, dd), 2.6 (1 H, br.s), 2.69 (1 H, t), 2.87 (3H, s), 3.31-3.36 (2H, m), 4.23 (1 H, dd), 7.15 (1 H, t), 7.29-7.42 (3H, m), 7.51-7.56 (2H, m), 7.66-7.73 (3H, m).
Description 40: 7-(Benzenesulfonyl)-8-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9- diazaspiro[4.4]nonan-4-one - Diastereomer 1 (D40)
PdCI2(Ph3P)2 (46.05 mg, 0.0700 mmol) was added to a degassed mixture of 7-(benzene- sulfonyl)-8-(3-bromophenyl)-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one (D39a) (304 mg, 0.6600 mmol), 2-fluorophenylboronic acid (110.15 mg, 0.7900 mmol) and sodium carbonate (208.6 mg, 1.97 mmol) in DME (6 ml_) and water (2 ml_) under N2 in a microwave vial, and the reaction was heated in the microwave at 120 °C for 1 hour. The mixture was diluted with water / EtOAc, filtered, and the phases separated. The organic layer was dried (Na2S04) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, equipped with a 25g SNAP cartridge, eluting with 0 to 100% EtOAc / i-hexane to afford 7- (benzenesulfonyl)-8-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one - Diastereomer 1 (D40) (238 mg, 0.4973 mmol, 75.8% yield) as a yellow foam.
NMR δΗ (CDCIs) 1.54-1.62 (1 H, m), 1.74 (1 H, dd), 1.98-2.08 (1 H, m), 2.02 (3H, s), 2.65 (1 H, t), 2.75 (1 H, br.s), 2.90 (3H, s), 3.03-3.12 (1 H, m), 3.25 (1 H, dt), 4.04 (1 H, dd), 7.15-7.66 (9H, m), 7.91-7.96 (3H, m), 8.02 (1 H, s).
Description 41 : 7-(Benzenesulfonyl)-8-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9- diazaspiro[4.4]nonan-4-one - Diastereomer 2 (D41)
PdCI2(Ph3P)2 (37.87 mg, 0.0500 mmol) was added to a degassed mixture of 7- (benzenesulfonyl)-8-(3-bromophenyl)-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one (D39b) (250. mg, 0.5400mmol), 2-fluorophenylboronic acid (90.59 mg, 0.6500 mmol) and sodium carbonate (171.55 mg, 1.62 mmol) in DME (3 ml_) and water (1 ml_) under N2 in a
microwave vial and the reaction was heated in the microwave at 120 °C for 1 hour. The mixture was diluted with water / EtOAc, filtered, and the phases separated. The organic layer was dried (Na2S04) and the solvent evaporated to afford a brown oil. This was combined with material from an earlier reaction and purified using a Biotage SP4, equipped with a 25g SNAP cartridge, eluting with 0 to 100% EtOAc / i-hexane to afford the 7-(benzenesulfonyl)-8- [3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one - Diastereomer 2 (D41) (255 mg, 0.5328 mmol) as a yellow foam.
NMR 5|H (CDCIa) 1.87 (3H, s), 2.01-2.1 1 (1 H, m), 2.32-2.42 (1 H, m), 2.55 (1 H, dd), 2.75 (1 H, dd), 2.86-3.01 (1 H, m), 2.98 (3H, t), 3.36 (2H, dd), 4.34 (1 H, dd), 7.12-7.50 (9H, m), 7.65- 7.71 (4H, m).
Examples 163 and 164
(3S,5R)-3-[3-(2-Fluorophenyl)phenyl]-3,8-dimethyl-4,8-diazaspiro[4.4]nonan-9-one (E163) and (3R,5S)-3-[3-(2-Fluorophenyl)phenyl]-3,8-dimethyl-4,8- diazaspi
Figure imgf000110_0001
5% Na(Hg) amalgam (570 mg, 0.4800 mmol) was added to a mixture of the 7-(benzene- sulfonyl)-8-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one (D40) (230 mg, 0.4800 mmol) and sodium phosphate, dibasic (238.79 mg, 1.68 mmol) in methanol (6 mL) and THF (3 mL) and the reaction was stirred at room temperature for 7 hrs. Additional Na(Hg) amalgam (100mg) was added and stirring was continued for 2 hrs. Further Na(Hg) amalgam (100mg) was added and stirring was continued for 2 hrs. The reaction was diluted with DCM and filtered. The organics were evaporated and the residue suspended in DCM. This was washed with water, dried (Na2S04) and the solvent evaporated to afford a clear oil (96 mg). NMR δΗ (CDCI3) 1.62 (3H, s), 1.66-1.75 (1 H, m), 1.91 (1 H, ddd), 2.00-2.35 (5H, m), 2.91 (3H, s), 3.18-3.30 (2H, m), 7.13-7.50 (6H, m), 7.55-7.60 (1 H, m), 7.74 (1 H, s) This was separated into enantiomers using chiral HPLC (AD-H column) eluting with 30:70 EtOH / heptanes to give a faster running isomer (@ 5.3 mins), (33 mg):
Optical Rotation = -16.4 (c=1.7, CHCI3)
This free base was dissolved in DCM (500 ul) followed by the addition of 1 M HCI in Et20 (1 equiv) and the solvent blown down to afford (3S,5R)-3-[3-(2-fluorophenyl)phenyl]-3,8- dimethyl-4,8-diazaspiro[4.4]nonan-9-one hydrochloride (E163) (33 mg, 0.0975 mmol, 34.4% yield)
MH+ = 339 C21 H23FN20 requires 338
The slower eluting isomer was also isolated (@ 5.8 mins), 30 mg:
Optical Rotation = +18.7 (c=1.5, CHCI3)
This material was dissolved in DCM (500 μΙ) followed by the addition of 1 M HCI in Et20 (1 equiv) and the solvent blown down to afford an off white solid. (3R,5S)-3-[3-(2- fluorophenyl)phenyl]-3,8-dimethyl-4,8-diazaspiro[4.4]nonan-9-one hydrochloride (E164) (30 mg, 0.0886 mmol, 31.3% yield)
MH+ = 339 C21 H23FN20 requires 338
Examples 165 and 166
(3R,5R)-3-[3-(2-Fluorophenyl)phenyl]-3,8-dimethyl-4,8-diazaspiro[4.4]nonan-9-one hydrochloride (E165) and (3S,5S)-3-[3-(2-Fluorophenyl)phenyl]-3,8-dimethyl-4,8- diazaspiro
Figure imgf000111_0001
5% Na(Hg) amalgam (1000 mg, 0.5300 mmol) was added to a mixture of the 7- (benzenesulfonyl)-8-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-3,9-diazaspiro[4.4]nonan-4-one (D41) (255 mg, 0.5300 mmol) and sodium phosphate, dibasic (264.74 mg, 1.86 mmol) in methanol (6 ml_) and THF (3 ml_) and the reaction was stirred at room temperature for 3 days. The reaction was diluted with DCM and filtered. The organics were evaporated and the residue suspended in DCM. This was washed with water, dried (Na2S04) and the solvent evaporated to afford a clear oil. This was purified using Biotage SP4 chromatography with a 25g SNAP cartridge, eluting with 0 to 10% MeOH / DCM (20 column volumes) to afford a colourless oil (62 mg): NMR δΗ (CDCI3) 1.53 (3H, s), 1.92-2.02 (1 H, m), 2.0 (1 H, br.s), 2.12- 2.35 (6H, m), 2.90 (3H, s), 3.31-3.36 (2H, m), 7.12-7.35 (3H, m), 7.40-7.53 (3H, m), 7.63- 7.68 (1 H, m), 7.74 (1 H, s) This was separated into enatiomers using chiral HPLC (AD-H) eluting with 30 / 70 EtOH / heptanes to give faster running isomer (@ 4.9 mins), (10 mg)
Optical Rotation = +28 (c = 0.5, CHCI3)
This was dissolved in DCM (500 μΙ) followed by the addition of 1 M HCI in Et20 (1 equiv) and the solvent blown down to afford a colourless solid (3R,5R)-3-[3-(2-fluorophenyl)phenyl]-3,8- dimethyl-4,8-diazaspiro[4.4]nonan-9-one (E165) (10 mg, 0.0295 mmol, 16.1 % yield)
MH+ = 339 C21 H23FN20 requires 338
The slower eluting isomer was also isolated (@ 5.3 mins), (14 mg but contain s 12% of the other isomer)
Optical Rotation = -22.8 (c = 0.7, CHCI3) - Note contains 12% of the corresponding (3R, 5R) isomer
This was re-purified by chromatography then dissolved in DCM (500 μΙ) followed by the addition of 1 M HCI in Et20 (1 equiv) and the solvent blown down to afford a colourless solid (3S,5S)-3-[3-(2-fluorophenyl)phenyl]-3,8-dimethyl-4,8-diazaspiro[4.4]nonan-9-one (E166) (8 mg,0.0236mmol, 12.904% yield)
MH+ = 339 C21 H23FN20 requires 338
BIOLOGICAL ASSAYS
The compounds of the invention were either tested in a QPatch NaV1.7 assay (referred to in the Table below as QP) or an lonWorks NaV1.7 Assay (referred to in the Table below as IW).
QPatch NaV1.7 Assay
HEK293-hNaV1.7 cells were grown in DMEM-F12 + 10% FBS culture media at 37°C. At a confluency of 50-70% cells were dissociated from culture flasks & triturated to ensure unicellular cell suspension; cell density was measured & adjusted to 2-3 x 106 cells/ml. Recordings were obtained using QPatch16x. The external solution was (in rtiM): NaCI, 128; KCI, 5; MgCI2, 2; CaCI2, 2; Glucose, 30; HEPES, 15; pH7.3, 305-315mOsm. Following seal formation and whole-cell access using internal solution (containing in mM: CsF, 135; EGTA/CsOH, 1/5; HEPES 10; NaCI, 10; pH 7.3, 310-320mOsM), voltage pulse protocols were applied. Initially a steady state inactivation voltage protocol was used to determine the half-maximal voltage for steady state inactivation (V1/2 SSI). Two holding voltages were used to determine test drug inhibition: -90mV, where most of the channels are in a closed state; and V1/2 SSI, where half of the channels are inactivated. Currents were elicited every 10 seconds by stepping to a membrane potential of OmV for 20ms. Four-point cumulative concentration responses were derived by determining the peak current amplitude at each concentration of test drug over 120 second application. Curves were fitted with the Hill equation yielding plC50 values at -90mV and V1/2 SSI holding potentials. lonWorks NaV1.7 Assay
HEK293-huNaV1.7 cells were grown in DMEM-F12 + 10% FBS culture media at 37°C. At a confluency of 50-70% cells were dissociated from culture flasks and triturated to ensure unicellular cell suspension. Currents were recorded at room temperature (21-23°C) using the lonWorksHT planar array electrophysiology technology (Molecular Devices Corp.). After cell addition a seal test was performed prior to antibiotic (amphotericin) circulation to achieve intracellular access. The intracellular solution contained the following (in rtiM): K-gluconate 100, KCI 40mM, MgCI2 3.2, EGTA 3, HEPES 5, adjusted to pH 7.3. The external solution contained the following (in rtiM): CaCI2 0.9, KCI 2.7, KH2P04 1.1 , MgCI2 0.5, NaCI 136.9, NaHP04 8. Trains of 10 20ms-long pulses delivered at a frequency of 10Hz, from the holding potential of -90 mV to 0 mV, were applied every 30s. Test compounds were applied for 3- 3.5 min. Tonic block was assessed by measuring the effect of test compounds on the peak current elicited by the first pulse in each train (i.e. a stimulation frequency of 0.033 Hz, and the equation: % Tonic block = (1-(Drug1/Ctl1)) x100. Data were fit using a logistic function in order to determine the IC50 and expressed as the negative log of the IC50 concentration (plC50). Use-dependent (UD) block was calculated using the following equation: % UD block = (1-((Drug10/drug1) /(Ctl10/Ctl1))) x100. Data presented here are the negative log of the concentration that caused a 15% inhibition (UD15) of the sodium current (pUD15).
Figure imgf000113_0001
4.3 5.8
4.5 6.1
4.5 5.8
4.3 5.3
4.6 5.3
4.5 6.1
4.6 5.9
4.0 5.1
5.6 6.4
4.4 6.0
4.9 6.4
4.6 5.8
4.9 5.5
4.5 5.9
4.3 4.8
4.0 4.7
4.6 6.2
4.3 5.7
4.2 5.8
4.1 5.5
4.7 6.3
4.0 4.7
4.4 5.9
4.8 6.2
4.0 4.5
4.2 4.9
4.2 4.5
4.2 4.5
4.4 5.0
4.4 5.3
4.4 5.0
4.5 5.6
4.4 5.4
4.9 5.0
4.7 4.8 43 4.5 4.8
44 4.4 4.9
45 4.6 5.1
46 4.7 5.0
47 1.7 1.3
48 3.8 4.3
49 4.5 4.9
50 4.0 4.5
51 4.8 5.7
52 4.2 4.9
53 4.2 4.4
54 4.4 5.5
55 4.4 4.7
56 4.0 5.1
57 3.9 4.5
58 4.2 4.6
59 4.6 5.1
60 4.4 4.6
61 4.0 4.8
62 4.3 5.1
63 4.5 5.0
64 4.6 5.2
65 4.1 4.7
66 3.8 4.5
67 4.4 4.6
68 4.2 4.7
69 4.6 4.9
70 4.3 5.1
71 4.8 5.5
72 4.7 5.2
73 4.4 4.9
74 4.4 5.1
75 4.3 4.7
76 4.6 5.5
77 4.6 5.3 78 5.3 5.4
79 5.5 5.4
80 4.0 4.8
81 4.7 5.7
82 5.0 5.7
83 5.3 5.7
84 4.2 5.4
85 5.0 5.3
86 4.7 4.9
87 5.0 5.5
88 4.5 5.2
89 5.4 5.9
90 5.0 5.5
91 5.1 5.6
92 4.2 4.7
93 4.4 5.4
94 3.9 4.8
95 4.3 5.5
96 4.2 5.3
97 4.8 6.5
98 5.0 5.4
99 4.3 6.2
100 5.1 6.6
101 4.6 5.0
102 4.3 4.8
103 4.1 4.7
104 4.2 5.8
105 4.1 5.5
106 4.0 5.4
107 4.7 5.7
108 4.3 6.2
109 4.1 5.9
110 4.4 6.1
11 1 4.0 5.4
112 4.2 5.3 113 4.2 5.3
114 4.2 4.3
115 4.1 5.8
116 4.7 5.2
117 4.6 5.6
118 4.8 5.1
119 4.6 6.0
120 4.3 5.2
121 4.3 5.2
122 4.4 5.4
123 4.3 4.8
124 3.6 4.5
125 4.1 4.3
126 3.6 4.7
127 3.7 4.3
128 3.7 4.8
129 4.6 5.5
130 3.3 4.3
131 4.3 4.6
132 4.3 4.6
133 4.2 5.0
134 4.3 4.8
135 4.1 4.4
136 4.1 4.4
137 4.3 4.6
138 4.0 4.4
139 3.8 4.6
140 4.0 4.6
141a 4.8 5.5
141 b 4.7 6.2
142 4.5 5.1
143 4.2 5.0
144 4.7 6.2
145 4.2 4.8
146 4.3 4.6 147 4.2 4.6
148 4.1 4.8
149 4.3 4.9
150 4.0 5.1
151 5.1 6.2
152 4.3 5.0
153 3.3 4.0
154 3.8 4.4
155 4.4 5.6
156 4.1 4.9
157 4.0 4.9
158 4.3 5.9
159 4.2 4.7
160 4.4 4.8
161 4 4.7
162 2.2 4.7
163 4.2 4.6
163 3.8 4.8
165 4.3 4.7
166 4 4.5

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000119_0001
(I)
wherein:
Ring A represents a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring;
n represents an integer selected from 1 to 4;
each R1 independently represents Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, haloCi_6 alkyl, Ci_6 alkoxy, haloCi_6 alkoxy, -Z-phenyl, -Z-Het, -CN, -NR6R7, wherein said Het group represents a 5- or 6-membered aromatic heterocyclic ring or a 4- to 7-membered non- aromatic heterocyclic ring, wherein said phenyl or Het group of R1 may be optionally substituted by one or more (e.g. 1 , 2 or 3) R8 groups and wherein n represents an integer greater than 1 , said R1 groups represent no more than one -Z-phenyl or one -Z-Het group; Z represents a bond or a linker selected from -0-, -CH2-, -CH2-0- or -0-CH2;
R6 and R7 independently represent hydrogen or Ci_6 alkyl or R6 and R7 together with the nitrogen atom to which they are attached join to form a 4- to 7-membered nitrogen containing non-aromatic heterocyclic ring;
R8 represents Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, halogen, haloCi_6 alkyl, Ci_6 alkoxy, haloCi.
6 alkoxy, -CN or -NR6R7;
m represents an integer selected from 0 to 4;
each R2 independently represents Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, halogen, haloCi_6 alkyl, Ci-6 alkoxy, haloCi.6 alkoxy, -CN or -NR6R7;
X represents -N=, -C(H)= or -C(R2)=;
R3 represents hydrogen or Ci_6 alkyl;
R4 represents hydrogen or Ci_6 alkyl;
each R5 independently represents Ci_3 alkyl;
Y represents -CH2- or -(CH2)2-; and
p represents an integer from 0 to 3.
2. A compound as defined in claim 1 , wherein Ring A represents phenyl, thienyl, pyridine or pyrimidine.
3. A compound as defined in claim 1 or claim 2, wherein n represents an integer selected from 1 to 2.
4. A compound as defined in any one of claims 1 to 3, wherein R1 independently represents Ci_6 alkyl, halogen, haloCi_6 alkyl, d-6 alkoxy, haloCi_6 alkoxy, -Z-aryl, -Z-Het or - NR6R7 wherein said phenyl groups are optionally substituted by 1 , 2 or 3 R8 groups selected from halogen or haloCi_6 alkoxy.
5. A compound as defined in any one of claims 1 to 4, wherein Z represents -0-, -CH2- O- or -0-CH2.
6. A compound as defined in any one of claims 1 to 5, wherein m represents 0 or 1.
7. A compound as defined in any one of claims 1 to 6, wherein R2 independently represents Ci_6 alkyl, halogen, haloCi_6 alkyl, Ci_6 alkoxy or haloCi_6 alkoxy.
8. A compound as defined in any one of claims 1 to 7, wherein R3 represents hydrogen, methyl or ethyl.
9. A compound as defined in any one of claims 1 to 8, wherein R4 represents hydrogen, methyl or ethyl.
10. A compound as defined in any one of claims 1 to 9, wherein p represents 0 or 1.
1 1. A compound as defined in claim 1 , which is selected from any one of compounds E1- E166 or a pharmaceutically acceptable salt or solvate thereof.
12. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
13. A compound of formula (I) as defined in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof for use in therapy.
14. A compound of formula (I) as defined in any one of claims 1 to 11 , or a
pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by modulation of voltage-gated sodium channels.
15. Use of a compound of formula (I) as defined in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by modulation of voltage-gated sodium channels.
16. A process for preparing a compound of formula (I) as defined in claim 1 , which comprises:
(a) preparing a compound of formula (I) as defined in claim 1 , wherein R4 represents hydrogen which comprises conducting a ring closure reaction upon a compound of formula (II):
Figure imgf000121_0001
(II)
or a protected derivative thereof, wherein R1 , R2, R3, R5, m, n, p, A, X and Y are as defined in claim 1 ;
(b) reacting a compound of formula (III):
Figure imgf000121_0002
(III)
or a protected derivative thereof, wherein R2, R3, R4, R5, m, p, X and Y are as defined in claim 1 and L1 represents a suitable leaving group selected from a halogen atom or an - SO2CF3 group, with a boronic acid derivative or an aryl-tin derivative of a compound of formula A-(R1)n, wherein A, n and R1 are as defined in claim 1 ;
(c) reacting a compound of formula (IV):
Figure imgf000122_0001
(IV)
or a protected derivative thereof, wherein R2, R3, R4, R5, m, p, X and Y are as defined in claim 1 , with a compound of formula L2-A-(R1)n, wherein A, n and R1 are as defined in claim 1 and L2 represents a suitable leaving group selected from a halogen atom or an -0-S02- CF3 group;
(d) deprotection of a protected derivative of a compound of formula (I);
(e) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and optional formation of a pharmaceutically acceptable salt of a compound of formula
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