WO2006030211A2 - Acyclic sulphonamides - Google Patents

Acyclic sulphonamides Download PDF

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Publication number
WO2006030211A2
WO2006030211A2 PCT/GB2005/003551 GB2005003551W WO2006030211A2 WO 2006030211 A2 WO2006030211 A2 WO 2006030211A2 GB 2005003551 W GB2005003551 W GB 2005003551W WO 2006030211 A2 WO2006030211 A2 WO 2006030211A2
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alkyl
methyl
moiety
substituents
amino
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PCT/GB2005/003551
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French (fr)
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WO2006030211A3 (en
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Christopher John Hobbs
Rosemary Lynch
Sarah Louise Mellor
Fleur Radford
Jenny Christine Gilbert
Stephen Stokes
Angela Glen
Andrea Fuimana
Christopher Geoffrey Earnshaw
Lars Jacob Stray Knutsen
Kathryn Elizabeth Sorrel Dean
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Vernalis (R & D) Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles

Definitions

  • the present invention relates to specific benzenesulfonamide derivatives which act as inhibitors of N-type calcium channels.
  • Mammalian ion channels are becoming increasingly well characterised, and this is especially true of calcium channels.
  • Voltage-gated calcium channels are critical components for the functioning of the nervous system, and they signal a painful event.
  • 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non-neuronal cells (Perez- Reyes, E.; Schneider, T. DrugDev. Res., 1994, 33, 295-318). These channels are now recognised as valid targets for pain therapeutics and as neuroprotective agents (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).
  • A is a 5- to 10-membered heteroaryl or heterocyclyl moiety, said moiety being optionally fused to a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6- membered heterocyclyl group;
  • B is a bond or a C 1 -C 6 alkyl or C 2 -C 6 alkenyl moiety; either (a) R 1 is hydrogen or C 1 -C 6 alkyl and R 2 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogen, hydroxy, thio, amino, -Het-L or -L-Het-L', wherein L and L 1 are the same or different and represent C 1 -C 6 alkyl or C 2 -C 6 alkenyl and Het is O, S or NR, wherein R is hydrogen or C 1 -C 6 alkyl, or (b) R 1 and R 2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl or a C 3 -C 8 carbocyclyl moiety;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or -L-Het-L', wherein L, L' and Het are as defined above;
  • - R 4 , R 5 and R 6 are the same or different and represent hydrogen, halogen, hydroxy, amino, thio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, HiOnO(C 1 -C 6 alkyl)amino or di(Ci-C 6 alkyl)amino;
  • the alkyl and alkenyl groups and moieties in B and R 1 to R 6 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents;
  • the heterocyclyl and carbocyclyl moieties formed by R 1 and R 2 being
  • a C 1 -C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C 1 -C 4 alkyl group or moiety, for example methyl, ethyl, «-propyl, /-propyl, R-butyl, /-butyl and /-butyl.
  • Preferred C 1 -C 6 alkyl groups include methyl, ethyl, /-propyl and /-butyl.
  • a divalent alkyl group or moiety can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
  • Examples of divalent alkyl moieties are methylene and 1,1 -ethyl moieties.
  • a preferred divalent alkyl moiety is a 1,1 -ethyl moiety.
  • a C 2 -C 6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C 2 -C 4 alkenyl group or moiety, for example ethenyl, n-propenyl and n-butenyl.
  • a preferred C 2 -C 6 alkenyl group is ethenyl.
  • an alkenyl group has only one double bond. This double bond is typically located at the V-position of the alkenyl group.
  • a divalent alkenyl group or moiety can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, fluorine or bromine.
  • a said C 1 -C 6 alkoxy group is typically a said C 1 -C 6 alkyl group attached to an oxygen atom.
  • a said C 1 -C 6 alkylthio group is typically a said C 1 -C 6 alkyl group attached to a thio group.
  • a C 1 -C 6 haloalkyl group is typically a said C 1 -C 6 alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1 , 2 or 3 said halogen atoms.
  • haloalkyl groups include perhaloalkyl groups such as -CX 3 wherein X is a said halogen atom.
  • Preferred haloalkyl groups are fluoroalkyl groups such as -CF 3 and -CHF 2 .
  • a particularly preferred haloalkyl group is -CF 3 .
  • a C 1 -C 6 haloalkoxy group is typically a said C 1 -C 6 alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1 , 2 or 3 said halogen atoms.
  • Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX 3 wherein X is a said halogen atom.
  • a particularly preferred haloalkoxy group is -OCF 3 .
  • a C 1 -C 6 haloalkylthio group is typically a said C 1 -C 6 alkylthio group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX 3 wherein X is a said halogen atom.
  • a particularly preferred haloalkylthio group is -SCF 3 .
  • a 5- to 10-membered heteroaryl group is typically a 5- to 10- membered monocyclic aromatic ring, such as a 5- or 6-membered ring, containing at least one heteroatom, for example 1 , 2 or 3 heteroatoms, selected from O, S and N.
  • heteroatoms for example 1 , 2 or 3 heteroatoms, selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl groups.
  • A represents a 5- to 10-membered heteroaryl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl group, it is preferably a 5- to 6-membered heteroaryl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl group.
  • A represents a 5- to 10-membered heteroaryl moiety fused to a cyclic group, it is preferably fused to a phenyl or pyridyl group.
  • fused groups include an oxazolyl moiety that is fused to a phenyl or pyridyl group to form a benzo[d] oxazolyl or oxazolopyridinyl group, respectively.
  • a C 3 -C 8 carbocyclyl group is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl group) or an unsaturated ring having only one double bond. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl and cyclohexyl groups are preferred.
  • a heterocyclyl group is typically a monocyclic, non-aromatic, saturated or unsaturated C 5 -C 10 carbocyclic ring, such as a C 5 -C 6 carbocyclic ring, in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a moiety selected from N, O, S, SO and S(O) 2 .
  • said moiety is selected from N, O and S.
  • saturated heterocyclyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, thiomorpholinyl, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl and oxazolidinyl.
  • suitable unsaturated heterocyclic groups include dihydro-oxazolyl, dihydroisoxazyl, dihydrothiazolyl, dihydroisothiazolyl, dihydro-oxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl and dihydropyridazinyl.
  • Preferred unsaturated heterocyclic groups are dihydro-oxazolyl, dihydroisoxazyl, dihydrothiazolyl, dihydroisothiazolyl, dihydroimidazolyl and dihydropyrazolyl. Dihydro-oxazolyl is particularly preferred.
  • A represents a 5- to 10-membered heterocyclyl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl group
  • it is preferably a 5- to 6-membered heterocyclyl moiety, and more preferably an unsaturated 5- to 6-membered heterocyclyl moiety, fused to a phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6-membered heterocyclyl group.
  • A represents a 5- to 10-membered heterocyclyl moiety fused to a cyclic group, it is preferably fused to a phenyl or pyridyl group.
  • A represents a 5- to 10-membered heterocyclyl moiety fused to a cyclic group, it is preferably fused to a phenyl or pyridyl group.
  • a compound of formula (I) contains more than one L, L 1 or Het moiety, each of the respective moieties is the same or different.
  • R in the or each Het moiety is hydrogen or C 1 -C 4 alkyl.
  • R in the or each Het moiety is hydrogen or methyl.
  • L in the or each R 1 , R 3 or A moiety is C 1 -C 4 alkyl.
  • L in the or each R 1 , R 3 or A moiety is C 1 -C 2 alkyl.
  • L 1 in the or each R 1 , R 3 or A moiety is C 1 -C 4 alkyl.
  • L 1 in the or each R 1 , R 3 or A moiety is C 1 -C 2 alkyl.
  • Het is O, S or NR, wherein R is as defined above.
  • Het is O.
  • the alkyl and alkenyl groups and moieties in B and R 1 to R 6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents.
  • the alkyl and alkenyl groups and moieties in B and R 1 to R 3 are unsubstituted or substituted by a single hydroxy substituent.
  • the alkyl and alkenyl groups and moieties in R 4 to R 6 are unsubstituted or substituted by one, two or three fluorine or chlorine substituents.
  • the heterocyclyl and carbocyclyl moieties formed by R 1 and R 2 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents.
  • the heterocyclyl and carbocyclyl moieties formed by R 1 and R 2 are unsubstituted.
  • the group A is substituted, only one of the substituents is a group selected from phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6- membered heterocyclyl.
  • the group A is unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -L-Het-L', phenyl, 5- to 6-membered heteroaryl, C 3 -C 6 carbocyclyl or 5- to 6- membered heterocyclyl, wherein L, L 1 and Het are as defined above.
  • the group A is unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C 1 -C 6 alkyl, -(C 1 -C 2 alkyl)-O-(Ci-C 2 alkyl), cyclopropyl or phenyl.
  • alkyl and alkenyl moieties in the substituents on A are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine and hydroxy substituents
  • the alkyl and alkenyl moieties in the substituents on A are unsubstituted or substituted by a single hydroxy substituent or by one, two or three fluorine or chlorine substituents.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents on A are unsubstituted or substituted by one, two or three futher unsubstituted substituents selected from fluorine, chlorine, bromine, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents on A are unsubstituted.
  • A is a 5- to 6-membered heteroaryl or heterocyclyl moiety, in particular a 5- to 6-membered heteroaryl or unsaturated heterocyclyl moiety, said moiety being optionally fused to a phenyl or 5- to 6-membered heteroaryl group.
  • A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl or dihydro-oxazolyl moiety, said moiety being optionally fused to a phenyl or pyridyl group.
  • A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, dihydro-oxazolyl, benzo[d] oxazolyl or oxazolopyridinyl moiety.
  • B is a bond or a C 1 -C 4 alkyl moiety.
  • B is a bond or a C 1 - C 2 alkyl moiety, for example a 1,1 -ethyl moiety.
  • R 1 is hydrogen or C 1 -C 4 alkyl.
  • R 1 is hydrogen or methyl.
  • R 2 is hydrogen or C 1 -C 6 alkyl.
  • R 2 is hydrogen or C 1 -C 4 alkyl. More preferably, R 2 is hydrogen or C 1 -C 4 alkyl group which is unsubstituted or substituted with a single hydroxy group.
  • R 1 and R 2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl moiety or C 3 -Cg carbocyclyl moiety, they typically form a saturated 5- to 6-membered heterocyclyl moiety or a C 3 -C 6 carbocyclyl moiety. Preferably, they form a C 3 -C 6 carbocyclyl moiety such as a cyclopropyl or cyclohexyl moiety.
  • R 3 is hydrogen, C 1 -C 6 alkyl or -L-Het-L 1 , wherein L, L' and Het are as defined above.
  • R 3 is hydrogen, C 1 -C 4 alkyl or -(C 1 -C 2 alkyl)-O-(Ci-C 2 alkyl). More preferably, R 3 is hydrogen, an unsubstituted -(C 1 -C 2 alkyl)-O-(C 1 -C 2 alkyl) group or a C 1 -C 4 alkyl group which is unsubstituted or carries a single hydroxy substituent.
  • R 4 , R 5 and R 6 are the same or different and represent hydrogen, fluorine, chlorine, bromine, hydroxy, amino, thio, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono(C 1 -C 4 alkyl)amino or CIi(C 1 -C 4 alkyl)amino.
  • R 4 , R 5 and R 6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or C 1 -C 2 alkyl.
  • R 4 , R 5 and R 6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or an unsubstituted C 1 -C 2 alkyl or C 1 -C 2 haloalkyl group.
  • Preferred compounds of formula (I) are those wherein: A is a 5- to 6-membered heteroaryl or unsaturated heterocyclyl moiety, said moiety being optionally fused to a phenyl or 5- to 6-membered heteroaryl group;
  • B is a bond or a C 1 -C 4 alkyl moiety; - either (a) R 1 is hydrogen or C 1 -C 4 alkyl and R 2 is hydrogen or C 1 -C 6 alkyl or (b)
  • R 1 and R 2 form, together with the carbon to which they are attached, a saturated 5- to 6- membered heterocyclyl moiety or a C 3 -C 6 carbocyclyl moiety;
  • R 3 is hydrogen, C 1 -C 6 alkyl or -L-Het-L 1 , wherein L and L' are the same or different and represent C 1 -C 4 alkyl and Het is O, S or NR, wherein R is hydrogen or C 1 - C 4 alkyl;
  • R 4 , R 5 and R 6 are the same or different and represent hydrogen, fluorine, chlorine, bromine, hydroxy, amino, thio, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono(Ci-C 4 alkyl)amino or di(C 1 -C 4 alkyl)amino;
  • the alkyl groups and moieties in B and R 1 to R 6 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents;
  • A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, dihydro-oxazolyl, benzo [d ⁇ oxazolyl or oxazolopyridinyl moiety;
  • B is a bond or a C 1 -C 2 alkyl moiety; - either (a) R 1 is hydrogen or methyl and R 2 is hydrogen or C 1 -C 4 alkyl or (b) R 1 and R 2 form, together with the carbon to which they are attached, a C 3 -C 6 carbocyclyl moiety;
  • R 3 is hydrogen, C 1 -C 4 alkyl or -(C J -C 2 alkyl)-O-(C 1 -C 2 alkyl);
  • R 4 , R 5 and R 6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or C 1 -C 2 alkyl;
  • the present invention further provides the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels.
  • Examples of particularly preferred compounds of formula (I) are: 1. N-(5-tert-Butyl-[l ,3,4]oxadiazol-2-ylmethyl)-2-chloro-N-methyl-4-trifluoro- methylbenzenesulfonarnide; 2. 2-Chloro-N-methyl-N-(5-methyl-[l ,3,4]oxadiazol-2-ylmethyl)-4-trifluoromethyl- benzenesulfonamide;
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g.
  • the compounds of the invention contain one or more chiral centre.
  • the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereoisomers.
  • Preferred compounds of the invention are optically active isomers.
  • preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free.
  • compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
  • Compounds of formula (I) may be prepared by a sulfonylation reaction, for example the reaction of a secondary amine (II) which may or may not contain a defined stereochemical centre and a phenyl sulfonyl chloride (III), wherein R 1 to R 6 are as defined above (Scheme A).
  • reaction of the amine and the sulfonyl halide of formula (III), wherein X is a halogen such as chlorine, bromine of fluorine may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, JV- ethylmorpholine or diisopropylethylamine.
  • a suitable solvent such as toluene or dichloromethane
  • a base for example triethylamine, JV- ethylmorpholine or diisopropylethylamine.
  • Both the amine (II) and phenyl sulfonyl chloride (III) are either known compounds or could be prepared by the skilled person utilising known methods.
  • Compounds of formula (I) may be prepared by the reaction of a sulfonylated amine of formula (FV) with an alkylating agent of formula R 3 -Y, wherein R 1 to R 6 are as defined above and Y is a leaving group such as halogen, methanesulfonate orp- toluenesulfonate (Scheme B).
  • the reaction of the amine and the alkylating agent may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, N- ethylmorpholine or diisopropylethylamine.
  • Both the secondary amine (IV) and R 3 -Y are either known compounds or could be prepared by the skilled person utilising known methods.
  • Compounds of formula (I) may be prepared by the reaction of a sulfonylated amine of formula (FV) with an alcohol of formula R 3 -OH (Scheme C), wherein R 1 to R 6 are as defined above.
  • the reaction of the amine and the alcohol may be performed for example under Mitsunobu conditions (Jenkins, I. D. Mitsunobu, O, In Encyclopedia of Reagents for Org. Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol.
  • Compounds of formula (I) may be prepared by the reaction of a N-alkylated-S-aryl- thiohydroxylamine of formula (V) with a suitable oxidizing agent such as m- chloroperbenzoic acid (MCPBA), oxone, or a suitable peroxide-based reagent.
  • MCPBA m- chloroperbenzoic acid
  • oxone oxone
  • typical reaction conditions would include dehydrative reactions or conditions such as iodine in the presence OfPh 3 P, in a solvent such as dichloromethane, to form 1,3,4-oxadiazoles.
  • the ring closure reaction would typically take place by utilisation of Lawesson's reagent or P 2 S 5 , in a suitable solvent such as toluene or dioxan.
  • Compounds of formula (I), wherein A is a heterocycle as defined above, may be prepared by sulfonylation of an amine of general formula (IX), which is linked via a hydrazide to a solid phase resin.
  • the sulfonylation reaction proceeds as outlined in Scheme A, and is followed by a step which cleaves the hydrazide form the resin, with a strong acid such as CF 3 CO 2 H.
  • the resultant product of general formula (X) is acylated and converted for example into oxadiazole and thiadiazole derivatives of formula (I), via an intermediate of formula (VIII), as described in Scheme E above.
  • This reaction proceeds under a variety of conditions, including dehydrative coupling.
  • Alternative conditions include reaction of an ester, mixed anhydride or acid of general formula (VII) with the nucleophilic ethanolamine to provide the intermediate (XIII).
  • This intermediate is converted into an oxazole derivative of formula (I), initially by oxidation of the hydroxyl group to a ketone under standard conditions, for example utilising Dess-Martin Periodinane or pyridinium chlorochromate, followed by cyclisation to an oxazole under dehydrative conditions, for example using Burgess Reagent.
  • This procedure can also be adapted for the synthesis of thiazole derivatives, for example by employing methods, familiar to one skilled in the art as outlined, for example, in Joule, J.A. and Mills, K.A., Heterocyclic Chemistry (Fourth edition), 2000, Blackwell Science Ltd, Oxford, UK, ISBN 0-632-05453-0.
  • the thus obtained compounds of formula (I) may be salified by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techniques, for example elution on a chiral chromatography column.
  • the compounds of the invention are found to be inhibitors of N-type calcium channels. Further, many preferred compounds of the invention exhibit selectivity over L-type calcium channels. The compounds of the invention are therefore therapeutically useful.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • inhalation One route of administration is inhalation.
  • the major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route.
  • the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
  • compositions of the invention therefore include those suitable for inhalation.
  • the present invention also provides an inhalation device containing such a pharmaceutical composition.
  • said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
  • said propellant is a fluorocarbon.
  • Nebulizers are devices capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.
  • Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.
  • said inhalation device contains a spacer.
  • a spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended.
  • nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form.
  • Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients.
  • Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter- patient variability.
  • Nasal delivery devices further allow medication to be administered in precise, metered doses.
  • the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.
  • a further route of administration is transdermal administration.
  • the present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • sublingual administration is also preferred.
  • the present invention therefore also provides a sub-lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g.
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
  • disaggregating agents e.g. starch, alginic acid, alginates or sodium starch glycolate
  • dyestuffs effervescing mixtures
  • dyestuffs effer
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the compounds of the present invention are therapeutically useful in the treatment or prevention of conditions mediated by N-type calcium channels.
  • the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • These compounds are useful as calcium channel antagonists thereby inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder.
  • N-type calcium channels are known to be closely involved in the mediation of pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. N-type calcium channels have been identified as being particularly important in the transmission of pain signals in the spinal cord (Chaplan S.R., Pogrel J 5 W., Yaksh TX. J. Pharm. Exp. Ther., 1994, 269, 1117-1123; Diaz, A., Dickenson, A.H. Pain, 1997, 69, 93-100).
  • the compounds of the invention are accordingly particularly effective in alleviating pain.
  • said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain.
  • the compounds of the invention are effective in alleviating both chronic and acute pain.
  • Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease.
  • a discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147.
  • Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system.
  • Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.
  • Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above. Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system.
  • Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb” pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.
  • trigeminal neuralgia a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease
  • diabetic neuropathy causalgia
  • neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease.
  • the compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain.
  • blockers of N-type calcium channels inhibit the release of excitatory amino acids, they can be used inter alia to inhibit damage to neuronal cells during anoxia, and function as neuroprotective agents, useful in the treatment of cerebral ischaemia or central nervous system injuries (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).
  • the compounds can also be utilised for the treatment of eye diseases (Chu, T-C; Potter, D.E. Research Communications in Pharmacology and Toxicology, 2001, 6, 263-275).
  • cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.
  • central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.
  • eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, diabetic macular oedema, retinal artery occlusion and retinitis.
  • the compounds of the invention can be used in the treatment of seizure disorders.
  • seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).
  • the compounds of the invention can also be utilised in the treatment of anxiety- related disorders and mood disorders, Bipolar disorder and post traumatic stress disorders.
  • the compounds of the invention can be utilised in the treatment of tinnitus, itch such as pruritoceptive, neuropathic, neurogenic and psychogenic itch, as well as urinary tract disorders such as urinary incontinence, and irritable bowel syndrome.
  • the compounds of the invention may also have application in disorders which are generally associated with blocking of L-type calcium channels, such as cardiovascular, antiasthmatic and antibronchoconstriction disorders for example in the prevention and treatment of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, premature labour, gastrointestinal motility disorders and cardiovascular disorders wherein the cardiovascular disorder is selected from the group consisting of hypertension, myocardial ischemia, angina, congestive heart failure, myocardial infarction and stroke.
  • the compounds of the invention can be utilised in the treatment of hypersensitivity disorders such as urinary tract disorders.
  • urinary tract disorders include, in particular, bladder dysfunctions such as overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia; bladder hyper-reflexia; urinary tract inflammation specifically bladder inflammation e.g interstitial cystitis; and urinary tract infection.
  • OAB overactive (or unstable) bladder
  • the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.
  • the compounds of the invention can also be used in the treatment of lower urinary tract symptoms (LUTS).
  • LUTS comprises three groups of symptoms, which are irritative, which comprises urgency, frequency and nocturia and which can be associated with OAB and benign prostatic hyperplasia (BHP), obstructive and post micturition symptoms.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to
  • N-Methylglycine, ethyl ester hydrochloride (Sarcosine hydrochloride) (0.63 g, 4.09 mmol) and Et 3 N (1.15 mL, 8.18 mmol) were stirred vigorously in CH 2 Cl 2 (20 mL) and (2-chloro-4-trifluoromethylbenzenesulfonyl chloride (1.14 g, 4.09 mmol) was introduced.
  • Example 2 The following example was prepared by a modification of the method used for Example 1:
  • Step l (S)-2- [(2-Chloro-4-trifluoromethyl-benzenesulfonyl)methylamino]propionic acid (0.25 g, 0.72 mmol) and 2-amino-3-hydroxypyridine (0.08 g, 0.72 mmol) were dissolved in THF (20 mL) and EDC (0.139 g, 0.72 mmol) was introduced, followed by HOBT (0.098 g, 0.72 mmol) and N-ethylmorpholine (0.185 mL, 1.45 mmol). The reaction mixture was treated with EtOAc (20 mL), washed with 5% citric acid solution (20 mL) and sat. aqueous NaHCO 3 (20 mL).
  • Solid supported hydrazinecarboxylic acid ester (attached via ester group to resin) (0.864 g, 1.296 mmol) was suspended in dry dimethylformamide (DMF) (10 mL).
  • DMF dry dimethylformamide
  • HOBT 0.263 g, 1.944 mmol
  • 2-[(9H-fluoren-9-ylmethoxycarbonyl)-methyl-amino]-2-methyl- propionic acid FMOC-protected 2-methyl-2-methylaminopropionic acid; Fluka 29250) (0.683g, 1.944 mmol) and diisopropyl carbodiimide (0.864 g, 1.944 mmol) were introduced, and the suspension was shaken at ambient temperature for 20 h.
  • the resin sample was washed with DMF (3 x 20 mL), CH 3 OH (3 x 20 mL) and CH 2 Cl 2 (5 x 20 mL), and the resin was dried under vacuum for 2 h.
  • the resin was suspended in DMF (8 mL), piperidine (2 mL) was introduced and the suspension was shaken for 1 h. The resin was washed with DMF (6 x 20 mL), CH 3 OH (5 x 20 mL) and CH 2 Cl 2 (6 x 20 mL), and the resin was dried under vacuum for 18 h.
  • the resin-linked amino acid hydrazide was sulfonylated as follows: 2-chloro-4- trifluoromethyl-benzenesulfonyl chloride (0.542 g, 1.944 mmol) was dissolved in CH 2 Cl 2 (10 niL) and Et 3 N (0.27 mL, 1.944 mmol) was added.
  • the resin product was suspended in a mixture Of CH 2 Cl 2 (10 mL) and CF 3 CO 2 H (10 mL) and the suspension was shaken at ambient temperature for 1.5 h.
  • the resin was collected by filtration and washed with CH 2 Cl 2 (2 x 20 mL).
  • the combined filtrates were evaporated to dryness in vacuo, and the trifmoroacetic acid salt of 2-chloro-N-(l- hydrazinocarbonyl-l-methyl-ethyl)-N-methyl-4-trifluoromethylbenzenesulfonamide was purified by cation exchange chromatography utilising IST-MP-TsOH cartridges as follows. The residue was dissolved in CH 3 OH (3 mL) and acidified with acetic acid
  • Step 3 2-Chloro-N-(l -hydrazinocarbonyl- 1 -methylethyl)-N-methyl-4-trifluoromethylbenzene- sulfonamide (0.039 g, 0.105 mmol) and Et 3 N (0.021g, 0.21 mmol) in CH 2 Cl 2 (2 mL) was treated with 2,2-dimethylpropionyl chloride (pivaloyl chloride) (0.013 g, 0.105 mmol). Saturated NaHCO 3 solution (20 mL) was added, the organic layer was separated, washed with 5% aqueous citric acid solution (5mL) and dried (MgSO 4 ) before being evaporated to a residue.
  • Step 4 Polymer supported triphenylphosphine (0.4 g, 0.39 mmol) was suspended in CH 2 Cl 2 (5 mL) and iodine (0.099 g, 0.39 mmol) was added, and the reaction vessel was shaken vigorously for 1 h.
  • Et 3 N (0.11 mL, 0.78 mmol) and 2-chloro-N- ⁇ 2-[N'-(2,2-dimethyl- propionyl)hydrazino]-l,l-dimethyl-2-oxoethyl ⁇ -N-methyl-4-trifluoromethy-l-benzene- sulfonamide was introduced, and the reaction mixture was shaken for 18 h at ambient temperature.
  • reaction mixture was filtered, passed through a short column of florisil, evaporated and the residue was purified by preparative HPLC eluting with EtOAc/hexane (1:3), to provide N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-l-methyl- ethyl]-2-chloro-N-methyl-4-trifluoromethyl-benzenesulfonamide (0.012 g, 27% over 2 steps), retention time 4.16 min (HPLC System A); mass spectrum (ES+) m/z 412 (M + H).
  • Step 2 2-Chloro-N- ⁇ 1 -[N'-(2,2-dimethylpropionyl)hydrazinocarbonyl]- 1 -methylethyl ⁇ -N- methyl-4-trifluoromethylbenzenesulfonamide (0.65 g, 1.57 mmol) was dissolved in PhCH 3 (30 mL) and Lawesson's reagent (0.95 g, 2.35 mmol) was added. The suspension was heated at 100°C for 3 h. The toluene was removed in vacuo, and the residue was treated with EtOAc (40 mL), washed with water (40 mL). The organic layer was separated, dried (MgSO 4 ) and evaporated in vacuo.
  • Methyl-(3-phenyl-[ 1 ,2,4]oxadiazol-5-ylmethyl)amine (0.142 g, 0.075 mmol) was dissolved in dry CH 2 Cl 2 (1 mL) and Et 3 N (0.21 niL, 0.152 g, 1.5 mmol) was introduced, followed by a solution of (2-chloro-4-trifuoromethylbenzenesulfonyl chloride (0.23 g, 0.825 mmol) in dry CH 2 Cl 2 (1 mL).
  • Oxalyl chloride (2.9 mL, 4.21 g, 33.2 mmol) was added dropwise to a stirred solution of DMF (2.42 g, 33.2 mmol) in CH 3 CN (150 mL) at -5 0 C, and stirred at this temperature for a further 15 min.
  • Step 2 (S)-2-Chloro-N-(l-cyano-ethyl)-4-trifluoromethylbenzenesulfonamide (3.49 g, 11.2 mmol) in CH 3 OH (90 mL) was added to a solution of NH 2 OH.HC1 (3.88 g, 55.8 mmol) and Na 2 CO 3 (5.92 g, 55.8 mmol) in water (110 mL). The reaction mixture was heated at reflux for 18 h, cooled and concentrated in vacuo to an aqueous mixture, which was extracted with EtOAc (4 x 100 mL) and the combined extracts were dried (MgSO 4 ).
  • This compound was prepared by reaction of (S)-2-chloro-4-trifluoromethyl-N-[l-(5- trifluoromethyl-[l,2,4]oxadiazol-3-yl) ethyl]benzenesulfonamide (0.225 g, 0.531 mmol) under Mitsunobu conditions as described for Example 20, to provide (S)-2-chloro-N- isopropyl-4-trifluoromethyl-N-[l-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)- ethyl]benzenesulfonamide (0.22 g, 95%).
  • Step 2 2-[(2-Chloro-4-trifluoromethylbenzenesulfonyl)methylamino]-N-(2-liydroxybutyl)- acetamide (0.33 g, 0.83 mmol) was dissolved in CH 2 Cl 2 (5 mL) and the solution was cooled in an ice bath. Dess-Martin Periodinane Reagent (2.5 mL, 0.875 mmol) was added dropwise with stirring, and the reaction mixture was stirred at ambient temperature for 60 h. Further CH 2 Cl 2 (20 mL) was added and the mixture was stirred vigorously with a mixture of 10% aqueous NaHCO 3 solution with a sodium sulphite solution present.
  • Step l n-Butyllithium (1.6M) (6.95 mL) was added to a solution of acetone oxime (0.41 g, 5.56 mmol) in dry THF (30 mL) and this mixture was stirred at 0 0 C for 1 h.
  • Step 2 (S)-2-Chloro-N-(4-hydroxyimino- 1 -methyl-2-oxo-pentyl)-N-methyl-4-trifluoromethyl- benzenesulfonamide (0.36 g, 0.89 mmol) was dissolved in a mixture Of CH 2 Cl 2 (5 mL) and Et 3 N (0.162 mL) and methanesulfonyl chloride (0.83 ⁇ L) was introduced at 0 0 C, and the reaction mixture was stirred at ambient temperature for 4 h. Further Et 3 N (1.3 equiv.) and methanesulfonyl chloride (1.2 equiv.) were added and stirring was continued for 18 h.
  • This compound was prepared by a sulfonylation procedure analogous to that utilised for Example 52.
  • the title compound was obtained (0.166 g, 58%); retention time 4.13 min (HPLC System B); mass spectrum (ES+) m/z 385 (M - H).
  • the human neuroblastoma cell line IMR32 has been used by a number of groups to investigate calcium ion channels either by electrophysiological or fluorescent techniques in low throughput assays (Carbone, E., et al. (1990) Pfl ⁇ gers Arch 416:170- 179; Rafferty, M., et al. (2000) Patent WO 00/06559; Seko, T., et al., (2001) Bioorg Med Chem Lett 11:2067-2070).
  • undifferentiated IMR32 cells constitutively express L-type calcium channels, whilst differentiated IMR32 cells express both N- and L-type channels. Therefore, undifferentiated IMR32 cells can be used to assay the L-type calcium channel and differentiated cells assayed in the presence of 5 ⁇ M nitrendipine can be used to study the N-type channels.
  • the Molecular Devices Corp FLEXstationTM was utilised to develop a medium throughput assay with undifferentiated and differentiated IMR32 cells labelled with Fluo-4. Opening of voltage-activated calcium channels was stimulated by depolarisation of cells with KCl, which was added by the FLEXstation' s fluidics system. The resulting influx of calcium into the cells was recorded by an increase in fluorescence. The assays were validated with known ion channel blockers.
  • IMR32 cells were grown in EMEM supplemented with 10% foetal bovine serum, 2 mM lutamine, 1% NEAA, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin. To differentiate the IMR32 cells, 1 mM dibutyryl cAMP and 2.5 ⁇ M bromodeoxyuridine were added to the cell culture media and cells maintained for 7-9 days.
  • HBSS Free cell dissociation buffer
  • the cells were then resuspended in assay buffer (HBSS containing Ca 2+ Mg 2+ and supplemented with 20 mM HEPES, pH 7.4) to give a total volume of 40 ml. 2 ⁇ M Fluo-4 and 50 ⁇ M probenecid were added and then the cells were incubated at 25 0 C for 30 min.
  • the cell pellet was resuspended in 40 ml assay buffer supplemented with 50 ⁇ M probenecid and incubated at 25 0 C for a further 30 min.
  • the cells were centrifuged as before and again resuspended in assay buffer supplemented with probenecid.
  • 200,000 cells were aliquoted into each well of a 96-well plate containing 0.001-100 ⁇ M compound to be tested (for the N-type assay 5 ⁇ M nitrendipine was also added to each well), in triplicate.
  • the final volume of compound and cells in assay buffer was 200 ⁇ l.
  • the plate containing cells was centrifuged at 300 rpm for 1 min with no brake in a Heraeus Labofuge 400E (rotor 8177).
  • the plate was then assayed using the FLEXstation (Molecular Devices Corp).
  • the excitation and emission wavelengths were 494 and 525 nm, respectively.
  • the calcium response was stimulated by the addition of 50 ⁇ l 250 niM KCl (50 mM final concentration) by the FLEXstation fluidics system.
  • SOFTmax Pro (Molecular Devices Corp) was used to calculate the change in fluorescence caused by calcium influx for each well and hence the IC 50 for each compound. The results are shown in the Table below.

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Abstract

Compounds of formula: (I) are found to antagonise N-type calcium channels wherein: - A is a 5- to 10-membered heteroaryl or heterocyclyl moiety, said moiety being optionally fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6- ­membered heterocyclyl group; - B is a bond or a C1-C6 alkyl or C2-C6 alkenyl moiety; - either (a) R1 is hydrogen or C1-C6 alkyl and R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogen, hydroxy, thio, amino, -Het-L or -L-Het-L', wherein L and L' are the same or different and represent C1-C6 alkyl or C2-C6 alkenyl and Het is O, S or NR, wherein R is hydrogen or C1-C6 alkyl or (b) R1 and R2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl or a C3-C8 carbocyclyl moiety; R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or -L-Het-L', wherein L, L' and Het are as defined above; and - R4, R5 and R6 are the same or different and represent hydrogen, halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, mono(C1-C6 alkyl)amino or di(C1-C6 alkyl)amino.

Description

ACYCLIC SULPHONAMIDES
The present invention relates to specific benzenesulfonamide derivatives which act as inhibitors of N-type calcium channels. Mammalian ion channels are becoming increasingly well characterised, and this is especially true of calcium channels. Voltage-gated calcium channels are critical components for the functioning of the nervous system, and they signal a painful event. To date, 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non-neuronal cells (Perez- Reyes, E.; Schneider, T. DrugDev. Res., 1994, 33, 295-318). These channels are now recognised as valid targets for pain therapeutics and as neuroprotective agents (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).
It has now surprisingly been found that particular compounds of the general formula (I) set out below act as inhibitors of N-type calcium channels. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000003_0001
wherein:
A is a 5- to 10-membered heteroaryl or heterocyclyl moiety, said moiety being optionally fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6- membered heterocyclyl group;
B is a bond or a C1-C6 alkyl or C2-C6 alkenyl moiety; either (a) R1 is hydrogen or C1-C6 alkyl and R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogen, hydroxy, thio, amino, -Het-L or -L-Het-L', wherein L and L1 are the same or different and represent C1-C6 alkyl or C2-C6 alkenyl and Het is O, S or NR, wherein R is hydrogen or C1-C6 alkyl, or (b) R1 and R2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl or a C3-C8 carbocyclyl moiety;
R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or -L-Het-L', wherein L, L' and Het are as defined above; - R4, R5 and R6 are the same or different and represent hydrogen, halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, HiOnO(C1-C6 alkyl)amino or di(Ci-C6 alkyl)amino; the alkyl and alkenyl groups and moieties in B and R1 to R6 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; the heterocyclyl and carbocyclyl moieties formed by R1 and R2 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; and the group A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, -Het-L, -L-Het-L1, phenyl, 5- to 10-membered heteroaryl, C3-C6 carbocyclyl or 5- to 10-membered heterocyclyl, wherein L, L1 and Het are as defined above, the alkyl and alkenyl moieties in said substituents being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents and said phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents being unsubstituted or substituted by one, two or three futher unsubstituted substituents selected from halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, mono(C1-C6 alkyl)amino and di(Ci-C6 alkyl)amino groups.
As used herein, a C1-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C1-C4 alkyl group or moiety, for example methyl, ethyl, «-propyl, /-propyl, R-butyl, /-butyl and /-butyl. Preferred C1-C6 alkyl groups include methyl, ethyl, /-propyl and /-butyl. A divalent alkyl group or moiety (or alkylene group or moiety) can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms. Examples of divalent alkyl moieties are methylene and 1,1 -ethyl moieties. A preferred divalent alkyl moiety is a 1,1 -ethyl moiety.
As used herein, a C2-C6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C2-C4 alkenyl group or moiety, for example ethenyl, n-propenyl and n-butenyl. A preferred C2-C6 alkenyl group is ethenyl. Typically an alkenyl group has only one double bond. This double bond is typically located at the V-position of the alkenyl group. A divalent alkenyl group or moiety (or alkenylene group or moiety) can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms. As used herein a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, fluorine or bromine. As used herein, a said C1-C6 alkoxy group is typically a said C1-C6 alkyl group attached to an oxygen atom. A said C1-C6 alkylthio group is typically a said C1-C6 alkyl group attached to a thio group.
As used herein, a C1-C6 haloalkyl group is typically a said C1-C6 alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1 , 2 or 3 said halogen atoms. Examples of haloalkyl groups include perhaloalkyl groups such as -CX3 wherein X is a said halogen atom. Preferred haloalkyl groups are fluoroalkyl groups such as -CF3 and -CHF2. A particularly preferred haloalkyl group is -CF3.
As used herein, a C1-C6 haloalkoxy group is typically a said C1-C6 alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1 , 2 or 3 said halogen atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX3 wherein X is a said halogen atom. A particularly preferred haloalkoxy group is -OCF3.
As used herein, a C1-C6 haloalkylthio group is typically a said C1-C6 alkylthio group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX3 wherein X is a said halogen atom. A particularly preferred haloalkylthio group is -SCF3.
As used herein, a 5- to 10-membered heteroaryl group is typically a 5- to 10- membered monocyclic aromatic ring, such as a 5- or 6-membered ring, containing at least one heteroatom, for example 1 , 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl groups. Pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, isoxazloyl, thiazolyl, oxadiazolyl and thiadiazolyl groups are preferred.
When A represents a 5- to 10-membered heteroaryl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6-membered heterocyclyl group, it is preferably a 5- to 6-membered heteroaryl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6-membered heterocyclyl group. When A represents a 5- to 10-membered heteroaryl moiety fused to a cyclic group, it is preferably fused to a phenyl or pyridyl group. Examples of such fused groups include an oxazolyl moiety that is fused to a phenyl or pyridyl group to form a benzo[d] oxazolyl or oxazolopyridinyl group, respectively.
As used herein, a C3-C8 carbocyclyl group is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl group) or an unsaturated ring having only one double bond. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl and cyclohexyl groups are preferred.
As used herein, a heterocyclyl group is typically a monocyclic, non-aromatic, saturated or unsaturated C5-C10 carbocyclic ring, such as a C5-C6 carbocyclic ring, in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a moiety selected from N, O, S, SO and S(O)2. Preferably, said moiety is selected from N, O and S. Examples of suitable saturated heterocyclyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, thiomorpholinyl, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl and oxazolidinyl. Examples of suitable unsaturated heterocyclic groups include dihydro-oxazolyl, dihydroisoxazyl, dihydrothiazolyl, dihydroisothiazolyl, dihydro-oxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl and dihydropyridazinyl. Preferred unsaturated heterocyclic groups are dihydro-oxazolyl, dihydroisoxazyl, dihydrothiazolyl, dihydroisothiazolyl, dihydroimidazolyl and dihydropyrazolyl. Dihydro-oxazolyl is particularly preferred.
When A represents a 5- to 10-membered heterocyclyl moiety fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6-membered heterocyclyl group, it is preferably a 5- to 6-membered heterocyclyl moiety, and more preferably an unsaturated 5- to 6-membered heterocyclyl moiety, fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6-membered heterocyclyl group. When A represents a 5- to 10-membered heterocyclyl moiety fused to a cyclic group, it is preferably fused to a phenyl or pyridyl group. For the avoidance of doubt, when a compound of formula (I) contains more than one L, L1 or Het moiety, each of the respective moieties is the same or different.
Typically, R in the or each Het moiety is hydrogen or C1-C4 alkyl. Preferably, R in the or each Het moiety is hydrogen or methyl.
Typically, L in the or each R1, R3 or A moiety is C1-C4 alkyl. Preferably, L in the or each R1, R3 or A moiety is C1-C2 alkyl.
Typically, L1 in the or each R1, R3 or A moiety is C1-C4 alkyl. Preferably, L1 in the or each R1, R3 or A moiety is C1-C2 alkyl.
Typically, Het is O, S or NR, wherein R is as defined above. Preferably, Het is O. Typically, the alkyl and alkenyl groups and moieties in B and R1 to R6 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents.
Preferably, the alkyl and alkenyl groups and moieties in B and R1 to R3 are unsubstituted or substituted by a single hydroxy substituent. Preferably, the alkyl and alkenyl groups and moieties in R4 to R6 are unsubstituted or substituted by one, two or three fluorine or chlorine substituents.
Typically, the heterocyclyl and carbocyclyl moieties formed by R1 and R2 are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents. Preferably, the heterocyclyl and carbocyclyl moieties formed by R1 and R2 are unsubstituted. Typically, when the group A is substituted, only one of the substituents is a group selected from phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6- membered heterocyclyl.
Typically, the group A is unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C1-C6 alkyl, C2-C6 alkenyl, -L-Het-L', phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6- membered heterocyclyl, wherein L, L1 and Het are as defined above.
Preferably, the group A is unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C1-C6 alkyl, -(C1-C2 alkyl)-O-(Ci-C2 alkyl), cyclopropyl or phenyl.
Typically, the alkyl and alkenyl moieties in the substituents on A are unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine and hydroxy substituents
Preferably, the alkyl and alkenyl moieties in the substituents on A are unsubstituted or substituted by a single hydroxy substituent or by one, two or three fluorine or chlorine substituents.
Typically, the phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents on A are unsubstituted or substituted by one, two or three futher unsubstituted substituents selected from fluorine, chlorine, bromine, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy groups.
Preferably, the phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents on A are unsubstituted.
Typically, A is a 5- to 6-membered heteroaryl or heterocyclyl moiety, in particular a 5- to 6-membered heteroaryl or unsaturated heterocyclyl moiety, said moiety being optionally fused to a phenyl or 5- to 6-membered heteroaryl group. Preferably, A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl or dihydro-oxazolyl moiety, said moiety being optionally fused to a phenyl or pyridyl group. More preferably, A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, dihydro-oxazolyl, benzo[d] oxazolyl or oxazolopyridinyl moiety.
Typically, B is a bond or a C1-C4 alkyl moiety. Preferably, B is a bond or a C1- C2 alkyl moiety, for example a 1,1 -ethyl moiety. Typically, R1 is hydrogen or C1-C4 alkyl. Preferably, R1 is hydrogen or methyl. Typically, R2 is hydrogen or C1-C6 alkyl. Preferably, R2 is hydrogen or C1-C4 alkyl. More preferably, R2 is hydrogen or C1-C4 alkyl group which is unsubstituted or substituted with a single hydroxy group. When R1 and R2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl moiety or C3-Cg carbocyclyl moiety, they typically form a saturated 5- to 6-membered heterocyclyl moiety or a C3-C6 carbocyclyl moiety. Preferably, they form a C3-C6 carbocyclyl moiety such as a cyclopropyl or cyclohexyl moiety. Typically, R3 is hydrogen, C1-C6 alkyl or -L-Het-L1, wherein L, L' and Het are as defined above. Preferably, R3 is hydrogen, C1-C4 alkyl or -(C1-C2 alkyl)-O-(Ci-C2 alkyl). More preferably, R3 is hydrogen, an unsubstituted -(C1-C2 alkyl)-O-(C1-C2 alkyl) group or a C1-C4 alkyl group which is unsubstituted or carries a single hydroxy substituent. Typically, R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine, hydroxy, amino, thio, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, mono(C1-C4 alkyl)amino or CIi(C1-C4 alkyl)amino. Preferably, R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or C1-C2 alkyl. Most preferably, R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or an unsubstituted C1-C2 alkyl or C1-C2 haloalkyl group. Preferred compounds of formula (I) are those wherein: A is a 5- to 6-membered heteroaryl or unsaturated heterocyclyl moiety, said moiety being optionally fused to a phenyl or 5- to 6-membered heteroaryl group;
B is a bond or a C1-C4 alkyl moiety; - either (a) R1 is hydrogen or C1-C4 alkyl and R2 is hydrogen or C1-C6 alkyl or (b)
R1 and R2 form, together with the carbon to which they are attached, a saturated 5- to 6- membered heterocyclyl moiety or a C3-C6 carbocyclyl moiety;
R3 is hydrogen, C1-C6 alkyl or -L-Het-L1, wherein L and L' are the same or different and represent C1-C4 alkyl and Het is O, S or NR, wherein R is hydrogen or C1- C4 alkyl; R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine, hydroxy, amino, thio, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, mono(Ci-C4 alkyl)amino or di(C1-C4 alkyl)amino; the alkyl groups and moieties in B and R1 to R6 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents; the heterocyclyl and carbocyclyl moieties formed by R1 and R2 being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine or hydroxy substituents; and the group A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C1-C6 alkyl, C2-C6 alkenyl, -L-Het-L', phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6-membered heterocyclyl, wherein L, L' and Het are as defined above, the alkyl and alkenyl moieties in the substituents on A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from fluorine, chlorine, bromine and hydroxy substituents and the phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents on A being unsubstituted or substituted by one, two or three futher unsubstituted substituents selected from fluorine, chlorine, bromine, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy groups. More preferred compounds of formula (I) are those wherein:
A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, dihydro-oxazolyl, benzo [d\ oxazolyl or oxazolopyridinyl moiety;
B is a bond or a C1-C2 alkyl moiety; - either (a) R1 is hydrogen or methyl and R2 is hydrogen or C1-C4 alkyl or (b) R1 and R2 form, together with the carbon to which they are attached, a C3-C6 carbocyclyl moiety;
R3 is hydrogen, C1-C4 alkyl or -(CJ-C2 alkyl)-O-(C1-C2 alkyl);
R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or C1-C2 alkyl;
1 "X the alkyl groups and moieties in B and R to R being unsubstituted or substituted by a single hydroxy substituent; the alkyl groups and moieties in R4 to R6 being unsubstituted or substituted by one, two or three fluorine or chlorine substituents; the carbocyclyl moieties formed by R1 and R2 being unsubstituted; and the group A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C1-C6 alkyl, -(C1-C2 alkyl)-O-(Ci- C2 alkyl), cyclopropyl or phenyl, the alkyl moieties in the substituents on A being unsubstituted or substituted by a single hydroxy substituent or by one, two or three fluorine or chlorine substituents and the cyclopropyl and phenyl substituents on A being unsubstituted. The present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof for use in a method of treating the human or animal body.
The present invention further provides the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels.
Examples of particularly preferred compounds of formula (I) are: 1. N-(5-tert-Butyl-[l ,3,4]oxadiazol-2-ylmethyl)-2-chloro-N-methyl-4-trifluoro- methylbenzenesulfonarnide; 2. 2-Chloro-N-methyl-N-(5-methyl-[l ,3,4]oxadiazol-2-ylmethyl)-4-trifluoromethyl- benzenesulfonamide;
3. N-(5-tert-Butyl-[l,3,4]oxadiazol-2-ylmemyl)-N-methyl-4- trifluoromethylbenzenesulfonamide;
4. N-Methyl-N-(5-methyl-[l ,3,4]oxadiazol-2-ylmethyl)-4- trifluoromethylbenzenesulfonamide;
5. (S)-2-Chloro-N-methyl-N-[l-(5-methyl-[l,3,4]oxadiazol-2-yl)-ethyl]-4- trifluoromethylbenzenesulfonamide;
6. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-methyl-4- trifluoromethylbenzenesulfonamide; 7. (R)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)ethyl]-2-chloro-N-methyl-4- trifluoromethylbenzenesulfonamide; 8. (^^-Chloro-N-methyl-N-tl-CS-methyl-Cl^^Joxadiazol-l-y^-ethyl]-^ trifluoromethylbenzenesulfonamide;
9. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-2-hydroxy-ethyl]-2-chloro-N-methyl-4- trifluoromethylbenzenesulfonamide; 10. (S)-2-Cliloro-N-[l-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide; l l. (S)-2-Chloro-N-[l-(5-cyclopropyl-[l,3,43oxadiazol-2-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
12. (S)-4-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)ethyl]-N- methylbenzenesulfonamide;
13. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2,4-dichloro-N- methylbenzenesulfonamide;
14. (S)-2,4-Dibromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)ethyl]-N- methylbenzenesulfonamide; 15. (S)-2-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-N-methyl-4- trifluoromethylbenzenesulfonamide;
16. (S)-4-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-fluoro-N-methyl- benzenesulfonamide;
17. (S)-4-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-methyl- benzenesulfonamide;
18. (S)-N-[I -(5-tert-Butyl-[l ,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-(2-methoxyethyl)-4- trifluoromethylbenzenesulfonamide;
19. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-ethyl-4- trifluoromethylbenzenesulfonamide; 20. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-isopropyl-4- trifluoromethylbenzenesulfonamide;
21. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-(2-hydroxyethyl)-4- trifluoromethylbenzenesulfonamide;
22. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-2-methyl-propyl]-2-chloro-N-methyl- 4-trifluoromethyl-benzenesulfonamide;
23. N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-cyclopropyl]-2-chloro-N-methyl-4- trifluoromethyl-benzenesulfonamide; 24. (S)-2-Chloro-N-methyl-4-trifluoromethyl-N-[ 1 -(5-trifluoromethyl-[ 1 ,3 ,4]oxadiazol- 2-yl)-ethyl] -benzenesulfonamide;
25. (S)-2-Chloro-N-methyl-N-[l-(5-ρhenyl-[l,3,4]oxadiazol-2-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide; 26. N-[2-(5-tert-Butyl-[l ,3,4]oxadiazol-2-yl)-ρropyl]-2-cmoro-N-methyl-4- trifluoromethyl-benzenesulfonamide;
27. (S)-4-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-2-methyl-ρropyl]-N-methyl- benzenesulfonamide;
28. 4-Bromo-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-ethyl]-N-(2-methoxy-ethyl)- benzenesulfonamide;
29. 2-Bromo-N-methyl-4-trifluoromethyl-N-[l-(5-trifluoromethyl-[l,3,4]oxadiazol-2- yl)-cyclopropyl]-benzenesulfonamide;
30. (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-2-methyl-propyl]-2-chloro-N- isopropyl-4-trifluoromethyl-benzenesulfonamide; 31. 4-Bromo-N- [ 1 -(5 -tert-butyl- [1,3,4] oxadiazol-2-yl)-cyclopropyl] -N-isopropyl- benzenesulfonamide;
32. 4-Bromo-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-cyclopropyl]-N-isopropyl- benzenesulfonamide;
33. (S)-2-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-N-isopropyl-4- trifluoromethyl-benzenesulfonamide;
34. 2-Bromo-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-cyclopropyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
35. (S)-2-Bromo-N-isopropyl-4-trifluoromethyl-N- [ 1 -(5 -trifluoromethyl- [1,3,4] oxadiazol-2-yl)-ethyl] -benzenesulfonamide ; 36. (S)-4-Bromo-N-[l-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-ethyl]-N-(2-methoxy-ethyl)- benzenesulfonamide;
37. (S)-2-Bromo-N-isopropyl-N-[l-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide;
38. 2-Bromo-N-[l-(5-isopropyl-[l,3,4]oxadiazol-2-yl)-cyclopropyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
39. (S)-2-Bromo-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)ethyl]-N-isopropyl-4- trifluoromethylbenzenesulfonamide; 40. (S)-4-Bromo-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-2-methylpropyl]-N- methylbenzenesulfonamide;
41. (S)-2-Chloro-N-[l-(5-cyclopropyl-[l,3,4]oxadiazol-2-yl)-2-methyl-propyl]-N- isopropyl-4-trifluoromethylbenzenesulfonamide; 42. (S)-4-Bromo~N-methyl-N-[2-methyl-l -(5-trifluoromethyl-[l ,3,4]oxadiazol-2-yl)~ propyl] -benzenesulfonamide;
43. N-[I -(5-tert-Butyl-[ 1 ,3,4]oxadiazol-2-yl)-l -methylethyl]-2-chloro-N-methyl-4- trifluoromethyl-benzenesulfonamide;
44. 2-Chloro-N-methyl-N-[l-methyl-l-(5-methyl-[l,3,4]thiadiazol-2-yl)ethyl]-4- trifluoromethylbenzenesulfonamide;
45. N-(5-tert-Butyl-[l,3,4]thiadiazol-2-ylmethyl)-N-metliyl-4-trifluoromethyl- benzenesulfonamide;
46. (S)-2-Chloro-N-methyl-N-[l-(5-methyl-[l,3,4]thiadiazol-2-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide; 47. (S)-2-Chloro-N-[l-(5-hydroxymethyl-[l,3,4]thiadiazol-2-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
48. (S)-N-[l-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-ethyl]-2-chloro-N-methyl-4- trifluoromethyl-benzenesulfonamide;
49. (S)-2-Chloro-N-isopropyl-N-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide;
50. (S)-2-Chloro-N-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
51. (S)-N-[l-(5-tert-Butyl-[l,2,4]oxadiazol-3-yl)-eihyl]-2-chloro-N-methyl-4- trifluoromethyl-benzenesulfonamide; 52. 2-Chloro-N-methyl-N-(3-phenyl-[l,2,4]oxadiazol-5-ylmethyl)-4-trifluorometliyl- benzenesulfonamide;
53. (S)-2-Chloro-N-[ 1 -(5-methoxymethyl-[ 1 ,2,4]oxadiazol-3-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
54. (S)-2-Chloro-N-[l-(5-hydroxymethyl-[l,2,4]oxadiazol-3-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
55. (S)-N-[l-(5-tert-Butyl-[l,2,4]oxadiazol-3-yl)-ethyl]-2-chloro-N-isoρropyl-4- trifluoromethyl-benzenesulfonamide; 56. (S)-2-Chloro-N-[l-(3-cyclopropyl-[l,2,4]oxadiazol-5-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide;
57. 2-Bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-cyclopropyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide; 58. (S)-2-Chloro-4-trifluoromethyl-N-[l-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)- ethyl] -benzenesulfonamide;
59. (S)-2-Chloro-N-isopropyl-4-trifluoromethyl-N-[l-(5-trifluoromethyl- [l,2,4]oxadiazol-3-yl)-ethyl]-benzenesulfonamide;
60. (S)-2-Chloro-N-methyl-4-trifluoromethyl-N-[ 1 -(5-trifluoromethyl-[ 1 ,2,4]oxadiazol- 3-yl)-ethyl]-benzenesulfonamide;
61. 2-Chloro-N-(5-ethyl-oxazol-2-ylmethyl)-N-methyl-4-trifluoromethyl- benzenesulfonamide;
62. N-(5-Ethyl-oxazol-2-ylmethyl)-N-niethyl-4-trifluoromethyl-benzenesulfonamide;
63. (S)-2-Chloro-N-methyl-N-(l-oxazolo[4,5-b]pyridin-2-yl-ethyl)-4-trifluorometliyl- benzenesulfonamide;
64. (S)-2-Chloro-N-[ 1 -(5-ethyl-oxazol-2-yl)-ethyl]-N-methyl-4-trifluorometliyl- benzenesulfonamide;
65. (S)-N-(l-Benzooxazol-2-yl-ethyl)-2-chloro-N-methyl-4-trifluoromethyl- benzenesulfonamide; 66. (S)-N-[l-(5-tert-Butyl-oxazol-2-yl)-ethyl]-2-chloro-N-methyl-4-trifluoromethyl- benzenesulfonamide;
67. (S)-2-Chloro-N-methyl-N-[ 1 -(5-methyl-4,5-dihydro-oxazol-2-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide;
68. (S)-2-Chloro-N-[ 1 -(4,5-dimethyl-oxazol-2-yl)-ethyl]-N-methyl-4-trifiuoromethyl- benzenesulfonamide;
69. N-[l-(5-tert-Butyloxazol-2-yl)cyclopropyl]-2-chloro-N-(2-methoxyethyl)-4- trifluoromethylbenzenesulfonamide;
70. (S)-2-Bromo-N-isopropyl-N-[l-(5-methyl-oxazol-2-yl)-ethyl]-4-trifluoromethyl- benzenesulfonamide; 71. (S)-2-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-ethyl]-N-isoproρyl-4-trifluoromethyl- benzenesulfonamide; 72. (S)-2-Chloro-N-methyl-N-[l-(5-methyl-oxazol-2-yl)-ethyl]-4-trifluoromethyl- benzenesulfonamide;
73. (S)-4-Bromo-N-(2-hydroxy-ethyl)-N- [ 1 -(5-methyl-oxazol-2-yl)-ethyl] - benzenesulfonamide; 74. (S)-2-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-2-methyl-propyl]-N-(2-hydroxy- ethyl)-4-trifluoroniethyl-benzenesulfonamide;
75. (S)-4-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-ethyl]-N-(2-hydroxy-ethyl)- benzenesulfonamide;
76. (S)-2-Bromo-N-(2-hydroxy-ethyl)-N-[2-methyl-l-(5-meth.yl-oxazol-2-yl)-proρyl]-4- trifluoromethyl-benzenesulfonamide;
77. 4-Bromo-N-isopropyl-N-[ 1 -(5-methyl-oxazol-2-yl)-cyclopropyl]- benzenesulfonamide;
78. 4-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-cyclopropyl]-N-isopropyl- benzenesulfonamide; 79. (S)-4-Bromo-N-methyl-N-[2-methyl-l -(5-methyl-oxazol-2-yl)-propyl]- benzenesulfonamide;
80. (S)-4-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-2-methyl-propyl]-N-methyl- benzenesulfonamide;
81. 2-Bromo-N-niethyl-N-[ 1 -(5-methyl-oxazol-2-yl)-cyclopropyl]-4-trifluoromethyl- benzenesulfonamide;
82. 2-Bromo-N-[l-(5-tert-butyl-oxazol-2-yl)-cyclopropyl]-N-methyl-4-trifluoromethyl- benzenesulfonamide;
83. 2-Chloro-N-(2-methoxy-ethyl)-N-[l-(5-methyl-oxazol-2-yl)-cyclopropyl]-4- trifluoromethylbenzenesulfonamide; 84. N-[I -(5-tert-Butyl-oxazol-2-yl)-cycloρroρyl]-2-chloro-N-(2-hydroxy-ethyl)-4- trifluoromethyl-benzenesulfonamide;
85. 2-Chloro-N-(2-hydroxyethyl)-N-[l-(5-methyloxazol-2-yl)cyclopropyl]-4- trifluoromethylbenzenesulfonamide;
86. (S)-2-Chloro-N-methyl-N-[l-(3-methyl-isoxazol-5-yl)-ethyl]-4-trifluoromethyl- benzenesulfonamide;
87. (S)-N-[l-(3-tert-Butyl-isoxazol-5-yl)-ethyl]-2-chloro-N-methyl-4-trifiuoromethyl- benzenesulfonamide; 88. 2-Chloro-N-methyl-N-(2-methyl-thiazol-4-ylmethyl)-4-trifluoronieth.yl- benzenesulfonamide;
89. 2-Chloro-N-[l-(2-methyl-tMazol-4-yl)-ethyl]-4-trifluoromethyl- benzenesulfonamide; 90. 2-Chloro-N-methyl-N-(2-phenyl-thiazol-4-ylmethyl)-4-trifluoromethyl- benzenesulfonamide;
91. 2-Chloro-N-methyl-N-[l-(2-methyl-thiazol-4-yl)-etliyl]-4-trifluorometliyl- benzenesulfonamide;
92. 2-Chloro-N-methyl-N-(l-pyridin-2-ylethyl)-4-trifluorometliyl-benzenesulfonamide; 93. 2-Chloro-N-methyl-4-trifluoro-methyl-N-[ 1 -(1 ,3,5-trimethyl- lH-pyrazol-4-yl)- ethyljbenzene-sulfonamide;
94. 2-Chloro-N-methyl-N-( 1 -pyridin-4-ylethyl)-4-trifluoromethyl-benzenesulfonamide;
95. 2-Chloro-N-methyl-N-(l -pyridin-3-ylethyl)-4-trifluoromethyl-benzenesulfonamide;
96. (S)-N-[l-(4-tert-Butyl-pyrimidin-2-yl)-ethyl]-2-chloro-4-trifluoromethyl- benzenesulfonamide;
97. (S)-N-[l-(4-tert-Butyl-pyrimidin-2-yl)-ethyl]-2-chloro-N-isopropyl-4- trifluoromethyl-benzenesulfonamide;
98. (S)-N-[l-(4-tert-Butyl-pyrimidm-2-yl)-etliyl]-2-chloro-N-methyl-4-trifiuoromethyl- benzenesulfonamide; and 99. 2-Chloro-N-[l-(5-methyl-[l,3,4]thiadiazol-2-yl)-cyclohexyl]-4-trifluoromethyl- benzenesulfonamide, and pharmaceutically acceptable salts thereof.
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. The compounds of the invention contain one or more chiral centre. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereoisomers. Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.
Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
Compounds of formula (I) may be prepared by a sulfonylation reaction, for example the reaction of a secondary amine (II) which may or may not contain a defined stereochemical centre and a phenyl sulfonyl chloride (III), wherein R1 to R6 are as defined above (Scheme A). The reaction of the amine and the sulfonyl halide of formula (III), wherein X is a halogen such as chlorine, bromine of fluorine, may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, JV- ethylmorpholine or diisopropylethylamine. Both the amine (II) and phenyl sulfonyl chloride (III) are either known compounds or could be prepared by the skilled person utilising known methods. Scheme A
Figure imgf000019_0001
(II) (III) (I)
Alternative ways of preparing some of the compounds of the present invention are detailed in Schemes B to F.
Compounds of formula (I) may be prepared by the reaction of a sulfonylated amine of formula (FV) with an alkylating agent of formula R3 -Y, wherein R1 to R6 are as defined above and Y is a leaving group such as halogen, methanesulfonate orp- toluenesulfonate (Scheme B). The reaction of the amine and the alkylating agent may be performed at room temperature in a suitable solvent, such as toluene or dichloromethane, in the presence of a base, for example triethylamine, N- ethylmorpholine or diisopropylethylamine. Both the secondary amine (IV) and R3 -Y are either known compounds or could be prepared by the skilled person utilising known methods.
Scheme B
Figure imgf000019_0002
Compounds of formula (I) may be prepared by the reaction of a sulfonylated amine of formula (FV) with an alcohol of formula R3-OH (Scheme C), wherein R1 to R6 are as defined above. The reaction of the amine and the alcohol may be performed for example under Mitsunobu conditions (Jenkins, I. D. Mitsunobu, O, In Encyclopedia of Reagents for Org. Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 8, pp 5379-5390) at room temperature in a suitable solvent, such as tetrahydrofuran (THF), toluene or dichloromethane, in the presence of an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and triphenylphosphine or a closely related equivalent such as diphenyl phosphine on a solid support. Both the secondary amine (IV) and R -OH are either known compounds or could be prepared by the skilled person utilising known methods.
Scheme C
Figure imgf000020_0001
Compounds of formula (I) may be prepared by the reaction of a N-alkylated-S-aryl- thiohydroxylamine of formula (V) with a suitable oxidizing agent such as m- chloroperbenzoic acid (MCPBA), oxone, or a suitable peroxide-based reagent. The reaction takes place in a suitable solvent, such as the ether-based solvents THF or dioxan. This reaction can take place across a range of temperatures from e.g. -100C to 6O0C, and may also be effected under phase transfer conditions.
Scheme D:
Figure imgf000020_0002
(V) (I) Compounds of formula (I), wherein A is a heterocycle as defined above, may be prepared by reaction of an ester, mixed anhydride or acid of general formula (VII) with a nucleophilic hydrazine derivative to provide a hydrazide compound of general formula (VIII). This reaction can proceed under a variety of conditions, including dehydrative coupling, ester displacement or other forms of nucleophilic displacement of an acid derivative, such as reaction with an acid chloride. Once the hydrazide (VIII) has been isolated, it can be converted into a range of heterocycles, to provide compounds of Formula (I), wherein A represents, for example, oxadiazole and thiadiazole derivatives. In the case of oxadiazoles, typical reaction conditions would include dehydrative reactions or conditions such as iodine in the presence OfPh3P, in a solvent such as dichloromethane, to form 1,3,4-oxadiazoles. hi the case of 1,3,4-thiadiazoles, the ring closure reaction would typically take place by utilisation of Lawesson's reagent or P2S5, in a suitable solvent such as toluene or dioxan.
Scheme E
Figure imgf000021_0001
0) (VUT)
Compounds of formula (I), wherein A is a heterocycle as defined above, may be prepared by sulfonylation of an amine of general formula (IX), which is linked via a hydrazide to a solid phase resin. The sulfonylation reaction proceeds as outlined in Scheme A, and is followed by a step which cleaves the hydrazide form the resin, with a strong acid such as CF3CO2H. The resultant product of general formula (X) is acylated and converted for example into oxadiazole and thiadiazole derivatives of formula (I), via an intermediate of formula (VIII), as described in Scheme E above.
Scheme F
Figure imgf000022_0001
Compounds of formula (I), wherein A is a heterocycle such as a [l,2,4]oxadiazole, can be prepared in two steps by reaction of an acid of formula (VII), R7 = H with a substituted N-hydroxyacetamidine to provide a compound of formula (XI). This reaction can proceed under a variety of conditions, including dehydrative coupling.
Alternative conditions would include reaction of an ester, mixed anhydride or acid of general formula (VII) with the nucleophilic N-hydroxyacetamidine to provide the intermediate (XI). This intermediate is converted into an [l,2,4]oxadiazole-containing compound of formula (I), under standard conditions such as a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Scheme G
Figure imgf000023_0001
Compounds of formula (I), wherein A is a heterocycle such as an oxazole, can be prepared in two steps by reaction of an acid of formula (VII), R7 = H with an ethanolamine derivative of general formula (XII) to provide a compound of formula (XIII). This reaction proceeds under a variety of conditions, including dehydrative coupling. Alternative conditions include reaction of an ester, mixed anhydride or acid of general formula (VII) with the nucleophilic ethanolamine to provide the intermediate (XIII). This intermediate is converted into an oxazole derivative of formula (I), initially by oxidation of the hydroxyl group to a ketone under standard conditions, for example utilising Dess-Martin Periodinane or pyridinium chlorochromate, followed by cyclisation to an oxazole under dehydrative conditions, for example using Burgess Reagent. This procedure can also be adapted for the synthesis of thiazole derivatives, for example by employing methods, familiar to one skilled in the art as outlined, for example, in Joule, J.A. and Mills, K.A., Heterocyclic Chemistry (Fourth edition), 2000, Blackwell Science Ltd, Oxford, UK, ISBN 0-632-05453-0. Scheme H
Figure imgf000024_0001
Compounds of formula (I), wherein A is a heterocycle such as an oxazole, can be prepared, in one step by reaction of a ketone of formula (XIV). This reaction proceeds under conditions where nitrogen is introduced, for example by reaction with ammonium acetate. This procedure can also be adapted for the synthesis of thiazole derivatives, by incorporating sulphur in the form of a thioester in an analogue of the sulfonamide
(XIV).
Scheme I
Figure imgf000024_0002
A variety of other heterocycles may be introduced as group A in compounds of formula (I), by commencing with suitable starting materials such as acids of formula (VII), R7 = H, by employing methods, familiar to one skilled in the art as outlined, for example, in Joule, J. A. and Mills, K. A., Heterocyclic Chemistry (Fourth edition), 2000, Blackwell Science Ltd, Oxford, UK, ISBN 0-632-05453-0.
The thus obtained compounds of formula (I) may be salified by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techniques, for example elution on a chiral chromatography column.
The compounds of the invention are found to be inhibitors of N-type calcium channels. Further, many preferred compounds of the invention exhibit selectivity over L-type calcium channels. The compounds of the invention are therefore therapeutically useful.
The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.
One route of administration is inhalation. The major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
Pharmaceutical compositions of the invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. Typically, said propellant is a fluorocarbon.
Further preferred inhalation devices include nebulizers. Nebulizers are devices capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.
Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant. Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended.
Another route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter- patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.
A further route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof. A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
The compounds of the present invention are therapeutically useful in the treatment or prevention of conditions mediated by N-type calcium channels.
Accordingly, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
These compounds are useful as calcium channel antagonists thereby inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder.
N-type calcium channels are known to be closely involved in the mediation of pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. N-type calcium channels have been identified as being particularly important in the transmission of pain signals in the spinal cord (Chaplan S.R., Pogrel J5W., Yaksh TX. J. Pharm. Exp. Ther., 1994, 269, 1117-1123; Diaz, A., Dickenson, A.H. Pain, 1997, 69, 93-100). Indeed, a series of recent clinical studies has provided confirmation of the important role of N-type calcium channels in pain transmission (Mathur, V.S.; McGuire, D.; Bowersox, S.S.; Miljanich, G.P.; Luther, R.R. Pharmaceutical News, 1998, 5, 25-29). The compounds of the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds of the invention are effective in alleviating both chronic and acute pain.
Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system. Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.
Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above. Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system.
Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb" pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.
Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain. One non-limiting definition of neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease. The compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain. Since blockers of N-type calcium channels inhibit the release of excitatory amino acids, they can be used inter alia to inhibit damage to neuronal cells during anoxia, and function as neuroprotective agents, useful in the treatment of cerebral ischaemia or central nervous system injuries (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250). The compounds can also be utilised for the treatment of eye diseases (Chu, T-C; Potter, D.E. Research Communications in Pharmacology and Toxicology, 2001, 6, 263-275).
Examples of cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.
Examples of central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.
Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, diabetic macular oedema, retinal artery occlusion and retinitis. By virtue of their inhibition of neurotransmitter release the compounds of the invention can be used in the treatment of seizure disorders. Examples of seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic). The compounds of the invention can also be utilised in the treatment of anxiety- related disorders and mood disorders, Bipolar disorder and post traumatic stress disorders.
Furthermore the compounds of the invention can be utilised in the treatment of tinnitus, itch such as pruritoceptive, neuropathic, neurogenic and psychogenic itch, as well as urinary tract disorders such as urinary incontinence, and irritable bowel syndrome.
The compounds of the invention may also have application in disorders which are generally associated with blocking of L-type calcium channels, such as cardiovascular, antiasthmatic and antibronchoconstriction disorders for example in the prevention and treatment of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, premature labour, gastrointestinal motility disorders and cardiovascular disorders wherein the cardiovascular disorder is selected from the group consisting of hypertension, myocardial ischemia, angina, congestive heart failure, myocardial infarction and stroke. The compounds of the invention can be utilised in the treatment of hypersensitivity disorders such as urinary tract disorders. Examples of urinary tract disorders include, in particular, bladder dysfunctions such as overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia; bladder hyper-reflexia; urinary tract inflammation specifically bladder inflammation e.g interstitial cystitis; and urinary tract infection. The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions. The compounds of the invention can also be used in the treatment of lower urinary tract symptoms (LUTS). LUTS comprises three groups of symptoms, which are irritative, which comprises urgency, frequency and nocturia and which can be associated with OAB and benign prostatic hyperplasia (BHP), obstructive and post micturition symptoms.
A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to
2 g-
The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting N-type calcium channels. There are many assays available to determine the activity of given compounds as N-type calcium channel antagonists, and a negative result in any one particular assay is therefore not determinative.
EXAMPLES
Example 1 : N-(5-tert-Butyl-[l,3,4] oxadiazol-2-ylmethyl)-2-chloro-N-methyl-4- trifluoro-methyl-benzenesulfonamide
Step l
N-Methylglycine, ethyl ester hydrochloride (Sarcosine hydrochloride) (0.63 g, 4.09 mmol) and Et3N (1.15 mL, 8.18 mmol) were stirred vigorously in CH2Cl2 (20 mL) and (2-chloro-4-trifluoromethylbenzenesulfonyl chloride (1.14 g, 4.09 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 18 h, washed with 10% hydrochloric acid (5 mL), saturated aqueous NaHCO3 solution (10 mL) dried (MgSO4) and evaporated in vacuo to afford [(2-chloro-4-trifiuoromethyl- benzenesulfonyl)methylamino]acetic acid ethyl ester (1.40 g, 95%) as a pale yellow oil. HPLC (System B) retention time 4.20 min. (Solvent:MeCN/H2O/0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min), mass spectrum (ES+) m/z 360 (M+H). This ethyl ester (1.33 g, 3.69 mmol) was dissolved in a mixture of THF (20 mL) and CH3OH (10 mL), and a 2M solution of NaOH (3.69 mL, 7.38 mmol), and the reaction mixture was stirred at ambient temperature for 18 h before being concentrated in vacuo. EtOAc (20 mL) and 10% aqueous HCl (10 mL) was added to the solution and the organic layer was separated, washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to afford [(2-chloro-4-trifluoromethylbenzenesulfonyl)methylamino]acetic acid as a colourless solid. HPLC (System B) retention time 2.86 min. (Solvent:MeCN/H2O/0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min.); mass spectrum (ES+) m/z 330 (M + H).
Step 2
[(2-Chloro-4-trifluoromethylbenzenesulfonyl)methylamino]acetic acid (0.30 g, 0.91 mol) and 2,2-dimethyl-propionic acid hydrazide (pivalic acid hydrazide) (0.21 g, 1.81 mmol) were dissolved in tetrahydrofuran (THF) (20 mL) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.226 g, 1.18 mmol) was introduced, followed by 1-hydroxybenzotriazole (HOBT) (0.159 g, 1.18 mmol) and diisopropylethylamine (0.234 g, 1.81 mmol). The reaction mixture was stirred at 400C for 18 h, evaporated to a residue and EtOAc (20 mL) and sat. aqueous NaHCO3 (10 mL) was added. The organic layer was separated, washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to provide the 2-chloro-N- {2-[N'-(2,2- dimethylpropionyl)hydrazino]-2-oxoethyl}-N-methyl-4-trifluoromethylbenzene- sulfonamide (0.28 g, 73%). HPLC (System A) retention time 3.66 min (Solvent: MeCN/H2O/0.05% HCO2H, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm Ld., Cl 8 reverse phase. Flow rate: 1.5 mL/min.) Mass spectrum (ES+) m/z 430 (M+H).
Step 3
Polymer supported triphenylphosphine (0.6 g, 0.6 mmol) and iodine (0.152 g, 0.6 mmol) were mixed in CH2Cl2 (3 mL) and the reaction vessel was shaken vigorously for I h. Et3N (0.121 g, 1.2 mmol) and 2-chloro-N- {2-[N'-(2,2-dimethylpropionyl)- hydrazino]-2-oxoethyl}-N-methyl-4-trifluoromethylbenzenesulfonamide (0.129 g, 0.30 mmol) were introduced, and the reaction mixture was shaken for 18 h at ambient temperature. The mixture was filtered, evaporated and the residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1 :3), to provide N-(5-tert- butyl-[l,3,4]oxadiazol-2-ylmethyl)-2-chloro-N-methyl-4-trifluoro-methyl-benzene- sulfonamide (0.096 g, 78%), retention time 4.16 min (HPLC System A); mass spectrum (ES+) m/z 412 (M + H).
The following compounds were prepared utilising the general procedure as described in Example 1:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
The following example was prepared by a modification of the method used for Example 1:
Example 63: (S)-2-Chloro-N-methyl-N-(l-oxazolo[4,5-b]pyridin-2-yl-ethyl)-4- trifluoromethyl-benzenesulfonamide
Step l (S)-2- [(2-Chloro-4-trifluoromethyl-benzenesulfonyl)methylamino]propionic acid (0.25 g, 0.72 mmol) and 2-amino-3-hydroxypyridine (0.08 g, 0.72 mmol) were dissolved in THF (20 mL) and EDC (0.139 g, 0.72 mmol) was introduced, followed by HOBT (0.098 g, 0.72 mmol) and N-ethylmorpholine (0.185 mL, 1.45 mmol). The reaction mixture was treated with EtOAc (20 mL), washed with 5% citric acid solution (20 mL) and sat. aqueous NaHCO3 (20 mL). The organic layer was separated, washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to a residue which was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1 :4), to provide (S)-2-[(2-chloro-4-trifluoromethylbenzenesulfonyl)methylamino]-N-(3- hydroxy-pyridin-2-yl)propionamide (0.213 g, 67%), retention time 2.40 min (HPLC System B); mass spectrum (ES+) m/z 439 (M + H). Step 2
(S)-2-[(2-chloro-4-trifluoromethyl-benzenesulfonyl)methylamino]-N-(3-hydroxy- pyridin-2-yl)propionamide (0.21 g, 0.49 mmol) was dissolved in dioxan (6 mL) and Ph3P (0.325 g, 1.24 mmol) was added. The mixture was heated to reflux for 1 h, cooled and di-isopropyl azodicarboxylate (0.366 mL, 1.86 mmol) was introduced, and the reaction mixture was heated at 900C for 1.5 h. The reaction mixture was cooled, evaporated in vacuo to a residue which was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1 :9 → 3:2), and purified further by preparative HPLC to provide (S)-2-chloro-N-methyl-N-(l-oxazolo[4,5-b]pyridin-2-yl-ethyl)-4-trifluoro- methylbenzenesulfonamide (0.029 g, 14%); retention time 3.99 min (HPLC System A); mass spectrum (ES+) m/z 420 (M + H).
Example 43 : N-[l-(5-tert-Butyl-[l,3,4] oxadiazoI-2-yl)-l-methyl-ethyl]-2-chloro-N- methyl-4-trifluoromethyl-benzenesulfonamide
Step l
Solid supported hydrazinecarboxylic acid ester (attached via ester group to resin) (0.864 g, 1.296 mmol) was suspended in dry dimethylformamide (DMF) (10 mL). HOBT (0.263 g, 1.944 mmol), 2-[(9H-fluoren-9-ylmethoxycarbonyl)-methyl-amino]-2-methyl- propionic acid (FMOC-protected 2-methyl-2-methylaminopropionic acid; Fluka 29250) (0.683g, 1.944 mmol) and diisopropyl carbodiimide (0.864 g, 1.944 mmol) were introduced, and the suspension was shaken at ambient temperature for 20 h. The resin sample was washed with DMF (3 x 20 mL), CH3OH (3 x 20 mL) and CH2Cl2 (5 x 20 mL), and the resin was dried under vacuum for 2 h.
Removal of FMOC group: The resin was suspended in DMF (8 mL), piperidine (2 mL) was introduced and the suspension was shaken for 1 h. The resin was washed with DMF (6 x 20 mL), CH3OH (5 x 20 mL) and CH2Cl2 (6 x 20 mL), and the resin was dried under vacuum for 18 h. The resin-linked amino acid hydrazide was sulfonylated as follows: 2-chloro-4- trifluoromethyl-benzenesulfonyl chloride (0.542 g, 1.944 mmol) was dissolved in CH2Cl2 (10 niL) and Et3N (0.27 mL, 1.944 mmol) was added. This whole solution was added to the dry resin from the previous stage, and the suspension was shaken for 18 h. The resin was washed with CH2Cl2 (5 x 20 mL), DMF (3 x 20 mL), CH3OH (3 x 20 mL) and CH2Cl2 (5 x 20 mL), and the resin was dried under vacuum for 18 h.
Step 2
The resin product was suspended in a mixture Of CH2Cl2 (10 mL) and CF3CO2H (10 mL) and the suspension was shaken at ambient temperature for 1.5 h. The resin was collected by filtration and washed with CH2Cl2 (2 x 20 mL). The combined filtrates were evaporated to dryness in vacuo, and the trifmoroacetic acid salt of 2-chloro-N-(l- hydrazinocarbonyl-l-methyl-ethyl)-N-methyl-4-trifluoromethylbenzenesulfonamide was purified by cation exchange chromatography utilising IST-MP-TsOH cartridges as follows. The residue was dissolved in CH3OH (3 mL) and acidified with acetic acid
(0.2 mL). The cartridge was conditioned with CH3OH (8 mL), and the crude solution of the hydrazide was loaded. Elution with a mixture Of CH2Cl2 (4 mL) and CH3OH (4 mL) was followed by retrieval of the hydrazide with a 2N solution of NH3 in CH3OH (12 mL). The solution containing product was evaporated to provide 2-chloro-N-(l- hydrazinocarbonyl- 1 -methyl-ethyl)-N-methyl-4-trifluoromethylbenzene-sulfonamide (0.077 g, 16%), retention time 4.35 min (HPLC System B); mass spectrum (ES+) m/z 440 (M + H).
Step 3 2-Chloro-N-(l -hydrazinocarbonyl- 1 -methylethyl)-N-methyl-4-trifluoromethylbenzene- sulfonamide (0.039 g, 0.105 mmol) and Et3N (0.021g, 0.21 mmol) in CH2Cl2 (2 mL) was treated with 2,2-dimethylpropionyl chloride (pivaloyl chloride) (0.013 g, 0.105 mmol). Saturated NaHCO3 solution (20 mL) was added, the organic layer was separated, washed with 5% aqueous citric acid solution (5mL) and dried (MgSO4) before being evaporated to a residue. The product, 2-chloro-N-{2-[N'-(2,2- dimethylpropionyl)hydrazino] -1,1 -dimethyl-2-oxoethyl} -N-methyl-4-trifluoromethy-l- benzenesulfonamide had a retention time of 1.65 min (HPLC System A); mass spectrum (ES+) m/z 457.96 (M + H).
Step 4 Polymer supported triphenylphosphine (0.4 g, 0.39 mmol) was suspended in CH2Cl2 (5 mL) and iodine (0.099 g, 0.39 mmol) was added, and the reaction vessel was shaken vigorously for 1 h. Et3N (0.11 mL, 0.78 mmol) and 2-chloro-N-{2-[N'-(2,2-dimethyl- propionyl)hydrazino]-l,l-dimethyl-2-oxoethyl}-N-methyl-4-trifluoromethy-l-benzene- sulfonamide was introduced, and the reaction mixture was shaken for 18 h at ambient temperature. The reaction mixture was filtered, passed through a short column of florisil, evaporated and the residue was purified by preparative HPLC eluting with EtOAc/hexane (1:3), to provide N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-l-methyl- ethyl]-2-chloro-N-methyl-4-trifluoromethyl-benzenesulfonamide (0.012 g, 27% over 2 steps), retention time 4.16 min (HPLC System A); mass spectrum (ES+) m/z 412 (M + H).
Example 20: (S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazole-2-yl)-ethyl]-2-chloro-N- isopropyl-4-trifluoromethylbenzenesulfonamide
Step 1
(S)-2-t-Butoxycarbonylaminopropionic acid (5.0 g, 26.4 mmol), pivalic anhydride (3.0 g, 26.4 mmol), 1-hydroxybenzotriazole (3.93 g, 29.1 mmol) and Et3N (7.4 mL, 52.8 mmol) were stirred vigorously in CH2Cl2 (40 mL) and EDC (4.52 g, 29.1 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 3 h, evaporated to a residue and purified by flash chromatography on silica gel, to provide the (S)- {2- [N'-(2,2-dimethylpropionyl)-hydrazino]-l-methyl-2-oxo-ethyl}carbamic acid tert-butyl ester. HPLC (System A) retention time 2.58 min (Solvent: MeCN/H2O/0.05% HCO2H, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min.) Mass spectrum (ES+) m/z 288 (M+H). Step 2
Polymer supported triphenylphospliine (7.0 g, 20.8 mmol) was suspended in CH2Cl2 (50 mL) and iodine (52 g, 0.6 mmol) was added. The suspension was shaken vigorously for 2 h. Et3N (5.87 mL, 41.76 mmol) and (S)-{2-[N'-(2,2-dimethylpropionyl)-hydrazino]- l-methyl-2-oxo-ethyl}carbamic acid tert-butyl ester (2.0 g, 6.96 mmol) were introduced, and the reaction mixture was shaken for 18 h at ambient temperature. The mixture was filtered, evaporated and the residue was purified by flash chromatography on silica gel eluting with EtOAc/isohexane (1:5), to provide (S)-[I -(5-tert-butyl- [l,3,4]oxadiazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.788 g, 94%), retention time 3.32 min (HPLC System A); mass spectrum (ES+) m/z 270 (M + H).
Step 3
(S)-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.788 g, 6.62 mmol)was dissolved in CH2Cl2 (30 mL) and CF3CO2H (30 mL) was added. The reaction mixture was stirred at ambient temperature for Ih, and the mixture was concentrated in vacuo to a residue which was co-evaporated with a mixture of PhCH3 (50 mL) and CH3OH (50 mL). The residue was dried under vacuum and purified by flash chromatography on silica gel eluting with EtOAc/isohexane (1:1), gradually increasing polarity to EtOAc/CH3OH (1:1) to provide (S)-l-(5-tert-butyl- [l,3,4]oxadiazol-2-yl)-ethylamine (1.54 g, 90%), with a retention time of 2.21 min (HPLC System B); mass spectrum (ES+) m/z 170.
Step 4
(S)-l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethylamine (1.0 g, 3.55 mmol) and Et3N (1.0 mL, 7.1 mmol) were mixed in CH2Cl2 (40 mL) and 2-chloro-4-trifluoromethyl- benzenesulfonyl chloride (1.0 g, 3.55 mmol) was introduced. The solution was stirred for 18 h at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/isohexane (1:1) to provide (S)-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]- 2-chloro-4-trifluoromethylbenzenesulfonamide (0.56 g, 39%), with a retention time of 3.77 min (HPLC System A); mass spectrum (ES+) m/z 413.8. Step 5
(S)-N-[l-(5-tert-Butyl-[l,3,4]oxadiazole-2-yl)-ethyl]-2-chloro-4-trifluoromethylbenzene sulfonamide (0.05 g, 0.122 mmol), solid supported Ph3P (0.162 g, 0.243 mmol) and 2- propanol (0.015 g, 0.243 mmol) were mixed in anhydrous THF (5 mL). Di-tert-butyl azodicarboxylate (0.049 g, 0.243 mmol) was introduced, and the reaction mixture was shaken at ambient temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/isohexane (1:1), followed by further purification by preparative HPLC, to provide (S)-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-2-chloro-N-isopropyl-4- trifluoro-methylbenzenesulfonamide (0.0133 g, 29%)), with a retention time of 4.29 (HPLC System A); mass spectrum (ES+) m/z 454.
The following compounds were prepared utilising the general procedure as described above for Example 20:
Figure imgf000041_0001
Figure imgf000042_0001
Example 12 : (S)-4-Bromo-N-[l-(5-tert-butyI-[l,3,4] oxadiazol-2-yI)ethyl]-N- methylbenzene-sulfonamide
Step l
Polymer supported triphenylphosphine (2.36 g, 7.08 mmol) was suspended in CH2Cl2 (70 niL) and iodine (52 g, 0.6 mmol) was added. The suspension was shaken vigorously for 50 min. Et3N (1.97 rnL, 14.16 mmol) and (S)-{2-[N'-(2,2-Dimethyl- propionyl)-hydrazino] - 1 -methyl-2-oxo-ethyl } -carbamic acid tert-butyl ester ( 1.067 g, 3.54 mmol) (prepared by the procedure described in Method C) as a solution in CH2Cl2 (20 mL) were introduced, and the reaction mixture was shaken for 18 h at ambient temperature. The mixture was filtered, evaporated and the residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1:9 → 1:4) to provide (S)-[I- (5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (0.825 g, 83%), retention time 3.65 min (HPLC System B); mass spectrum (ES+) m/z 284 (M + H).
Step 2
(S)-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]carbamic acid tert-butyl ester (0.825 g, 2.91 mmol) was dissolved in CH2Cl2 (7 mL) and CF3CO2H (2 x 0.433 mL, 11.64 mmol) was added in two batches 2 hours apart, while stirring at ambient temperature. Stirring was continued for 24 h, and the reaction mixture was evaporated in vacuo to provide (S)-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-ethyl]methylamine; retention time 2.39 min (HPLC System B); mass spectrum (ES+) m/z 184 (M + H).
Step 3
(S)-[l-(5-tert-Butyl-[l,3,4]oxadiazol-2-yl)-ethyl]methylamine (0.088 g, 0.48 mmol) and Et3N (0.12 mL, 0.81 mmol) were stirred vigorously in CH2Cl2 (6 mL) and (4- bromobenzenesulfonyl chloride (0.123 g, 0.48 mmol) in CH2Cl2 (2 mL) was introduced. The reaction mixture was stirred at ambient temperature for 18 h, diluted CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 solution (5 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1 :9 → 1 :4) followed by further purification by preparative HPLC to provide (S)-4-bromo-N-[l-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)ethyl]-N- methylbenzenesulfonamide (0.023 g); retention time 3.88 min (HPLC System B); mass spectrum (ES+) m/z 403 (M + H).
The following compounds were prepared from the corresponding aminoalkyl heterocycles, utilising the sulphonylation procedure described for Example 12:
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
The following compounds were prepared from aminoalkyl heterocyles using the final sulphonylation step of Example 12:
Figure imgf000046_0002
Figure imgf000047_0001
Example 44: 2-Chloro-N-methyl-N-[l-methyl-l-(5-methyI-[l,3,4]-thiadiazoI-2- yI)ethyl]-4-trifluoromethylbenzenesulfonamide
Step l
2-[(2-Chloro-4-trifluoromethylbenzenesulfonyl)methylammo]-2-methylpropionic acid (0.721 g, 2 mmol), (CH3CO)2O (0.178 g, 2.4 mmol), HOBT (0.284 g, 2.1 mmol) and Et3N (0.562 niL, 4 mmol) were mixed in CH2Cl2 (30 mL) and stirred for 18 h. Further reagents, i.e. (CH3CO)2O, HOBT and Et3N were introduced, first 40%, then 50% of the initial amounts, and the reaction mixture was heated at 400C for 18 h, cooled and evaporated to a residue. The residue was treated with EtOAc (20 mL), washed with 5% citric acid solution (20 mL) and sat. aqueous NaHCO3 (20 mL). The organic layer was separated, washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to provide 2-chloro-N- { 1 - [N'-(2,2-dimethyl-propionyl)hydrazinocarbonyl] - 1 - methyl-ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide (0.65 g, 78%), retention time 3.24 min (HPLC System B); mass spectrum (ES+) m/z 416 (M + H).
Step 2 2-Chloro-N- { 1 -[N'-(2,2-dimethylpropionyl)hydrazinocarbonyl]- 1 -methylethyl} -N- methyl-4-trifluoromethylbenzenesulfonamide (0.65 g, 1.57 mmol) was dissolved in PhCH3 (30 mL) and Lawesson's reagent (0.95 g, 2.35 mmol) was added. The suspension was heated at 100°C for 3 h. The toluene was removed in vacuo, and the residue was treated with EtOAc (40 mL), washed with water (40 mL). The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a mixture of isohexane and ethyl acetate (4:1), to provide the desired to provide 2-chloro-N~methyl-N-[l -methyl- 1 -(5- methyl-[l,354]thiadiazol-2-yl)ethyl]-4-trifluoromethylbenzenesulfonamide product as a white solid (0.221 g, 34%); retention time 3.95 min (HPLC System B); mass spectrum (ES+) m/z AU (M + H).
The following compounds were prepared utilising the general procedure as described in Example 44:
Figure imgf000048_0001
Example 48: (S)-N-[l-(3-tert-Butyl-[l,2,4]oxadiazol-5-yl)-ethyl]-2-chloro-N-methyl- 4-trifluoromethylbenzenesulfonamide
Step l
(S)-2-[(2-Chloro-4-trifluoromethyl-benzenesulfonyl)methylamino]propionic acid (0.10 g, 0.289 mmol) andN-hydroxy-2,2-dimethylpropionamidine (0.067 g, 0.578 mmol) were dissolved in THF (3 niL). EDC (0.072 g, 0.375 mmol) was introduced, followed by 1-hydroxybenzotriazole (0.051 g, 0.375 mmol) and diisopropylethylamine (0.578 mmol). The reaction mixture was stirred at 400C for 2 h, evaporated to a residue and purified by flash chromatography on silica gel, to provide the desired (S)-2-[(2-chloro- 4-trifluoromethyl-benzenesulfonyl)-methyl-amino]propionic acid, [0-(JV-hydroxy-2,2- dimethyl-propionamidine)]ester (0.090 g, 70%). HPLC (System B) retention time 4.08 min. (Solvent:MeCN/H2O/0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min), mass spectrum (ES+) m/z AAA (M+H).
Step 2
(S)-2-[(2-chloro-4-trifluoromethyl-benzenesulfonyl)-methyl-amino]-propionic acid, [O- (N-hydroxy-2,2-dimethyl-propionamidine)]ester (90mg, 0.203 mmol) was heated in m- xylene (5 mL) at reflux temperature for 18 h. The reaction mixture was cooled, evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel, eluting with EtOAc/hexane (1 :19) to provide the desired (S)-N-[l-(3-tert- butyl-[l,2,4]oxadiazol-5-yl)-ethyl]-2-chloro-N-methyl-4-trifluoromethylbenzene- sulfonamide (0.065 g, 76%), with a retention time of 4.65 min (HPLC System B); mass spectrum (ES+) m/z 426.
The following compound was prepared utilising the general procedure as described for Example 48:
Figure imgf000049_0001
Figure imgf000050_0001
Example 52: 2-Chloro-N-methyl-N-(3-phenyl-[l,2,4]oxadiazol-5-ylmethyl)-4- trifluoromethyl-benzenesulfonamide
Methyl-(3-phenyl-[ 1 ,2,4]oxadiazol-5-ylmethyl)amine (0.142 g, 0.075 mmol) was dissolved in dry CH2Cl2 (1 mL) and Et3N (0.21 niL, 0.152 g, 1.5 mmol) was introduced, followed by a solution of (2-chloro-4-trifuoromethylbenzenesulfonyl chloride (0.23 g, 0.825 mmol) in dry CH2Cl2 (1 mL). The reaction mixture was shaken at ambient temperature for 18 h, and purified by flash chromatography on silica gel, eluting with a mixture of isohexane and ethyl acetate (19:1), to provide the desired product as a white solid (0.184 g, 57%). HPLC (System B) retention time 4.54 min. (Solvent:MeCN/H2O/ 0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min), mass spectrum (ES+) m/z 432 (M+H).
Example 59: (S)-2-Chloro-N-isopropyl-4-trifluoromethyl-N-[l-(5-trifluoromethyl- [l,2,4]oxadiazol-3~yl)ethyl]benzenesulfonamide
Step l
Oxalyl chloride (2.9 mL, 4.21 g, 33.2 mmol) was added dropwise to a stirred solution of DMF (2.42 g, 33.2 mmol) in CH3CN (150 mL) at -50C, and stirred at this temperature for a further 15 min. A suspension of (S)-2-(2-chloro-4-trifluoromethyl- benzenesulfonyl amino)-propionamide (9.14 g, 27.6 mmol) and pyridine (5.6 mL, 5.47 g, 69.1 mmol) in CH3CN (70 mL) was added slowly to the reaction mixture, which was stirred at -50C for 45 min. The reaction mixture was evaporated in vacuo and water (200 mL) was added followed by EtOAc (200 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined extracts were dried (MgSO4). The residue on evaporation was purified by flash chromatography on silica gel, eluting with a mixture of EtOAc/isohexane (1 :4), to provide (S)-2-chloro-N- (l-cyano-ethyl)-4-trifluoromethylbenzenesulfonamide (3.51 g, 41%).
Step 2 (S)-2-Chloro-N-(l-cyano-ethyl)-4-trifluoromethylbenzenesulfonamide (3.49 g, 11.2 mmol) in CH3OH (90 mL) was added to a solution of NH2OH.HC1 (3.88 g, 55.8 mmol) and Na2CO3 (5.92 g, 55.8 mmol) in water (110 mL). The reaction mixture was heated at reflux for 18 h, cooled and concentrated in vacuo to an aqueous mixture, which was extracted with EtOAc (4 x 100 mL) and the combined extracts were dried (MgSO4). Evaporation afforded (S)-2-(2-chloro-4-trifluoromethylbenzenesulfonylamino)-N- hydroxypropion-amidine as a pale yellow solid (3.47 g, 90%); HPLC (System B) retention time 2.29 min. (Solvent:MeCN/H2O/ 0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min), mass spectrum (ES+) m/z 346 (M+H).
Step 3
(S)-2-(2-Chloro-4-trifluoromethylbenzenesulfonylamino)-N-hydroxypropionamidine (1.0 g, 2.89 mmol) was mixed with CF3CO2H (2.9 mL, 4.29 g, 37.6 mmol) and (CF3CO2)O (2.9 mL, 4.31 g, 20.5 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h. The reagents were removed in vacuo, the residue was co- evaporated with PhCH3 (3 x 10 mL) and was purified by flash chromatography on silica gel, eluting with a mixture of EtOAc/isohexane (1 :4), to provide (S)-2-chloro-4- trifiuoromethyl-N-[l-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl) ethyl]benzenesulfonamide as a white solid (0.485 g , 40 %); HPLC (System B) retention time 3.21 min. (Solvent:MeCN/H2O/ 0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 mL/min), mass spectrum (ES+) m/z 424 (M+H).
Step 4
This compound was prepared by reaction of (S)-2-chloro-4-trifluoromethyl-N-[l-(5- trifluoromethyl-[l,2,4]oxadiazol-3-yl) ethyl]benzenesulfonamide (0.225 g, 0.531 mmol) under Mitsunobu conditions as described for Example 20, to provide (S)-2-chloro-N- isopropyl-4-trifluoromethyl-N-[l-(5-trifluoromethyl-[l,2,4]oxadiazol-3-yl)- ethyl]benzenesulfonamide (0.22 g, 95%). 1H NMR δ 8.27 (IH, d, J= 8.8, Ar-H), 7.76 (IH, d, J= 1.5, Ar-H), 7.66 (IH, dd, J= 8.8 and 1.8, Ar-H), 5.44 (IH, q, J= 7.0, NCH), 2.98 (3H, s, NCH3), 1.70 (3H, d, J= 7.0, CCH3).
The following compounds were prepared utilising the general procedure as described for Example 59:
Figure imgf000052_0001
Figure imgf000053_0001
Example 61 : 2-Chloro-N-(5-ethyloxazol-2-ylmethyl)-N-methyl-4-trifluoromethyl- benzenesulfonamide
Step l
[(2-Chloro-4-trifluorometliylbenzenesulfonyl)methylamino]acetic acid (0.30 g, 0.91 mol) and l-amino-2-butanol (0.161 g, 1.81 mmol) were dissolved in THF (20 mL) and EDC (0.226 g, 1.18 mmol) was introduced, followed by 1-hydroxybenzotriazole (0.159 g, 1.18 mmol) and diisopropylethylamine (0.234 g, 1.81 mmol). The reaction mixture was stirred at 4O0C for 18 h, evaporated to a residue and purified by flash chromatography on silica gel, to provide the 2-[(2-chloro-4-trifluoromethyl- benzenesulfonyl)methylamino]-N-(2-hydroxybutyl)acetamide (0.33 g, 90%). HPLC (System A) retention time 3.59 min. (Solvent:MeCN/H2O/0.05% NH4OH, 5-95% gradient H2O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., Cl 8 reverse phase. Flow rate: 1.5 niL/min.); mass spectrum (ES+) m/z 403.
Step 2 2-[(2-Chloro-4-trifluoromethylbenzenesulfonyl)methylamino]-N-(2-liydroxybutyl)- acetamide (0.33 g, 0.83 mmol) was dissolved in CH2Cl2 (5 mL) and the solution was cooled in an ice bath. Dess-Martin Periodinane Reagent (2.5 mL, 0.875 mmol) was added dropwise with stirring, and the reaction mixture was stirred at ambient temperature for 60 h. Further CH2Cl2 (20 mL) was added and the mixture was stirred vigorously with a mixture of 10% aqueous NaHCO3 solution with a sodium sulphite solution present. The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL); the combined organic layers were washed with 10% aqueous NaHCO3 solution and dried (MgSO4). The solid 2-[(2-chloro-4-trifluoromethyl- benzenesulfonyl)-methyl-amino]-N-(2-oxobutyl)acetamide obtained on evaporation (0.26 g, 79%) had a retention time of 3.74 min (HPLC System A); mass spectrum (ES+) m/z 401, and was pure enough to use directly in the next stage.
Step 3
2-[(2-chloro-4-trifluoromethyl-benzenesulfonyl)-methyl-amino]-N-(2-oxobutyl)- acetamide (0.1O g, 0.25 mmol) was dissolved in dioxan (10 mL) and the dehydrating reagent methyl N-(triethylammoniosulfonyl)carbamate) (Burgess Reagent) (119 mg, 0.5 mmol) was introduced. The reaction mixture was heated at 900C for 1 h, cooled and EtOAc (20 mL) was added. The organic layer was washed with 10% aqueous NaHCO3 solution and dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane (1 :4), to provide 2- chloro-N-(5-ethyl-oxazol-2-ylmethyl)-N-methyl-4-trifluoromethylbenzenesulfonamide (0.04 g, 42%), which had a retention time of 3.67 min (HPLC System A); mass spectrum (ES+) m/z 383.
Example 68: (S)-2-Chloro-N-[l-(4,5-dimethyl-oxazol-2-yl)-ethyl]-N-methyl-4- trifluoromethyl-benzenesulfonamide Step l
(S)-2-[(2-Chloro-4-methyl-benzenesulfonyl)-methyl-amino]propionic acid (1.0 g, 3.43 mtnol) was dissolved in dry THF (50 mL). 3-Hydroxy-2-butanone (0.26 g, 3.43 mmol) and Ph3P (0.76 g, 3.43 mmol) were introduced, and the mixture was stirred at ambient temperature for 10 min. before being cooled to O0C. Di-isopropyl azodicarboxylate (DIAD) (0.57 mL, 3.43 mmol) was introduced, and the reaction mixture was stirred at ambient temperature for 4h. The reaction mixture was evaporated in vacuo, treated with EtOAc (20 mL), washed with 5% citric acid solution (20 mL) and sat. aqueous NaHCO3 (20 mL). The organic layer was separated, washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to a residue which was purified by flash chromatography on silica gel eluting with CH2Cl2 /isohexane (4:1) to provide (S)-2-[(2- chloro-4-methyl-benzenesulfonyl)-methyl-amino]propionic acid 1- methyl-2-oxopropyl ester (0.35 g, 29%), retention time 4.15 min (HPLC System B); mass spectrum (ES+) m/z 416 (M + H).
Step 2
Ammonium acetate (1.16 g, 15.04 mmol) and glacial acetic acid (0.9 mL) were added to a solution of (S)-2-[(2-chloro-4-methyl-benzenesulfonyl)-methyl-amino]propionic acid l-methyl-2-oxopropyl ester (0.35 g, 0.84 mmol) in 1,2-dichloroethane (20 mL). The solution was heated at 9O0C for 2h, cooled to 0°C and IN NaOH (7 mL) was added. The organic layer was separated, washed with saturated brine (10 mL) and dried (MgSO4). The residue on evaporation was purified by flash chromatography on silica gel eluting with CH2Cl2 /isohexane (4:1) to provide (S)-2-chloro-N-[l-(4,5-dimethyl- oxazol-2-yl)-ethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide (0.21 g, 66%), retention time 4.41 min (HPLC System B); mass spectrum (ES+) m/z 397 (M + H).
The following compounds were prepared utilising the general procedures, or close variants, which would be familiar to those skilled in the art, as described for Examples 61 and 68:
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
The following compound was prepared by the method used for Example 63
Figure imgf000058_0002
Example 86: (S)-2-Chloro-N-methyl-N-[l-(3-methyl-isoxazol-5-yl)-ethyl]-4- trifluoromethyl-benzenesulfonamide
Step l n-Butyllithium (1.6M) (6.95 mL) was added to a solution of acetone oxime (0.41 g, 5.56 mmol) in dry THF (30 mL) and this mixture was stirred at 00C for 1 h. A solution of (S)-(2-[(2-chloro-4-trifluoromethylbenzenesulfonyl)-methyl-amino]-propionic acid methyl ester (1.0 g, 2.78 mmol) in THF (5 mL) was introduced, and the reaction mixture was stirred at 00C for a further 3 h. Saturated NH4Cl solution and EtOAc (20 mL) was added, and the organic layer was washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to a residue which was purified by flash chromatography on silica gel eluting with isohexane/EtOAc (4:1 — > 1:1) to provide (S)- 2-chloro-N-(4-hydroxyimino- 1 -methyl-2-oxo-pentyl)-N-methyl-4- trifluoromethylbenzenesulfonamide (0.37 g, 33%) %), retention time 3.63 min (HPLC System B); mass spectrum (ES+) m/z 399 (M - H).
Step 2 (S)-2-Chloro-N-(4-hydroxyimino- 1 -methyl-2-oxo-pentyl)-N-methyl-4-trifluoromethyl- benzenesulfonamide (0.36 g, 0.89 mmol) was dissolved in a mixture Of CH2Cl2 (5 mL) and Et3N (0.162 mL) and methanesulfonyl chloride (0.83 μL) was introduced at 00C, and the reaction mixture was stirred at ambient temperature for 4 h. Further Et3N (1.3 equiv.) and methanesulfonyl chloride (1.2 equiv.) were added and stirring was continued for 18 h. IN aqueous HCl solution was added, and the organic layer was washed with saturated brine (10 mL), dried (MgSO4) and evaporated in vacuo to a residue which was purified by flash chromatography on silica gel. Elution with isohexane/EtOAc (9:1), followed by final purification by preparative HPLC provided (S)-2-chloro-N-methyl-N-[l-(3-methyl-isoxazol-5-yl)-ethyl]-4-trifluoromethyl- benzenesulfonamide (0.10 g, 29%); retention time 4.02 min (HPLC System B); mass spectrum (ES+) m/z 383 (M - H).
The following compound was prepared utilising the general procedure as described for Example 86:
Figure imgf000060_0001
Example 88 : 2-Chloro-N-methyl-N-(2-methyl-thiazol-4-ylmethyl)-4- trifluoromethyl-benzenesulfonamide
This compound was prepared by a sulfonylation procedure analogous to that utilised for Example 52. The title compound was obtained (0.166 g, 58%); retention time 4.13 min (HPLC System B); mass spectrum (ES+) m/z 385 (M - H).
The following compounds were prepared utilising the general procedure described for Example 88:
Figure imgf000060_0002
Figure imgf000061_0001
The following compounds were prepared utilising the procedures described above:
Figure imgf000061_0002
BIOLOGICAL SCREENING
N-type calcium channel inhibition in IMR32 cells
The human neuroblastoma cell line IMR32 has been used by a number of groups to investigate calcium ion channels either by electrophysiological or fluorescent techniques in low throughput assays (Carbone, E., et al. (1990) Pflϋgers Arch 416:170- 179; Rafferty, M., et al. (2000) Patent WO 00/06559; Seko, T., et al., (2001) Bioorg Med Chem Lett 11:2067-2070).
It has been shown that undifferentiated IMR32 cells constitutively express L-type calcium channels, whilst differentiated IMR32 cells express both N- and L-type channels. Therefore, undifferentiated IMR32 cells can be used to assay the L-type calcium channel and differentiated cells assayed in the presence of 5 μM nitrendipine can be used to study the N-type channels.
The Molecular Devices Corp FLEXstation™ was utilised to develop a medium throughput assay with undifferentiated and differentiated IMR32 cells labelled with Fluo-4. Opening of voltage-activated calcium channels was stimulated by depolarisation of cells with KCl, which was added by the FLEXstation' s fluidics system. The resulting influx of calcium into the cells was recorded by an increase in fluorescence. The assays were validated with known ion channel blockers.
IMR32 cells were grown in EMEM supplemented with 10% foetal bovine serum, 2 mM lutamine, 1% NEAA, 100 U/ml penicillin and 100 μg/ml streptomycin. To differentiate the IMR32 cells, 1 mM dibutyryl cAMP and 2.5 μM bromodeoxyuridine were added to the cell culture media and cells maintained for 7-9 days.
Cells were detached from tissue culture surfaces using an enzyme free cell dissociation buffer (Invitrogen) after washing with a Ca2+Mg2+ free Hanks buffered saline solution (HBSS). The cells were then resuspended in assay buffer (HBSS containing Ca2+Mg2+ and supplemented with 20 mM HEPES, pH 7.4) to give a total volume of 40 ml. 2 μM Fluo-4 and 50 μM probenecid were added and then the cells were incubated at 25 0C for 30 min. Following centrifugation in a Heraeus Megafuge 1.0 (rotor 2704) for lmin at 1000 rpm, the cell pellet was resuspended in 40 ml assay buffer supplemented with 50 μM probenecid and incubated at 25 0C for a further 30 min. The cells were centrifuged as before and again resuspended in assay buffer supplemented with probenecid. 200,000 cells were aliquoted into each well of a 96-well plate containing 0.001-100 μM compound to be tested (for the N-type assay 5 μM nitrendipine was also added to each well), in triplicate. The final volume of compound and cells in assay buffer was 200 μl. The plate containing cells was centrifuged at 300 rpm for 1 min with no brake in a Heraeus Labofuge 400E (rotor 8177).
The plate was then assayed using the FLEXstation (Molecular Devices Corp). The excitation and emission wavelengths were 494 and 525 nm, respectively. The calcium response was stimulated by the addition of 50 μl 250 niM KCl (50 mM final concentration) by the FLEXstation fluidics system. SOFTmax Pro (Molecular Devices Corp) was used to calculate the change in fluorescence caused by calcium influx for each well and hence the IC50 for each compound. The results are shown in the Table below.
RESULTS
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000067_0001
wherein:
A is a 5- to 10-membered heteroaryl or heterocyclyl moiety, said moiety being optionally fused to a phenyl, 5- to 6-membered heteroaryl, C3-C6 carbocyclyl or 5- to 6- membered heterocyclyl group;
B is a bond or a C1-C6 alkyl or C2-C6 alkenyl moiety; - either (a) R1 is hydrogen or C1-C6 alkyl and R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogen, hydroxy, thio, amino, -Het-L or -L-Het-L', wherein L and L' are the same or different and represent C1-C6 alkyl or C2-C6 alkenyl and Het is O, S or NR, wherein R is hydrogen or C1-C6 alkyl or (b) R1 and R2 form, together with the carbon to which they are attached, a 5- to 10-membered heterocyclyl or a C3-C8 carbocyclyl moiety;
R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or -L-Het-L', wherein L, L' and Het are as defined above;
R4, R5 and R6 are the same or different and represent hydrogen, halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, mono(Ci-C6 alkyl)amino or di(Ci-C6 alkyl)amino; the alkyl and alkenyl groups and moieties in B and R1 to R6 being unsubstiruted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; the heterocyclyl and carbocyclyl moieties formed by R1 and R2 being unsubstiruted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents; and the group A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino, thio, C1- C6 alkyl, C2-C6 alkenyl, -Het-L, -L-Het-L', phenyl, 5- to 10-membered heteroaryl, C3-C6 carbocyclyl or 5- to 10-membered heterocyclyl, wherein L, L1 and Het are as defined above, the alkyl and alkenyl moieties in said substituents being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from halogen, hydroxy, amino and thio substituents and said phenyl, heteroaryl, carbocyclyl and heterocyclyl substituents being unsubstituted or substituted by one, two or three futher unsubstituted substituents selected from halogen, hydroxy, amino, thio, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, mono(C1-C6 alkyl)amino and di(C]!-C6 alkyl)amino groups.
2. A compound according to claim 1 , wherein R is hydrogen or methyl.
3. A compound according to either claim 1 or claim 2, wherein L and L' are the same or different and are C1-C4 alkyl.
4. A compound according to any one of the preceding claims, wherein A is a 5- to 6-membered heteroaryl or unsaturated heterocyclyl moiety, said moiety being optionally fused to a phenyl or 5- to 6-membered heteroaryl group.
5. A compound according to any one of the preceding claims, wherein B is a bond or a C1-C4 alkyl moiety.
6. A compound according to any one of the preceding claims, wherein R1 is hydrogen or C1-C4 alkyl.
7. A compound according to any one of the preceding claims, wherein R2 is hydrogen or C1-C6 alkyl.
8. A compound according to any one of claims 1 to 5, wherein R1 and R2 form, together with the carbon to which they are attached, a saturated 5- to 6-membered heterocyclyl moiety or a C3-C6 carbocyclyl moiety.
9. A compound according to any one of the preceding claims, wherein R3 is hydrogen, C1-C6 alkyl or -L-Het-L'.
10. A compound according to any one of the preceding claims, wherein R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine, hydroxy, amino, thio, C1-C4 alkyl, Ci-C4 alkoxy, C1-C4 alkylthio, mono(C1-C4 alkyl)amino or CIi(C1-C4 alkyl)amino.
11. A compound according to any one of the preceding claims wherein: A is a pyridyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, dihydro-oxazolyl, benzo [d] oxazolyl or oxazolopyridinyl moiety;
B is a bond or a C1-C2 alkyl moiety; either (a) R1 is hydrogen or methyl and R2 is hydrogen or C1-C4 alkyl or (b) R1 and R2 form, together with the carbon to which they are attached, a C3-C6 carbocyclyl moiety;
R3 is hydrogen, C1-C4 alkyl or -(C1-C2 3UCyI)-O-(C1 -C2 alkyl); R4, R5 and R6 are the same or different and represent hydrogen, fluorine, chlorine, bromine or C1-C2 alkyl; the alkyl groups and moieties in B and R to R being unsubstituted or substituted by a single hydroxy substituent; the alkyl groups and moieties in R4 to R6 being unsubstituted or substituted by one, two or three fluorine or chlorine substituents; the carbocyclyl moieties formed by R1 and R2 being unsubstituted; and the group A being unsubstituted or substituted by one, two or three substituents which are the same or different and are selected from C1-C6 alkyl, -(C1-C2 alkyl)-O-(Ci- C2 alkyl), cyclopropyl or phenyl, the alkyl moieties in the substituents on A being unsubstituted or substituted by a single hydroxy substituent or by one, two or three fluorine or chlorine substituents and the cyclopropyl and phenyl substituents on A being unsubstituted.
12. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding claims, for use in a method of treating the human or animal body.
13. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding claims, and a pharmaceutically acceptable carrier or diluent.
14. A pharmaceutical composition according to claim 13, which is in the form of a tablet, capsule, troche, lozenge, aqueous or oily suspensions, dispersible powders or granules or a sub-lingual tablet.
15. A pharmaceutical composition according to either claim 13 or claim 14, which is in a format suitable for parenteral, intranasal or transdermal administration or administration by inhalation.
16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels.
17. A method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
18. Use according to claim 16, or a method according to claim 17, wherein said condition mediated by N-type calcium channels is pain.
19. Use according to claim 16, or a method according to claim 17, wherein said condition mediated by N-type calcium channels is urinary incontinence.
20. Use according to claim 16, or a method according to claim 17, wherein said condition mediated by N-type calcium channels is an anxiety-related disorder or mood disorder, Bipolar disorder or post traumatic stress disorder.
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