.0
`
`Europaisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`@ Publication number:
`
`0 636 623 A1
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 94115107.8
`
`@ Date of filing: 06.06.91
`
`@ Int. CL6: C07D 413/06, A61K 31/40,
`C07D 413/14, C07D 403/06,
`C07D 401/14
`
`This application was filed on 26 - 09 - 1994 as a
`divisional application to the application
`mentioned under INID code 60.
`
`Priority: 07.06.90 GB 9012672
`01.02.91 GB 9102132
`
`Date of publication of application:
`01.02.95 Bulletin 95/05
`
`Publication number of the earlier application in
`accordance with Art.76 EPC: 0 486 666
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GRIT LI LU NL SE
`
`@ Applicant: THE WELLCOME FOUNDATION
`LIMITED
`Unicorn HOUSE
`160 Euston Road
`
`London NW1 2BP (GB)
`
`@ Inventor: Robertson, Alan Duncan
`
`@ lndole derivatives as 5-HT1- like agonists.
`
`Langley Court
`Beckenham,
`Kent BR3 3BS (GB)
`Inventor: Hill, Alan Peter
`Langley Court
`Beckenham,
`Kent BR3 3BS (GB)
`Inventor: Glen, Robert Charles
`Langley Court
`Beckenham,
`Kent BR3 3BS (GB)
`Inventor: Martin, Graeme Richard
`Langley Court
`Beckenham,
`Kent BR3 3BS (GB)
`
`Representative: Rollins, Anthony John et al
`Group Patents & Agreements
`The Wellcome Foundation Ltd
`
`Langley Court
`Beckenham
`
`Kent BR3 3BS (GB)
`
`@ The present invention is concerned with compounds of formula (I)
`
`(I)
`
`H N
`
`wherein
`
`n is an integar of from 0 to 3;
`W is a group of formula (i), (ii), or (iii)
`
`   
`


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`Lannett Holdings, Inc. LAN 1015
`
`Rank Xerox (UK) Business Services
`(3.10/3.09/3.3.4)
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`EP0636623A1
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`EP 0 636 623 A1
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`(i)
`
`(ii)
`
`(iii)
`
`wherein R is hydrogen or C1—4 alkyl, X is -0-, -8-, -NH-, or -CH2-, Y is oxygen or sulphur and the chiral centre *
`in formula (i) or (ii) is in its (8) or (R) form or is a mixture thereof in any proportions; and
`Z is a group of formula (iv), (v), or (vi)
`
`(I)
`
`2
`
`H N
`
`w
`
`\ <CH2>,,
`
`wherein R‘ and R2 are independently selected from hydrogen and C1—4 alkyl and R3 is hydrogen or C1—4 alkyl;
`and their salts, solvates and physiologically functional derivatives, with processes for their preparation, with
`medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and
`treatment of migraine.
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`

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`EP 0 636 623 A1
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`The present invention is concerned with new chemical compounds, their preparation, pharmaceutical
`formulations containing them and their use in medicine, particularly the prophylaxis and treatment of
`migraine.
`Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in
`both the periphery and the brain. According to the classification and nomenclature proposed in a recent
`article (Bradley e_t al, Neuropharmac., 2_5, 563 (1986)), these receptors may be classified into three main
`types, v_iz. "5-HT1-like". 5-HT2 and 5-HT3. Various classes of compounds have been proposed as 5-HT
`agonists or antagonists for therapeutic use, but these have not always been specific to a particular type of
`5-HT receptor. European Patent Specification 0313397 describes a class of 5-HT agonists which are
`specific to a particular type of "5—HT1—like" receptor and are effective therapeutic agents for the treatment of
`clinical conditions in which a selective agonist for this type of receptor is indicated. For example,
`the
`receptor in question mediates vasoconstriction in the carotid vascular bed and thereby modifies blood flow
`therein. The compounds described in the European specification are therefore beneficial in the treatment or
`prophylaxis of conditions wherein vasoconstriction in the carotid vascular bed is indicated, for example,
`migraine, a condition associated with excessive dilation of the carotid vasculature. However,
`it is within the
`scope of the earlier application that the target tissue may be any tissue wherein action is mediated by "5-
`HT1-like" receptors of the type referred to above.
`We have now found a further class of compounds having exceptional "5-HT1-like" receptor agonism
`and excellent absorption following oral dosing. These properties render the compounds particularly useful
`for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and
`headache associated with vascular disorders, hereinafter referred to collectively as "migraine".
`According to the first aspect of the present invention, therefore, there is provided a compound of formula (I)
`
`(I)
`
`H N /
`
`Z
`
`K (CH2),
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`wherein
`
`n is an integer of from 0 to 3;
`W is a group of formula (i), (ii), or (iii)
`
`N R
`
`*
`
`X
`
`(i)
`
`R
`
`N
`
`X
`
`,,
`
`(ii)
`
`Y
`
`Ne
`
`RN
`
`(iii)
`
`0
`
`wherein R is hydrogen or C1—4 alkyl, X is -O-, -S-, -NH-, or -CH2-, Y is oxygen or sulphur and the chiral
`centre * in formula (i) or (ii) is in its (8) or (R) form or is a mixture thereof in any proportions; and
`Z is a group of formula (iv), (v), or (vi)
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`CHZCHZNRIRZ
`
`/
`
`NR3
`
`3
`
`NR
`
`(iv)
`
`(V)
`
`(vi)
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`wherein R‘ and R2 are independently selected from hydrogen and C1—4 alkyl and R3 is hydrogen or C1—4
`alkyl;
`and salts, solvates and physiologically functional derivatives thereof.
`Compounds of formula (I) having particularly desirable properties for the treatment and prophylaxis of
`migraine include those wherein n is 1, W is a group of formula (i) and Z is a group of formula (iv) or (vi). Of
`these, compounds of formula (I) wherein n is 1, W is a group of formula (i) wherein R is hydrogen, X is -0-
`and Y is oxygen and Z is a group of formula (iv) or (vi) wherein R‘ = R2 = hydrogen or methyl are
`particularly preferred.
`Two compounds of formula (I) having exceptional properties for the treatment and prophylaxis of
`migraine are N,N-dimethyl-2-[5-(2-oxo-1,3-oxazolidin-4-yl-methyl)-1H-indol-3-yl]ethylamine and 3-(1-methyl-
`4-piperidyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indole in either their
`(S) or
`(R) form or as a mixture
`thereof in any proportions. The salts and solvates of these compounds, for example, the hydrate maleates,
`are particularly preferred.
`their
`Physiologically acceptable salts are particularly suitable for medical applications because of
`greater aqueous solubility relative to the parent,
`i_e basic, compounds. Such salts must clearly have a
`physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present
`invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric,
`citric, sulphuric, lactic, or tartaric acid. The succinate and chloride salts are particularly preferred for medical
`purposes. Salts having a non-physiologically acceptable anion are within the scope of the invention as
`useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic,
`for example, i_n @, situations.
`According to a second aspect of the present invention, there is provided a compound of formula (I) or a
`physiologically acceptable salt,
`solvate, or physiologically functional derivative thereof
`for use as a
`therapeutic agent, specifically as a "5-HT1-like" receptor agonist, for example, as a carotid vasoconstrictor
`in the prophylaxis arid treatment of migraine. As
`indicated, however,
`target organs for
`the present
`compounds other than the carotid vasculature are within the scope of the present invention.
`The amount of a compound of formula (I), or a salt or solvate thereof, which is required to achieve the
`desired biological effect will depend on a number of factors such as the specific compound, the use for
`which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of
`migraine may be expected to lie in the range 0.01 to 5mg per kilogram body weight. Unit doses may
`contain from 1
`to 100mg of a compound of formula (I), for example, ampoules for injection may contain
`from 1
`to 10mg and orally administrable unit dose formulations such as tablets or capsules may contain
`from 1
`to 100mg. Such unit doses may be administered one or more times a day, separately or in multiples
`thereof. An intravenous dose may be expected to lie in the range 0.01 to 0.15mg/kg and would typically be
`administered as an infusion of from 0.0003 to 0.15mg per kilogram per minute. Infusion solutions suitable
`for this purpose may contain from 0.01 to 10mg/ml.
`When the active compound is a salt or solvate of a compound of formula (I), the close is based on the
`cation (for salts) or the unsolvated compound.
`Hereinafter references to "compound(s) of formula (I)'' will be understood to include physiologically
`acceptable salts and solvates thereof.
`there are provided pharmaceutical
`therefore,
`invention,
`the present
`According to a third aspect of
`compositions comprising, as active ingredient, at least one compound of formula (I) and/or a pharmacologi-
`cally acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These
`pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a
`"5-HT1-like" receptor agonist
`is indicated, for example, migraine. The carrier must be pharmaceutically
`acceptable to the recipient and must be compatible with,
`i.e. not have a deleterious effect upon, the other
`ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated with at least
`one compound of formula (I) as a unit dose formulation, for example, a tablet which may contain from 0.05
`to 95% by weight of the active ingredient.
`If desired, other physiologically active ingredients may also be
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`EP 0 636 623 A1
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`incorporated in the pharmaceutical compositions of the invention.
`(for example,
`Possible formulations include those suitable for oral, sublingual, buccal, parenteral
`subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration. The most suitable
`means of administration for a particular patient will depend on the nature and severity of the condition being
`treated and on the nature of the active compound, but, where possible, oral administration is preferred.
`Formulations suitable for oral administration may be provided as discrete units, such as tablets,
`capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as
`powders or granules; as solutions or suspensions in aqueous or non—aqueous liquids; or as oil—in—water or
`water—in—oil emulsions.
`
`Formulations suitable for sublingual or buccal administration include lozenges comprising the active
`compound and,
`typically, a flavoured base, such as sugar and acacia or
`tragacanth, and pastilles
`comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
`Formulations suitable for parenteral administration typically comprise sterile aqueous solutions contain-
`ing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood
`of the intended recipient. Although such solutions are preferably administered intravenously, they may also
`be administered by subcutaneous or intramuscular injection.
`Formulations suitable for
`rectal administration are preferably provided as unit-dose suppositories
`comprising the active ingredient and one or more solid carriers forming the suppository base, for example,
`cocoa butter.
`
`lotions, pastes,
`Formulations suitable for topical or intranasal application include ointments, creams,
`gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly,
`lanolin,
`polyethylene glycols, alcohols, and combinations thereof The active ingredient is typically present in such
`formulations at a concentration of from 0.1 to 15% w/w.
`
`The formulations of the invention may be prepared by any suitable method, typically by uniformly and
`intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both,
`in the
`required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
`For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or
`granules of the active ingredient and one or more optional
`ingredients, such as a binder,
`lubricant,
`inert
`diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active
`ingredient and inert liquid diluent.
`Aqueous solutions for parenteral administration are typically prepared by dissolving the active com-
`pound in sufficient water to give the desired concentration and then rendering the resulting solution sterile
`and isotonic.
`
`Thus, according to a fourth aspect of the present invention, there is provided the use of a compound of
`formula (I)
`in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for
`which a "5-HT1—like" receptor agonist is indicated, for example, migraine.
`According to a fifth aspect, there is provided a method for the prophylaxis or treatment of a clinical
`condition in a mammal, for example, a human, for which a "5—HT1—like" receptor agonist is indicated, for
`example, migraine, which comprises the administration to said mammal of a therapeutically effective
`amount of a compound of formula (I) or of a physiologically acceptable salt, solvate, or physiologically
`functional derivative thereof.
`
`According to a sixth aspect of the invention, compounds of formula (I) wherein Z is a group of formula
`(iv) may be prepared by reacting a compound of formula (II) (isolated or i_n sifl - @).
`
`W
`\ (CH2),
`
`NHNH2
`
`(H)
`
`wherein n and W are as hereinbefore defined, with a compound of formula (III)
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`or a carbonyl—protected form thereof, such as the dimethyl or diethyl acetal, wherein L is a suitable leaving
`group, such as chlorine, or a protected amino group, either of which may be converted i_n $3 to an amino
`group, or is —NR‘ R2 where R‘ and R2 are as hereinbefore defined. The reaction is typically carried out by
`refluxing the compounds in a polar solvent system, for example, ethanol/water, dilute acetic acid, or water in
`the presence of an acidic ion exchange resin, for example, 'Amberlyst 15'.
`Standard N-alkylation methods may be used to convert compounds of formula (I) wherein Z is a group of
`formula (iv) and R‘ and/or R2 are hydrogen to corresponding compounds wherein R‘ and/or R2 are C1—4
`alkyl.
`Compounds of formula (I) wherein Z = (iv) and R‘ = R2 = C1—4. alkyl may be prepared from the
`corresponding compound wherein R‘ = R2 = H by methods of N,N-dialkylation well known to those skilled
`in the art, for example, by treatment with the appropriate aldehyde in the presence of a reducing system,
`for example, sodium cyanoborohydride/ acetic acid, in a polar solvent, such as methanol.
`Compounds of formula (I) wherein Z = (iv) and R‘ or R2 = C1—4 alkyl may be prepared from the
`corresponding compound wherein R‘ = R2 = H by N-benzylation using benzaldehyde and a suitable
`reducing agent,
`for example, sodium borohydride,
`in a polar solvent, such as ethanol, followed by N-
`alklyation using a suitable agent, such as the appropriate dialkyl sulphate, typically in the presence of a
`base, for example, anhy. potassium carbonate,
`in a polar aprotic solvent, such as DMF, and finally N-
`debenzylation,
`typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent, such as
`ethanol.
`
`Hydrazines of formula (II) may be prepared from the corresponding aniline of formula (IV)
`
`NH2
`
`(Iv)
`
`W
`\<cH2),,
`
`wherein n and W are as hereinbefore defined, by diazotisation followed by reduction. Diazotisation is
`typically carried out using sodium nitrite/c.HCl and the resulting diazo product reduced i_n sifl using, for
`example,
`tin(II) chloride/c.HCl. The resulting hydrazine may be isolated or converted to a compound of
`formula (I) i_n sifl.
`Anilines of formula (IV) may be prepared by reduction of
`formula (V)
`
`the corresponding p-nitro compound of
`
`N02
`
`(V)
`
`W
`\(cH2>,,
`
`wherein n and W are as hereinbefore defined, typically by catalytic hydrogenation using, for example, Pd/C
`in a polar solvent system, such as an acidified mixture of ethanol, water and ethyl acetate.
`Anilines of formula (IV) wherein W is a group of formula (i) or (ii) may also be prepared by cyclising a
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`EP 0 636 623 A1
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`compound of formula (X)(X|||)
`
`H(R4)N
`
`mvk
`
`(CH2)ll
`
`or (XXXIV)
`
`H(R4 NR/K
`
`NH2
`
`(XXXIII)
`
`NH2
`
`XXXIV)
`
`wherein n and X are as hereinbefore defined and R4 is -CO2 R5 where R5 is C1—4 alkyl, typically by heating
`in the presence of a base, such as sodium methoxide.
`Compounds of formula (X)(X|||) wherein X is oxygen may be prepared by reducing a corresponding
`C1—4 alkyl ester using, for example, sodium borohydride, in a polar solvent system, such as ethanol/water,
`at 0°C. The ester may be prepared by esterifying the corresponding carboxylic acid using, for example, the
`appropriate alcohol and HCl or by reducing the corresponding E-nitro compound, for example, by catalytic
`hydrogenation. Both the acid and the p-nitro compound may be prepared from the corresponding p-
`nitroaminoacid, the acid by N-aikoxycarbonyiation using, for example, R5 OCOCI where R5 is as herein-
`before defined, followed by reduction of the nitro group, for example, by catalytic hydrogenation, or by
`reduction of the nitro group followed by N-aikoxycarbonyiation, and the p-nitro compound by N-aikoxycar-
`bonyiation (as for the acid) followed by esterification using, for example, the appropriate alcohol and HCl, or
`by esterification followed by N-aikoxycarbonyiation. The p—nitroaminoacid may be obtained commercially or
`prepared from readily available starting materials by methods known to those skilled in the art or obtainable
`from the chemical literature, for example, by p-nitration of the corresponding aminoacid using, for example,
`C.H2SO4/C.HNO3 at 0°C.
`Compounds of formula (XXXIV) wherein X is oxygen may be prepared by reducing the corresponding
`dinitro compound, typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent, such as
`ethanol. The dinitro compound may be prepared by reacting the appropriate aldehyde with nitromethane,
`typically in the presence of a base, for example, sodium methoxide,
`in a polar solvent, such as methanol,
`followed by p-nitration using, for example, c.H2SO4/c.HNO5, or by p-nitration of the appropriate aldehyde
`followed by reaction with nitromethane. The aldehyde may be obtained commercially or prepared from
`readily available starting materials by methods known to those skilled in the art or obtainable from the
`chemical literature.
`
`p-Nitro compounds of formula (V) may be prepared by
`(a) in the case where W is a group of formula (i) in which Y is oxygen or sulphur, reacting a compound
`of formula (\/I)
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`EP 0 636 623 A1
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`H(R)N /H (CH2)n
`
`N02
`
`(VI)
`
`wherein n, R and X are as hereinbefore defined, with a compound of formula (VII)
`
`(V11)
`
`wherein Y is as hereinbefore defined and L and L‘, which may be the same or different, are suitable
`leaving groups, for example, chlorine, ethoxy, trichloromethyl, trichloromethoxy, or imidazoyl, for exam-
`ple,
`in the case where L = L‘ = chlorine,
`in a non-polar solvent, such as toluene, in the presence of a
`base, for example, potassium hydroxide.
`(b) in the case where W is a group of formula (ii) in which Y is oxygen or sulphur, reacting a compound
`of formula (VIII)
`
`N02
`
`H(R)N
`
`(CH2)n
`
`(VIII)
`
`wherein n, R and X are as hereinbefore defined, with a compound of formula (VII) wherein Y, L and L‘
`are as hereinbefore defined, typically using the reaction conditions described in (a);
`(c) in the case where W is a group of formula (iii), reacting a compound of formula (IX)
`
`HO
`
`\(cH2)n
`
`N02
`
`ax)
`
`wherein n is as hereinbefore defined, with a compound of formula (X)
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`EP 0 636 623 A1
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`0
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`0
`
`in the presence
`
`wherein R is as hereinbefore defined, typically in a polar aprotic solvent, such as DMF,
`of DEAD/Phs P.
`Compounds of formula (VI) may be prepared by ring-opening a compound of formula (V) wherein n is
`as hereinbefore defined and W is a group of formula (i) in which R, X and Y are as hereinbefore defined, for
`example, by refluxing in 2N aqu. KOH.
`Compounds of formula (VI) wherein X is oxygen may be prepared by esterification of the corresponding
`carboxylic acid, typically by treatment with thionyl chloride and an appropriate alcohol at -10°C, followed by
`reduction of
`the ester using,
`for example, sodium borohydride,
`in a polar solvent system, such as
`ethanol/water, at 0°C. The acid may be obtained commercially or prepared from readily available starting
`materials by methods known to those skilled in the art or obtainable from the chemical
`literature, for
`example, by E-nitration of the corresponding aminoacid using, for example, c.H2 S04/c.HNO3 at 0°C.
`Compounds of formula (VIII) may be prepared by ring-opening a compound of formula (V) wherein n is
`a hereinbefore defined and W is a group of formula (ii) in which R, X and Y are as hereinbefore defined, for
`example, by refluxing in 2N aqu. KOH.
`Compounds of formula (III), (VII), (IX) and (X) may be obtained commercially or prepared from readily
`available starting materials by methods known to those skilled in the art or obtainable from the chemical
`literature.
`
`E-Nitro compounds of formula (V) wherein W is a group of formula (i) or (ii) may also be prepared by p-
`nitration of a compound of formula (XXXVI)
`
`W
`\(cH2),,
`
`(XXXVI)
`
`wherein n and W are as hereinbefore defined, using, for example, c.H2SO4/c.HNO3 at 0°C.
`Compounds of formula (X)O(V|) may be prepared by reacting a compound of formula ()OO(Vll)
`
`H(R)N
`
`HXXJ\(CH2),,
`
`I
`
`(XXXV11)
`
`or (XXXVIII)
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`EP 0 636 623 A1
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`Hm
`
`(CH2).
`
`(XXXVIII)
`
`wherein n, R and X are as hereinbefore defined, with a compound of formula (VII) wherein Y, L and L‘ are
`as hereinbefore defined, typically in the presence of a base, for example, potassium hydroxide,
`in a non-
`polar solvent, such as toluene.
`Compounds of formula (X)<XVll) and (XXXVIII) may be prepared by reducing the corresponding nitro
`compounds,
`typically by catalytic hydrogenation using,
`for example, Pd/C in a polar solvent, such as
`ethanol. The nitro compound corresponding to the compound of formula (XX)O/ll) may be prepared by
`reacting a compound of formula (XXIV)
`
`02N
`
`\(CH2)n+1
`
`(xxw)
`
`in the
`wherein n is as hereinbefore defined, with paraformaldehyde in a polar aprotic solvent, such as DMF,
`presence of a base,
`for example, sodium methoxide, at 0°C, or by esterification of the corresponding
`carboxylic acid, typically by treatment with thionyl chloride and an appropriate alcohol at -10°C, followed by
`reduction of the ester group using, for example, sodium borohydride,
`in a polar solvent system, such as
`ethanol/water, at 0°C. The nitro compound corresponding to the compound of formula (XXXVIII) may be
`prepared by reacting the appropriate aldehyde with nitromethane, typically in the presence of a base, for
`example, sodium methoxide,
`in a polar solvent, such as methanol. The compound of formula (XXIV), the
`acid and the aldehyde may be obtained commercially or prepared from readily available starting materials
`by methods known to those skilled in the art or obtainable from the chemical literature.
`in which R is C1—4
`p—Nitro compounds of formula (V) wherein W is a group of formula (i),
`(ii), or (iii)
`alkyl may be prepared from the corresponding compound of formula (V) wherein R is hydrogen by N-
`alkylation using a suitable agent, such as the appropriate dialkyl sulphate, typically in the presence of a
`base, for example, sodium hydride, in a non—polar solvent, such as THF.
`Compounds of formula (I) wherein W is a group of formula (i) or (ii) may also be prepared by reacting a
`compound of formula ()0/)
`
`(XV)
`
`HN
`
`H(R)N
`
`HR/K ((3112),,
`
`or (XXV)
`
`10
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`

`
`(XXV)
`
`HN
`
`/
`
`z
`
`EP 0 636 623 A1
`
`HX
`
`H(R)NK/K
`
`((3112),,
`
`wherein n, R, X and Z are as hereinbefore defined, with a compound of formula (VII) wherein Y, L and L‘ are
`as hereinbefore defined, for example, in the case where L = L‘ = ethoxy, by heating in the presence of a
`base, for example, potassium carbonate.
`Compounds of formula ()0/) may be prepared by ring-opening a compound of formula (I) wherein n and
`Z are as hereinbefore defined and W is a group of formula (i)
`in which R, X and Y are as hereinbefore
`defined, for example, by refluxing in 2N aqu. KOH.
`Compounds of formula (XV) wherein X is oxygen may be prepared by esterification of the correspond-
`ing carboxylic acid, typically by treatment with thionyl chloride and an appropriate alcohol at -10°C, followed
`by reduction of
`the ester using, for example, sodium borohydride,
`in a polar solvent system, such as
`ethanol/water, at 0°C. The acid may be prepared by ring-opening a compound of formula (XVI)
`
`HN
`
`/
`
`(CH2)n
`
`(XVI)
`
`0
`
`R‘N
`
`NR
`
`0
`
`wherein n, R and Z are as hereinbefore defined and R5 is hydrogen or benzyl, typically by refluxing in
`water in the presence of a base, for example, barium hydroxide.
`Compounds of formula (XVI) wherein n =# 0 may be prepared by reducing a compound of formula
`(XVII)
`
`Z
`
`(XVII)
`
`CH
`
`\«:H2>,.-,
`
`0
`
`R N
`
`°§(
`R6N
`
`wherein n, R, R‘ and Z are as hereinbefore defined, typically by catalytic hydrogenation using, for example,
`Pd/C in a polar solvent system, such as ethanol/water. Alternatively, an enantioselective reducing agent,
`such as Rh(cod)(dipamp)+BF4‘ (JCS, Chem. Comm. 275(1991)), may be used to reduce the double bond
`and thereby introduce a chiral centre at the 4-position of the dioxoimidazole ring. The reduction step may
`be used to convert a compound of formula (XVII) wherein Z is a group of formula (v) into a compound of
`
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`5
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`
`EP 0 636 623 A1
`
`formula (XVI) wherein Z is a group of formula (vi).
`Compounds of formula (XVII) may be prepared by reacting a compound of formula (XVIII)
`
`H N /
`
`z(xvm)
`
`OHC
`\ (CH2)n -1
`
`in the case where R5 is to be hydrogen, a compound of
`wherein n and Z are as hereinbefore defined, with,
`formula (X) wherein R is as hereinbefore defined, typically by heating in glac. acetic acid in the presence of
`ammonium acetate.
`
`Compounds of formula (XVIII) may be prepared by the reduction/ hydrolysis of the corresponding nitrile,
`typically using Raney nickel and sodium hypophosphite in a mixture of water, acetic acid and pyridine. The
`nitrile may be prepared by reacting a compound of formula (XIX)
`
`(XIX)
`
`H N
`
`/
`
`NC\
`
`(CH2),,_1
`
`wherein n is as hereinbefore defined, with,
`appropriate compound of formula (XXVIII)
`
`in the case where Z is to be a group of formula (v) or (vi), the
`
`(XXVU1)
`
`wherein R3 is as hereinbefore defined, typically by refluxing in a polar solvent, such as methanol,
`presence of base, for example, potassium hydroxide.
`Compounds of formula (XIX) and (XXVII) may be obtained commercially or prepared from readily
`available starting materials by methods known to those skilled in the art or obtainable from the chemical
`literature. Compounds of formula (XVI) wherein n = 0 may be obtained by the same means.
`Compounds of formula (XVI) wherein R5 is benzyl and Z is a group of formula (iv) may be prepared by
`reacting a compound of formula (XXXV)
`
`in the
`
`o
`
`NR
`
`N
`
`3/
`
`(CH2)n
`
`NHNH2
`
`(XXXV)
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`12
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`

`
`EP 0 636 623 A1
`
`wherein n and R are as hereinbefore defined, with a compound of formula (III) wherein L is as hereinbefore
`defined, typically using the reaction conditions described above for the reaction of (II) with (III).
`Hydrazines of formula (XXXV) may be prepared from the corresponding aniline,
`typically using the
`reaction conditions described above for the conversion of
`(IV)
`to (II). The aniline may be prepared by
`reducing the corresponding p-nitro compound, typically using the reaction conditions described above for
`the conversion of (V) to (IV). The p-nitro compound may be prepared by reacting the corresponding p-
`nitroaminoacid with benzyl isocyanate in the presence of base, for example, potassium hydroxide, in a polar
`solvent, such as water. The p—nitroaminoacid may be obtained commercially or prepared from readily
`available starting materials by methods known to those skilled in the art or obtainable from the chemical
`literature, for example, by p—nitration of the corresponding aminoacid using, for example, c.H2SO4/c.HNO3
`at 0°C.
`
`Compounds of formula (XV) wherein R is hydrogen may be prepared by reducing a compound of
`formula (XX)
`
`(XX)
`
`HN /
`
`Z
`
`O2N
`
`HX\/k(CH2)n
`
`wherein n, X and Z are as hereinbefore defined, typically by catalytic hydrogenation using, for example,
`Pd/C in a polar solvent, such as ethanol. The same step may be used to convert a compound of formula
`(XX) wherein Z is a group of formula (v) into a compound of formula (XV) wherein Z is a group of formula
`(vi).
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`Compounds of formula (X)() wherein X is oxygen may be prepared by reacting a compound of formula
`(XXI)
`
`(XXI)
`
`HN
`
`/
`
`z
`
`o,N\
`
`(CH2)n+1
`
`wherein n and Z are as hereinbefore defined, with paraformaldehyde in a polar aprotic solvent, such as
`DMF, in the presence of a base, for example, sodium methoxide, at 0°C.
`Compounds of formula (XXI) may be prepared by reacting a compound of formula (XXII)
`
`(XXII)
`
`HN /
`
`o N
`
`2 \(cH2)
`
`n+1
`
`in the case where Z is to be a group of formula (v) or (vi), the
`wherein n is as hereinbefore defined, with,
`appropriate compound of formula ()()(V|||) wherein R3 is as hereinbefore defined, typically by heating in
`glac. acetic acid.
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`EP 0 636 623 A1
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`Compounds of formula (XXII) wherein n ¢ 0 may be prepared by reducing a compound of formula
`(XXIII)
`
`(XXIII)
`
`H N /
`
`o2N /CH
`\CH / \(CH2)n-1
`
`wherein n is as hereinbefore defined, using, for example, sodium borohydride and 40% w/v aqu. NaOH in a
`polar aprotic solvent, such as acetonitrile, at 0°C.
`Compounds of formula (XXIII) may be prepared by heating the appropriate aldehyde with nitromethane
`in the presence of ammonium acetate. The aldehyde may be prepared from a compound of formula (XIX)
`wherein n is as hereinbefore defined using the reaction conditions described above for preparing a
`compound of formula (XVIII) from the corresponding nitrile.
`Compounds of formula (XXII) wherein n = 0 may be obtained commercially or prepared from readily
`available starting materials by methods known to those skilled in the art or obtainable from the chemical
`literature.
`
`Compounds of formula (XXI) wherein n at 0 may also be prepared from a compound of formula ()<)(XIX)
`
`H N
`
`/
`
`(XXXIX)
`
`/cH\
`
`wherein n and Z are as hereinbefore defined, using reaction conditions analogous to those used to convert
`(XXIII)
`to (XXII). Compounds of formula (XXXIX) may be prepared from a compound of formula (XVIII)
`wherein n and Z are as hereinbefore defined using reaction conditions analogous to those used to prepare
`(XXIII) from the appropriate aldehyde and nitromethane.
`Compounds of formula (XX) wherein X is other than oxygen may be obtained commercially or prepared
`from readily available starting materials by methods known to those skilled in the art or obtainable from the
`chemical literature.
`
`Compounds of formula ()O(V) may be prepared by ring-opening a compound of formula (I) wherein n
`and Z are as hereinbefore defined and W is a group of formula (ii) in which R, X and Y are as hereinbefore
`defined, for example, by refluxing in 2N aqu. KOH.
`Compounds of formula (I) wherein W is a group of formula (i) in which Y is sulphur may be prepared by
`refluxing a compound of formula (XV) wherein n, R and X are as hereinbefore defined, with a compound of
`formula (VII) wherein Y is sulphur and L and L‘ are as hereinbefore defined,
`for example, N,N'-
`thiocarbonylimidazole, typically in an aprotic solvent, such as THF.
`Compounds of formula (I) wherein W is a group of formula (ii) in which Y is sulphur may be prepared
`by refluxing a compound of formula (XXV) wherein n, R and X are as hereinbefore defined, with a
`compound of formula (VII) wherein Y is sulphur and L and L‘ are as hereinbefore defined, for example, N,N'-
`thiocarbonylimidazole, typically in an aprotic solvent, such as THF.
`Compounds of formula (I) wherein W is a group of formula (iii) and Z is a group of formula (v) or (vi)
`may also be prepared by cyclising a compound of formula (XXVI)
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`14
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`

`
`HV
`
`L
`
`/
`
`Z
`
`EP 0 636 623 A1
`
`RN——j
`R7o2c«—’/
`
`0
`
`N
`
`wherein n and R are as hereinbefore defined, Z is a group of formula (v) or (vi) and R7 is C1—4 alkyl,
`typically by heating in aqueous acid, for example, 2N HCI.
`Compounds of formula (XXVI) wherein Z is a group of formula (v) may be prepar