WO2001098274A2 - Sulphonamide derivatives - Google Patents

Sulphonamide derivatives Download PDF

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Publication number
WO2001098274A2
WO2001098274A2 PCT/GB2001/002705 GB0102705W WO0198274A2 WO 2001098274 A2 WO2001098274 A2 WO 2001098274A2 GB 0102705 W GB0102705 W GB 0102705W WO 0198274 A2 WO0198274 A2 WO 0198274A2
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Prior art keywords
benzoic acid
benzoylamino
group
formula
compounds
Prior art date
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PCT/GB2001/002705
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French (fr)
Inventor
Alan Findlay Haughan
Christopher Lowe
George Martin Buckley
Hazel Joan Dyke
Frances Celia Anne Galvin
Stephen Robert Mack
Johannes Wilhelm Georg Meissner
Trevor Morgan
Robert John Watson
Catherine Louise Picken
Karen Ann Runcie
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Celltech Chiroscience Limited
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Application filed by Celltech Chiroscience Limited filed Critical Celltech Chiroscience Limited
Priority to AU2001274265A priority Critical patent/AU2001274265A1/en
Publication of WO2001098274A2 publication Critical patent/WO2001098274A2/en

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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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • This invention relates to a series of sulphonamides, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
  • the cyclic nucleotides cAMP and cGMP are known to be responsible for the regulation of a variety of intracellular processes.
  • the levels of these nucleotides are modulated by the stimulation of adenylate or guanylate cyclases and by the activity of phosphodiesterase enzymes.
  • Phosphodiesterases (PDEs) specifically convert cyclic nucleotides to inactive analogues. Eleven PDE gene familes have been identified to date, based on substrate specificity and regulatory characteristics.
  • PDE7 is a low KM CAMP specific enzyme which is insensitive to the standard
  • PDE4 inhibitor rolipram.
  • PDE7 is thought to play an important role in T cell activation [Beavo et al, Science (1999), 283: 848], which implies that inhibitors of PDE7 should have benefit in T cell mediated diseases.
  • PDE7 has been detected in airway epithelial cells [Barnes et al, Am. J. Respir. Cell Mol. Biol. (1999) 20: 292] so inhibitors should be beneficial in diseases of the airway.
  • Certain sulfonamide amide compounds are generally disclosed in International Specification No. WO-A-9938845 as modulators of PPAR ⁇ activity.
  • International Specification No. WO-A-9932433 also generally discloses certain sulfonamide amide compounds for use as inhibitors of 15- lipoxygenase.
  • International Specification No. WO-A-0052144 specifically discloses the use of 3-(4-bromophenylsulfamoyl)- ⁇ /-(3-nitrophenyl)benzamide as an ecto-phosphatase inhibitory molecule.
  • W, X, Y and Z which may be the same or different, each represents a nitrogen atom or a C(R 5 ) group [in which R 5 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO2 or -CN group] provided that two or more of W,X,Y and Z are C(R 5 ) groups; R 1 , R 2 and R 3 , which may be the same or different, each is an atom or group -L 1 (Alk 1 ) r L 2 (R 6 ) s in which L 1 and L 2 , which may be the same or different, is each a covalent bond or a linker atom or group, r is zero or the integer 1 , Alk 1 is an aliphatic or heteroaliphatic chain, s is an integer 1 , 2 or 3 and R 6 is a hydrogen or halogen atom or a group selected from alkyl, -OR 7
  • R 4 represents an optionally substituted phenyl, 1- or 2- naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group; and the salts, solvates, hydrates and N-oxides thereof; provided that the compound of formula (1 ) is not 3-(4- bromophenylsulfamoyl)- ⁇ /-(3-nitrophenyl)benzamide.
  • Optional substituents present on groups represented by R 4 include one, two, three or more groups, each represented by the group R 4a , where R 4a is a -L 1 (Alk 1 ) r L 2 (R 6 )s group as generally defined above and more specifically described hereinafter provided that -L 1 (Alk 1 ) r L 2 (R 6 ) s does not represent -H. Where more than one R 4a substituent is present, these may be the same or different.
  • each L 1 and/or L 2 group may be for example an -O- or -S- atom or a -C(O)-, -C(S)-, -S(O)-, - S(0) 2 -, -N(R 10 )- [where R 10 is a hydrogen atom or a C ⁇ _6 alkyl, e.g.
  • Alk 1 When Alk 1 is present in the compounds of the invention it may be a C1-10 aliphatic chain, for example a straight or branched chain C- ⁇ -6alkylene, e.g. C ⁇ -3alkylene, C 2 -6alkenylene, e.g. C 2 _4alkenylene, or C 2 -6alkynylene, e.g. C-2-4 alkynylene chain.
  • Each of said chains may be optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by L 3 [where L 3 is an atom or group as just described for L 1 ], to form an Alk 1 heteroaliphatic chain.
  • Particular examples of aliphatic chains represented by Alk 1 include -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 2 CH 2 -, -CH(CH 3 )CH 2 -, -(CH 2 )3CH 2 -. -CH(CH 3 )CH 2 CH 2 -,
  • each of said groups may be optionally interrupted by one or two atoms and/or groups L 3 to form a heteroaliphatic chain.
  • substituent R 6 when the substituent R 6 is present in compounds of formula (1 ) as a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
  • Alkyl groups represented by the group R 6 include straight or branched C-i- 6 alkyl groups, e.g. C ⁇ - 3 alkyl groups such as methyl or ethyl groups.
  • Optionally substituted alkyl groups represented by R 7 , R 8 and/or R 9 in compounds of the invention include those alkyl groups just mentioned for R 6 optionally substituted by one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxy or C-
  • R 6 When R 6 is present in compounds of formula (1 ) as a cycloaliphatic group it may be an optionally substituted C 3 _ ⁇ o cycloaliphatic group. Particular examples include optionally substituted C 3 - ⁇ ocycloalkyl, e.g. C 3 -7 cycloalkyl or C 3 - ⁇ o cycloalkenyl e.g. 3-7 cycloalkenyl groups.
  • Heterocycloaliphatic groups represented by R 6 include the cycloaliphatic groups just described for R 6 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups represented by L 4 , where L 4 is an atom or group as described above for L 1 .
  • R 6 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3- cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1 ,3-dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyl imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, 1 ,4- dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1 ,3,5-trithianyl, oxazinyl, e.g.
  • Optional substituents which may be present on R 6 cycloaliphatic and heterocycloaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, C ⁇ _6alkyl, e.g. methyl or ethyl, C-i- ⁇ alkoxy, e.g. methoxy or ethoxy or hydroxyl groups.
  • the heterocycloaliphatic groups may be attached to the remainder of the molecule of formula (1) through any appropriate ring carbon or heteroatom.
  • Aryl groups represented by the group R 6 include for example mono- or bicyclic C6- ⁇ 2 optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
  • Heteroaryl groups represented by R 6 include for example C1-9 optionally substituted heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the heteroaromatic groups may be for example monocyclic or bicyclic heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • heteroaryl groups represented by R 6 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1 ,3,5-triazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, isobenzofuryl, is
  • the aryl or heteroaryl groups represented by R 6 may be attached to the remainder of the molecule of formula (1) through any available ring carbon or nitrogen atom as appropriate.
  • Optional substituents present on the aryl or heteroaryl groups represented by R 6 include one, two, three or more aroms or groups as described generally above and specifically below in relation to the group R 5 . Where more than one substituent is present, these may be the same or different.
  • each R 6 atom or group may be the same or different and may be attached to the same or different atoms, particularly for example to form groups such as Alk 1 (R 6 2 )or -Alk 1 (R6) 3 .
  • substituents represented by R 1 , R 2 and/or R 3 in compounds of the invention include hydrogen and halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C-i- ⁇ alkyl, e.g. methyl or ethyl, haloC ⁇ _6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. -C(OH)(CF 3 ) 2 , C-
  • halogen atoms e.g. fluorine, chlorine, bromine or iodine atoms
  • C-i- ⁇ alkyl e.g. methyl or ethyl
  • haloC ⁇ _6alkyl
  • halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C ⁇ _ ⁇ alkylthio e -9- methylthio or ethylthio, or -(Alk 1 ) r R 6a groups in which Alk 1 is a straight or branched C ⁇ - 3 alkylene chain, r is zero or an integer 1 and R6 a is a -OH, -SH, -N(R )(R 8 ), -CN, -C0 2 R 7 , -NO 2 , -CON(R 7 )(R8), .
  • R 5 is present in compounds of formula (1) as a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
  • Alkyl groups represented by the groups R 5 in compounds of the invention include straight or branched C ⁇ -6alkyl groups as described above for the group R 6 .
  • Haloalkyl groups represented by R 5 include those alkyl groups just mentioned substituted by one, two or three halogen atoms, e.g. fluorine or chlorine atoms. Particular examples include -CH 2 F, -CHF and -CF 3 groups.
  • Alkoxy groups represented by R 5 include straight or branched C-i- ⁇ alkoxy groups, e.g. C ⁇ - 3 aikoxy groups such as methoxy or ethoxy groups.
  • Haloalkoxy groups represented by R 5 include those just mentioned alkoxy groups substituted by one, two or three halogen atoms, e.g. fluorine or chlorine atoms, particular examples include -OCH 2 F, -OCHF 2 and -OCF 3 groups.
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • each of W, X, Y and Z is preferably a C(R 5 ) group.
  • One particular group of compounds of this type has the formula (1 a):
  • R 1 , R 2 , R 3 , R 4 and R 5 are as generally and particularly defined herein for compounds of formula (1) and the salts, solvates, hydrates and N-oxides thereof.
  • R 4 is preferably a phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group optionally substituted by one or two R 4a substituents as defined herein. Especially preferred is when R 4 is substituted by one or two R 4a substituents.
  • R 4 is a substituted phenyl, 1-naphthyl or pyridyl group.
  • R 3 is in particular a hydrogen atom.
  • One particular class of compounds of this later type has the formula (1b):
  • R 2 , R 4 and R 5 are as generally and particularly defined herein for compounds of formula (1 );
  • R 1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1 ); and the salts, solvates, hydrates and N-oxides thereof.
  • R 2 , R 4 and R 5 are as generally and particularly defined herein for compounds of formula (1 );
  • R 1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1); and the salts, solvates, hydrates and N-oxides thereof.
  • R 5 is preferably a hydrogen atom.
  • R 7 and R 8 which may be the same or different, are preferably a hydrogen atom or an alkyl group. Particularly preferred R 1 substituents are -C0 2 H, -NO 2 or tetrazolyl groups.
  • R 4 in compounds of the invention is preferbaly substituted with one or two R 4a substituents selected from fluorine, chlorine, bromine or iodine atoms, or methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, -N(R 7 )(R 8 ), -CN, -C0 2 R 7 , -N0 2 , -CON(R )(R 8 ), -COR 7 - -S0 2 R 7 or -SC>2N(R 7 )(R8) groups.
  • R 7 and R 8 which may be the same or different, are preferably a hydrogen atom or an alkyl group.
  • R 4a substituents are fluorine, chlorine, bromine or iodine atoms, or methyl, ethyl, trifluoromethyl, -C0 2 C(CH 3 ) 3 , -CONH(CH 2 CH 3 ), or - CONH(C(CH 3 ) 2 ) groups.
  • One particular group of compounds of the invention includes:
  • Another particular group of compounds of the invention includes:
  • Compounds according to the invention are potent inhibitors of PDE7.
  • the ability of the compounds to act in this way may be simply determined by employing a test such as those described in the Examples hereinafter.
  • the compounds according to the invention are of particular use in the prophylaxis and treatment of diseases in which in which inhibition of PDE7 can have a therapeutic benefit for example in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, in transplant rejection, in graft v host disease, psoriasis, in pannus formation in rheumatoid arthritis, restenosis following angioplasty and atherosclerosis, in osteoporosis and in diseases in which cells receive pro-inflammatory signals such as asthma, inflammatory bowel disease, pancreatitis, chronic obstructive pulmonary disease, chronic bronchitis, atopic dermatitis and allergic rhinitis.
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus
  • transplant rejection in transplant rejection
  • graft v host disease psoriasis
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1 ) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non- aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1 ) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (1 ) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoro- methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoro- methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols R to R 9 , W, X, Y, Z, L , L 2 , L 3 , Alk 1 , r and s when used in the text and formulae are to be understood to represent those groups described above in relation to formula (1 ) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W.
  • deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • a compound of formula (1 ) may be prepared by coupling an acid of formula (2):
  • Active derivatives of acids of formula (2) include anhydrides, esters and acid halides, e.g. acid chorides, and may be obtained by standard procedures.
  • the coupling reaction may be performed using standard conditions for reactions of this type.
  • the reaction may be carried out with an active derivative of the acid of formula (2) in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or N,N- diisopropylethylamine, or a cyclic amine, such as pyridine or N- methylmorpholine, or a hydride, such as sodium hydride in an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon, such as dichloromethane or dichlorobenzene, at a low temperature, e.g. around -30°C to around ambient temperature.
  • a base e.g. an organic base such as an amine, e.g. triethylamine or N
  • the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as i-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxy- benzotriazole.
  • a condensing agent for example a diimide such as i-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide
  • a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxy- benzotriazole.
  • the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the ani
  • a compound of formula (1 ) may be prepared by reaction of a sulphonyl halide of formula (4):
  • Hal is a halogen atom such as a chlorine, bromine or iodine atom, with an amine of formula R 4 NH 2 in the presence of a base, for example an organic amine such as pyridine or triethylamine at or around ambient temperature.
  • a base for example an organic amine such as pyridine or triethylamine at or around ambient temperature.
  • the intermediate acids of formula (2) and sulphonyl halides of formula (4) may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions as described below and in the Examples hereinafter.
  • Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formula (1) where appropriate functional groups exist in these compounds.
  • a number of the intermediate anilines of formula (3) and amines R 4 NH 2 for use in the reactions described above are known, others can be derived therefrom using these standard synthetic methods.
  • compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation.
  • compounds containing a -L 1 H, -L 1 (Alk 1 ) r L 2 H or -Alk 1 L 2 H, group (where L 1 and L 2 is each a linker atom or group) may be treated with an alkylating agent (R 6 ) s L 2 Alk 1 X 1 or R 6 X 1 in which X 1 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethyl- sulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
  • R 6 alkylating agent
  • X 1 is a leaving
  • the reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydro- furan.
  • a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride
  • a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydro- fur
  • compounds containing a -L 1 H, -L 1 (Alk) r L 2 H or - Alk L 2 H group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X 1 is replaced by a -C(0)X 2 , C(S)X 2 , -N(R 6 )COX 2 or -N(R 6 )C(S)X 2 group in which X 2 is a leaving atom or group as described for X 1 .
  • the reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature.
  • a halogenated hydrocarbon e.g. dichloromethane or carbon tetrachloride
  • an amide e.g. dimethylformamide
  • the acylation or thioacylation may be carried out under the same conditions with an acid or thioacid (for example one of the alkylating agents described above in which X 1 is replaced by a -C0 2 H or -COSH group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclohexyl- carbodi-imide, advantageously in the presence of a catalyst such as a N- hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzo- triazole.
  • the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction.
  • compounds may be obtained by sulphonylation of a compound containing an -OH group by reaction with one of the above alkylating agents but in which X 1 is replaced by a -S(0)Hal or -S0 2 Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • a base for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • compounds containing a -L 1 H, -L 2 H or -L 3 H group as defined above may be coupled with one of the alkylation agents just described but in which X 1 is replaced by an -OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
  • ester groups -CO 2 R 7 in the compounds may be converted to the corresponding acid [-C0 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the group R 7 .
  • Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous ether or alcohol, e.g. an aqueous cyclic ether such as aqueous tetrahydrofuran or an aqueous alcohol such as aqueous methanol at an elevated temperature.
  • an organic or inorganic acid e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkal
  • -OR 7 groups [where R 7 represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • Alcohol [-OH] groups may also be obtained by hydrogenation of a corresponding -OCH 2 R 6 group (where R 6 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature.
  • -OH groups may be generated from the corresponding ester [-C0 2 R 7 ] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • alcohol -OH groups in the compounds may be converted to a corresponding -OR 7 group (where R 7 is an optionally substituted alkyl group) by coupling with a reagent R 7 OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazo- dicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazo- dicarboxylate.
  • Aminosulphonylamino [-NHSO2NH2] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [- NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
  • amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol
  • amine [-NH 2 ] groups in the compounds may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-NO2] group may be reduced to an amine [-NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • Catalytic hydrogenation is particularly useful for the preparation of intermediate amines of formula (3) from their corresponding nitro analogues.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around - 78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example, a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around - 78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • sulphur atoms in the compounds may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • Tetrazolyl groups in the compounds may be obtained by cycloaddition using a corresponding nitrile and an azide, e.g. sodium azide, optionally in the presence of a catalyst e.g. a Lewis acid such as aluminium chloride in an aprotic solvent such as dimethylformamide at an elevated temperature.
  • a catalyst e.g. a Lewis acid such as aluminium chloride in an aprotic solvent such as dimethylformamide at an elevated temperature.
  • N-oxides of compounds of formula (1 ) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1 ) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
  • a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
  • diastereomeric derivatives e.g. salts
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers of formula (1 ) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1 ) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Chromatography, recrystalliation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • 2-f3-(2-Methyl-5-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid A solution of 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) in dichloromethane (5ml) was treated with 3-amino-4- methylbenzotrifluoride (100mg) and pyridine (0.46ml). The mixture was stirred at room temperature for 12h and then diluted with dichloromethane (40ml). The organic solution was washed with 2M hydrochloric acid, dried (magnesium sulfate) and filtered.
  • PDE7 hydrolyses cAMP to 5'AMP, a linear nucleotide.
  • the assay used to determine this activity is based on the observation that linear nucleotides bind preferentially to SPA yttrium silicate beads, compared to cyclic nucleotides, in the presence of zinc sulphate.
  • the 5'AMP, the product therefore binds directly to the beads and cAMP does not.
  • the binding of the radiolabelled product to the bead brings it into close enough proximity to allow tritium to excite the scintillant in the bead.
  • the PDE7 assay was carried out using Amersham Pharmacia SPA technology (Amersham Pharmacia Biotech). The assay was buffered with 50mM Tris containing 8.3mM MgCI 2 and 1.7mM EGTA pH 7.5. Assay buffer, inhibitor, cAMP 0.029 ⁇ M, final) and 3 H-cAMP ( ⁇ 5nM, final concentration) were pipetted into a 96 well microtitre plate. The reaction was initiated with the addition of 20 ⁇ l of PDE7 enzyme [see Michaeli, T et al (1993) J. Biol. Chem. 268, 12925-12932] to give a final volume of 100 ⁇ l. The assay was incubated for 30 minutes at 30°C. The reaction was terminated by the addition of 50 ⁇ l SPA yttrium silicate beads. The plates were then sealed, mixed and counted on a Packard TopCount scintillation counter (Canberra Packard).
  • compounds according to the invention have IC50 values of around 10 ⁇ M and less, typically around 1 ⁇ M and less.

Description

SULPHONAMIDE DERIVATIVES
This invention relates to a series of sulphonamides, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
The cyclic nucleotides cAMP and cGMP are known to be responsible for the regulation of a variety of intracellular processes. The levels of these nucleotides are modulated by the stimulation of adenylate or guanylate cyclases and by the activity of phosphodiesterase enzymes. Phosphodiesterases (PDEs) specifically convert cyclic nucleotides to inactive analogues. Eleven PDE gene familes have been identified to date, based on substrate specificity and regulatory characteristics. PDE7 is a low KM CAMP specific enzyme which is insensitive to the standard
PDE4 inhibitor, rolipram. PDE7 is thought to play an important role in T cell activation [Beavo et al, Science (1999), 283: 848], which implies that inhibitors of PDE7 should have benefit in T cell mediated diseases. In addition, PDE7 has been detected in airway epithelial cells [Barnes et al, Am. J. Respir. Cell Mol. Biol. (1999) 20: 292] so inhibitors should be beneficial in diseases of the airway.
We have now found a series of sulphonamides which are potent and selective inhibitors of PDE7. The compounds are thus of use in the prophylaxis and treatment of diseases in which inhibition of PDE7 can have a therapeutic benefit.
Certain sulfonamide amide compounds are generally disclosed in International Specification No. WO-A-9938845 as modulators of PPARγ activity.
International Specification No. WO-A-9932433 also generally discloses certain sulfonamide amide compounds for use as inhibitors of 15- lipoxygenase. International Specification No. WO-A-0052144 specifically discloses the use of 3-(4-bromophenylsulfamoyl)-Λ/-(3-nitrophenyl)benzamide as an ecto-phosphatase inhibitory molecule.
Thus according to one aspect of the invention we provide a compound of formula (1 ):
Figure imgf000003_0001
(1 )
wherein
W, X, Y and Z which may be the same or different, each represents a nitrogen atom or a C(R5) group [in which R5 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO2 or -CN group] provided that two or more of W,X,Y and Z are C(R5) groups; R1, R2 and R3, which may be the same or different, each is an atom or group -L1(Alk1)rL2(R6)s in which L1 and L2, which may be the same or different, is each a covalent bond or a linker atom or group, r is zero or the integer 1 , Alk1 is an aliphatic or heteroaliphatic chain, s is an integer 1 , 2 or 3 and R6 is a hydrogen or halogen atom or a group selected from alkyl, -OR7 [where R7 is a hydrogen atom or an optionally substituted alkyl group], -SR7, -NR R8 [where R8 is as just defined for R7 and may be the same or different], -N02, -CN, -C02R7, -S03H, -S(0)R7, -SO2R7, - OCO2R7, -CONR R8, OCONR7R8, -CSNR7R8, -OCR7, -OCOR7, -N(R7)COR8, -N(R7)CSR8, -S(0)NR7R8, -S02NR7R8, -N(R7)S02R8, -N(R7)CON(R8)(R9) [where R9 is a hydrogen atom or an optionally substituted alkyl group], -N(R7)CSN(R8)R9), -N(R7)SO2N(R8)(R9),
-C(R7)=NO(R8), cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group]; provided that one or more of R\ R2 or R3 is a substituent other than a hydrogen atom; R4 represents an optionally substituted phenyl, 1- or 2- naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group; and the salts, solvates, hydrates and N-oxides thereof; provided that the compound of formula (1 ) is not 3-(4- bromophenylsulfamoyl)-Λ/-(3-nitrophenyl)benzamide.
Optional substituents present on groups represented by R4 include one, two, three or more groups, each represented by the group R4a, where R4a is a -L1(Alk1)rL2(R6)s group as generally defined above and more specifically described hereinafter provided that -L1 (Alk1 )rL2(R6)s does not represent -H. Where more than one R4a substituent is present, these may be the same or different.
In compounds of the invention, when a pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group represented by R4 is present it is linked to the remainder of the compound through any available carbon atom in the R4 ring.
When in the compound of formula (1 ) L1 and/or L2 is present as a linker atom or group in a substituent R1, R2, R3 and/or R4a, each L1 and/or L2 group may be for example an -O- or -S- atom or a -C(O)-, -C(S)-, -S(O)-, - S(0)2-, -N(R10)- [where R10 is a hydrogen atom or a Cι_6 alkyl, e.g. methyl or ethyl, group], -CON(R 0)-, -OC(0)N(R10)-, -CSN(R10)-, -N(R10)CO-, -N(R10)C(0)0-, -N(R °)CS-, -SON(R10)-, -S02N(R )-, -N(R 0)SO2-, -N(R10)CON(R10)-, -N(R10)CSN(R10)-, -N(R10)SON(R10)- or -N(R10)SO2N(R10)- group. Where the linker group contains two R10 substituents these may be the same or different.
When Alk1 is present in the compounds of the invention it may be a C1-10 aliphatic chain, for example a straight or branched chain C-ι-6alkylene, e.g. Cι-3alkylene, C2-6alkenylene, e.g. C2_4alkenylene, or C2-6alkynylene, e.g. C-2-4 alkynylene chain. Each of said chains may be optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by L3 [where L3 is an atom or group as just described for L1], to form an Alk1 heteroaliphatic chain.
Particular examples of aliphatic chains represented by Alk1 include -CH2-, -CH2CH2-, -(CH2)2CH2-, -CH(CH3)CH2-, -(CH2)3CH2-. -CH(CH3)CH2CH2-,
-CH2CH(CH3)CH2-, -C(CH3)2CH2-(CH2)4CH2-, -(CH2)5CH2-, -CHCH-, -CHCHCH2-, -CH2CHCH2-, -CHCH(CH2)2-, -CH2CHCHCH2-,
-(CH2)2CHCH2, -CC-, -CCCH2-, -CH2CC-, -CC(CH2)2-, -CH2CCCH2-, or -(CH2)2CC- chains. Where appropriate each of said groups may be optionally interrupted by one or two atoms and/or groups L3 to form a heteroaliphatic chain.
When the substituent R6 is present in compounds of formula (1 ) as a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
Alkyl groups represented by the group R6 include straight or branched C-i- 6 alkyl groups, e.g. Cι-3alkyl groups such as methyl or ethyl groups.
Optionally substituted alkyl groups represented by R7, R8 and/or R9 in compounds of the invention include those alkyl groups just mentioned for R6 optionally substituted by one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxy or C-|.3 alkoxy e.g. methoxy or ethoxy groups.
When R6 is present in compounds of formula (1 ) as a cycloaliphatic group it may be an optionally substituted C3_ιo cycloaliphatic group. Particular examples include optionally substituted C3-ιocycloalkyl, e.g. C3-7 cycloalkyl or C3-ιo cycloalkenyl e.g. 3-7 cycloalkenyl groups.
Heterocycloaliphatic groups represented by R6 include the cycloaliphatic groups just described for R6 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups represented by L4, where L4 is an atom or group as described above for L1.
Particular examples of R6 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3- cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1 ,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, 1 ,4- dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1 ,3,5-trithianyl, oxazinyl, e.g. 2H-1.3-, 6H-1.3-, 6H-1.2-, 2H-1 ,2- or 4H-1.4- oxazinyl, 1 ,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p- isoxazinyl, oxathiazinyl, e.g. 1 ,2,5 or 1 ,2,6-oxathiazinyl, or 1 ,3,5,2- oxadiazinyl groups.
Optional substituents which may be present on R6 cycloaliphatic and heterocycloaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, Cι_6alkyl, e.g. methyl or ethyl, C-i-βalkoxy, e.g. methoxy or ethoxy or hydroxyl groups. The heterocycloaliphatic groups may be attached to the remainder of the molecule of formula (1) through any appropriate ring carbon or heteroatom.
Aryl groups represented by the group R6 include for example mono- or bicyclic C6-ι2 optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
Heteroaryl groups represented by R6 include for example C1-9 optionally substituted heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaryl groups represented by R6 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1 ,3,5-triazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2- b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8- tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.
The aryl or heteroaryl groups represented by R6 may be attached to the remainder of the molecule of formula (1) through any available ring carbon or nitrogen atom as appropriate.
Optional substituents present on the aryl or heteroaryl groups represented by R6 include one, two, three or more aroms or groups as described generally above and specifically below in relation to the group R5. Where more than one substituent is present, these may be the same or different.
Where more than one atom or group R6 is present in -L1(Alk1)rL2(R6)s [i.e. where s is an integer two or three] it is understood that each R6 atom or group may be the same or different and may be attached to the same or different atoms, particularly for example to form groups such as Alk1(R6 2)or -Alk1(R6)3.
Particular examples of substituents represented by R1, R2 and/or R3 in compounds of the invention include hydrogen and halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C-i-βalkyl, e.g. methyl or ethyl, haloCι_6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. -C(OH)(CF3)2, C-|. βalkoxy, e.g. methoxy or ethoxy, haloCι_6alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, Cι_ βalkylthio e-9- methylthio or ethylthio, or -(Alk1)rR6a groups in which Alk1 is a straight or branched Cι-3alkylene chain, r is zero or an integer 1 and R6a is a -OH, -SH, -N(R )(R8), -CN, -C02R7, -NO2, -CON(R7)(R8), . CSN(R )(R8), -COR7, -N(R7)COR8, -N(R7)CSR8, -S02R7, -S02N(R7)(R8), -N(R7)S02R8, -N(R7)CON(R8)(R9), -N(R )CSN(R8), -N(R )S02N(R7)(R8), -C(R )=NO(R8) or optionally substituted cyclo- pentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, phenyl, phenoxy, benzyloxy, pyridyl, pyrimidinyl or tetrazolyl group. The same substituents, other than a hydrogen atom may be present as R4a atoms or groups in compounds of the invention.
When R5 is present in compounds of formula (1) as a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
Alkyl groups represented by the groups R5 in compounds of the invention include straight or branched Cι-6alkyl groups as described above for the group R6. Haloalkyl groups represented by R5 include those alkyl groups just mentioned substituted by one, two or three halogen atoms, e.g. fluorine or chlorine atoms. Particular examples include -CH2F, -CHF and -CF3 groups.
Alkoxy groups represented by R5 include straight or branched C-i-βalkoxy groups, e.g. Cι-3aikoxy groups such as methoxy or ethoxy groups. Haloalkoxy groups represented by R5 include those just mentioned alkoxy groups substituted by one, two or three halogen atoms, e.g. fluorine or chlorine atoms, particular examples include -OCH2F, -OCHF2 and -OCF3 groups.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that where compounds of formula (1 ) exist as geometrical isomers and/or exantiomers or diastereomers then the invention extends to all such isomers of the compounds of formula (1 ), and to mixtures thereof, including racemates.
In the compounds according to the invention, each of W, X, Y and Z is preferably a C(R5) group. One particular group of compounds of this type has the formula (1 a):
Figure imgf000009_0001
wherein R1, R2, R3, R4 and R5 are as generally and particularly defined herein for compounds of formula (1) and the salts, solvates, hydrates and N-oxides thereof.
In general in compounds of formulae (1) and (1a) R4 is preferably a phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group optionally substituted by one or two R4a substituents as defined herein. Especially preferred is when R4 is substituted by one or two R4a substituents. In one particular group of compounds of the invention R4 is a substituted phenyl, 1-naphthyl or pyridyl group. In compounds of this type and in general in compounds of the invention R3 is in particular a hydrogen atom. One particular class of compounds of this later type has the formula (1b):
Figure imgf000010_0001
wherein R2, R4 and R5 are as generally and particularly defined herein for compounds of formula (1 ); R1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1 ); and the salts, solvates, hydrates and N-oxides thereof.
Compounds of formula (1 b) in which R2 is a hydrogen atom form a further particular class of compound according to the invention. A further class of compounds according to the invention has the formula (1 b) in which R2 is a methoxy group.
Another particular class of compounds has the formula (1c):
Figure imgf000010_0002
wherein R2, R4 and R5 are as generally and particularly defined herein for compounds of formula (1 );
R1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1); and the salts, solvates, hydrates and N-oxides thereof.
Compounds of formula (1c) in which R2 is a hydrogen atom form a further particular class of compound according to the invention.
In compounds of the invention R5 is preferably a hydrogen atom. R1 in compounds of the invention is preferably a fluorine, chlorine, bromine or iodine atom, or a methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, -N(R7)(R8), -CN, -CO2R7, - N02l -CON(R7)(R8), -COR7- -SO2R > -S02N(R7)(R8), -C(R7)=NO(R8), pyridyl, or tetrazolyl group. R7 and R8, which may be the same or different, are preferably a hydrogen atom or an alkyl group. Particularly preferred R1 substituents are -C02H, -NO2 or tetrazolyl groups.
R4 in compounds of the invention is preferbaly substituted with one or two R4a substituents selected from fluorine, chlorine, bromine or iodine atoms, or methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, -N(R7)(R8), -CN, -C02R7, -N02, -CON(R )(R8), -COR7- -S02R7 or -SC>2N(R7)(R8) groups. R7 and R8, which may be the same or different, are preferably a hydrogen atom or an alkyl group. Especially preferred R4a substituents are fluorine, chlorine, bromine or iodine atoms, or methyl, ethyl, trifluoromethyl, -C02C(CH3)3, -CONH(CH2CH3), or - CONH(C(CH3)2) groups.
One particular group of compounds of the invention includes:
4-[3-(2-nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid
-erf-butyl ester;
4-[3-(2-nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid ethyl amide; 2-[3-(4-chloro-3-nitrophenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-chloro-2-methylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-bromo-5-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-chloro-4-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2,4-dimethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-bromophenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-bromo-2-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid; 2-[3-(2,4-dichlorophenylsulfamoyl)benzoylamino]benzoic acid; 2-[3-(2-chloro-4-methylphenylsulfamoyl)benzoylamino]benzoic acid; 2-[3-(4-chloronaphthalen-1-ylsulfamoyl)benzoylamino]benzoic acid; 2-[3-(4-ethylcarbamoyl-2-methylphenylsulfamoyl)benzoylamino] benzoic acid; 3-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid; and the salts, solvates, hydrates and N-oxides thereof.
Another particular group of compounds of the invention includes:
2-[3-(4-bromo-2-ethylphenylsulfamoyl)-benzoylamino]benzoic acid; 2-[3-(2-methyl-6-trifluoromethyl-pyridin-3-ylsulfamoyl)benzoylamino] benzoic acid;
2-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid;
2-({1-[3-(3-chlorophenylsulfamoyl)phenyl]methanoyl}amino)benzoic acid;
2-({1-[3-(4-trifluoromethylphenylsulfamoyl)phenyl]methanoyl}amino)- benzoic acid;
2-[3-(2-methyl-4-fluorophenylsulfamoyl)benzoylamino]benzoic acid;
5-methoxy-2-({1-[3-(4-trifluoromethylphenylsulfamoyl)-phenyl]- methanoyl}amino)benzoic acid;
2-[3-(2-methyl-5-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid; and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent inhibitors of PDE7. The ability of the compounds to act in this way may be simply determined by employing a test such as those described in the Examples hereinafter.
The compounds according to the invention are of particular use in the prophylaxis and treatment of diseases in which in which inhibition of PDE7 can have a therapeutic benefit for example in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, in transplant rejection, in graft v host disease, psoriasis, in pannus formation in rheumatoid arthritis, restenosis following angioplasty and atherosclerosis, in osteoporosis and in diseases in which cells receive pro-inflammatory signals such as asthma, inflammatory bowel disease, pancreatitis, chronic obstructive pulmonary disease, chronic bronchitis, atopic dermatitis and allergic rhinitis.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1 ) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non- aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds for formula (1 ) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1 ) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoro- methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R to R9, W, X, Y, Z, L , L2, L3, Alk1, r and s when used in the text and formulae are to be understood to represent those groups described above in relation to formula (1 ) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
Thus according to a further aspect of the invention, a compound of formula (1 ) may be prepared by coupling an acid of formula (2):
Figure imgf000015_0001
or an active derivative thereof with an aniline of formula (3):
Figure imgf000015_0002
or a salt thereof. Active derivatives of acids of formula (2) include anhydrides, esters and acid halides, e.g. acid chorides, and may be obtained by standard procedures.
The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out with an active derivative of the acid of formula (2) in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or N,N- diisopropylethylamine, or a cyclic amine, such as pyridine or N- methylmorpholine, or a hydride, such as sodium hydride in an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon, such as dichloromethane or dichlorobenzene, at a low temperature, e.g. around -30°C to around ambient temperature.
Where an acid of formula (2) is used, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as i-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxy- benzotriazole. Alternatively, the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the aniline of formula (3).
In a further process according to the invention, a compound of formula (1 ) may be prepared by reaction of a sulphonyl halide of formula (4):
Figure imgf000016_0001
Where Hal is a halogen atom such as a chlorine, bromine or iodine atom, with an amine of formula R4NH2 in the presence of a base, for example an organic amine such as pyridine or triethylamine at or around ambient temperature.
The intermediate acids of formula (2) and sulphonyl halides of formula (4) may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions as described below and in the Examples hereinafter. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formula (1) where appropriate functional groups exist in these compounds. Additionally, although a number of the intermediate anilines of formula (3) and amines R4NH2 for use in the reactions described above are known, others can be derived therefrom using these standard synthetic methods.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a -L1H, -L1 (Alk1 )rL2H or -Alk1L2H, group (where L1 and L2 is each a linker atom or group) may be treated with an alkylating agent (R6)sL2Alk1X1 or R6X1 in which X1 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethyl- sulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydro- furan.
In another example, compounds containing a -L1H, -L1(Alk)rL2H or - Alk L2H group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X1 is replaced by a -C(0)X2, C(S)X2, -N(R6)COX2 or -N(R6)C(S)X2 group in which X2 is a leaving atom or group as described for X1. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methyl-morpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature. Alternatively, the acylation or thioacylation may be carried out under the same conditions with an acid or thioacid (for example one of the alkylating agents described above in which X1 is replaced by a -C02H or -COSH group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclohexyl- carbodi-imide, advantageously in the presence of a catalyst such as a N- hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzo- triazole. Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction.
In a further example compounds may be obtained by sulphonylation of a compound containing an -OH group by reaction with one of the above alkylating agents but in which X1 is replaced by a -S(0)Hal or -S02Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a -L1H, -L2H or -L3H group as defined above may be coupled with one of the alkylation agents just described but in which X1 is replaced by an -OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
In a further example, ester groups -CO2R7 in the compounds may be converted to the corresponding acid [-C02H] by acid- or base-catalysed hydrolysis depending on the nature of the group R7. Acid- or base- catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous ether or alcohol, e.g. an aqueous cyclic ether such as aqueous tetrahydrofuran or an aqueous alcohol such as aqueous methanol at an elevated temperature.
In a further example, -OR7 groups [where R7 represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
Alcohol [-OH] groups may also be obtained by hydrogenation of a corresponding -OCH2R6 group (where R6 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, -OH groups may be generated from the corresponding ester [-C02R7] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol -OH groups in the compounds may be converted to a corresponding -OR7 group (where R7 is an optionally substituted alkyl group) by coupling with a reagent R7OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazo- dicarboxylate.
Aminosulphonylamino [-NHSO2NH2] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [- NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature. In a further example amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [-NH2] groups in the compounds may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [-NO2] group may be reduced to an amine [-NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid. Catalytic hydrogenation is particularly useful for the preparation of intermediate amines of formula (3) from their corresponding nitro analogues.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around - 78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1, L2 or L3 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
Tetrazolyl groups in the compounds may be obtained by cycloaddition using a corresponding nitrile and an azide, e.g. sodium azide, optionally in the presence of a catalyst e.g. a Lewis acid such as aluminium chloride in an aprotic solvent such as dimethylformamide at an elevated temperature.
N-oxides of compounds of formula (1 ) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1 ) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1 ) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1 ) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1 ) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystalliation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention.
All temperatures are in °C.
The following abbreviations are used:
TLC - thin layer chomatography; DMF - N, Λ/-dimethylformamide
INTERMEDIATE 1
3-(2-Nitrophenylcarbamoyl)benzenesulfonyl chloride
A mixture of 3-(chlorosulfonyl)benzoyl chloride (1.0g), 2-nitroaniline
(0.58g) and pyridine (0.68ml) in dichloromethane (20ml) was stirred under an atmosphere of nitrogen for 4.5h. The mixture was diluted with dichloromethane (30ml), washed with 2N hydrochloric acid (100ml), dried
(magnesium sulfate) and the solvent removed in vacuo to give the title compound (1.41g) as a yellow solid.
TLC Rf 0.65 (50% ethyl acetate in hexane)
The following compound was prepared by a similar procedure.
INTERMEDIATE 2 2-(3-Chlorosulfonylbenzoylamino)benzoic acid methyl ester Prepared from 3-(chlorosulphonyl)benzoyl chloride (2.0g) and methyl anthranilate (1.3g) to give the title compound (1.9g) as a white solid. TLC Rf 0.7 (50% ethyl acetate in hexane) INTERMEDIATE 3 3-(4-Chlorophenylsulfamoyl)benzoic acid A mixture of 3-(chlorosulfonyl)benzoic acid (500mg), 4-chloroaniline (304mg) and pyridine (0.92ml) in dichloromethane (30ml) was stirred overnight at room temperature under an atmosphere of nitrogen. The mixture was diluted with dichloromethane (30ml) and washed with 2N hydrochloric acid (100ml) and water (80ml). Methanol (10ml) was added to the dichloromethane and the organic layer dried (magnesium sulfate). The solvent was removed in vacuo and the residue purified by wet flash chromatography on silica eluting with 50% ethyl acetate in hexane then ethyl acetate to give the title compound (257mg) as a white solid. TLC Rf 0.40 (ethyl acetate)
The following compound was prepared by a similar procedure.
INTERMEDIATE 4 3-(4-Trifluoromethylphenylsulfamoyl)benzoic acid
Prepared from 3-(chlorosulfonyl)benzoic acid (4.11g) and 4- aminobenzotrifluoride (2.94g) to give the title compound (5.02g) as a white solid.
Η NMR (200MHZ, d6-DMSO) δ 13.55 (1 H, bs), 11.00 (1 H, s), 8.34 (1 H, s), 8.17 (1H, d), 8.05 (1H, d), 7.49-7.78 (3H, m), 7.30 (2H, d). INTERMEDIATE 5 1 -(4-Amino-3-methylphenyl)-1 -morpholin-4-yl-methanone
To a solution of 1-(3-methyl-4-nitrophenyl)-1-morpholin-4-yl-methanone (0.66g) in ethanol (30ml) was added 10% palladium on carbon (60mg) and the mixture stirred under an atmosphere of hydrogen for 2.5h. The reaction mixture was filtered through a Celite® pad and washed through with ethanol. The filtrate was concentrated in vacuo and evaporated in vacuo from hexane twice more to furnish the title compound (0.54g) as a pale pink solid.
1H NMR (200MHz, d6-DMSO) δ 7.22 (1 H, s), 7.15 (1 H, d), 6.66 (1 H, d), 3.60-4.00 (10H, m), 2.20 (3H, s).
EXAMPLE 1
2-[3-(4-Chloro-3-nitrophenylsulfamoyl)benzoylamino]benzoic acid methyl ester
A solution of 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (0.20g) in dichloromethane (20ml) was stirred at room temperature. 4- Chloro-3-nitroaniline (0.12g) was added followed by pyridine (0.08ml) and the resulting mixture stirred overnight. The mixture was diluted with dichloromethane (20ml), washed with 2N hydrochloric acid (40ml), dried (magnesium sulfate) and the solvent removed in vacuo to give the title compound (0.31 g) as a yellow foam. TLC Rf 0.52 (50% ethyl acetate in hexane)
The following compounds were prepared in a similar manner.
EXAMPLE 2
2-[3-(4-Chloro-2-methylphenylsulfamoyl)benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(0.1 Og) and 4-chloro-2-methylaniline (0.048g) to give the title compound (0.10g) as a pink solid.
TLC Rf 0.73 (50% ethyl acetate in hexane)
EXAMPLE 3
2-[3-(2-Bromo-5-trifluoromethylphenylsulfamoyl)benzoylamino]- benzoic acid methyl ester Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(0.1 Og) and 2-bromo-5-(trifluoromethyl)aniline (0.14g) to give the title compound (0.13g) as a pink solid.
TLC Rf 0.65 (50% ethyl acetate in hexane)
EXAMPLE 4 2-[3-(2-Chloro-4-trifluoromethylphenylsulfamoyl)benzoylamino]- benzoic acid methyl ester
Prepared from 2-(3-chlorosuifonylbenzoylamino)benzoic acid methyl ester
(0.10g) and 4-amino-3-chlorobenzotrifluoride (0.11g) to give the title compound (0.13g) as a pink solid (0.13g). TLC Rf 0.62 (50% ethyl acetate in hexane)
EXAMPLE 5
2-[3-(2,4-Dimethylphenylsulfamoyl)benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) and 2,4-dimethylaniline (0.07ml) to give the title compound
(79mg) as a pink solid.
TLC Rf 0.41 (33% ethyl acetate in hexane)
EXAMPLE 6
2-[3-(4-Bromophenylsulfamoyl)benzoylamino]benzoic acid methyl ester Prepared from 2-(3-chlorosuIfonylbenzoylamino)benzoic acid methyl ester
(100mg) and 4-bromoaniline (50mg) to give the title compound (55mg) as a pink solid.
TLC Rf 0.50 (diethyl ether) EXAMPLE 7
2-[3-(4-Bromo-2-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(0.35g) and 2-amino-5-bromobenzotrifluoride (0.24g) to give the title compound (0.40g) as a gummy white solid.
TLC Rf 0.54 (diethyl ether)
EXAMPLE 8
2-[3-(2,4-Dichlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(0.35g) and 2,4-dichloroaniline (0.16g) to give the title compound (0.46g) as a white solid.
TLC Rf 0.45 (diethyl ether)
EXAMPLE 9 2-[3-(2-Chloro-4-methylphenylsulfamoyl)benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosuIfonylbenzoylamino)benzoic acid methyl ester
(0.35g) and 2-chloro-4-methylaniline (0.12ml) to give the title compound
(0.48g) as a white solid. TLC Rf 0.53 (diethyl ether)
EXAMPLE 10
2-[3-(4-Chloronaphthalen-1-ylsulfamoyl)benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (0.35g) and 1-amino-4-chloronaphthalene (0.18g) to give the title compound (0.45g) as a white solid.
TLC Rf 0.50 (diethyl ether)
EXAMPLE 11
2-[3-(4-Hydroxycarbonyl-2-methylphenylsulfamoyl)benzoylamino] benzoic acid methyl ester Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(2.0g) and 4-amino-3-methylbenzoic acid (0.85g) to give the title compound (0.20g) as a white solid.
TLC Rf 0.50 (ethyl acetate) EXAMPLE 12
2-[3-(4-Bromo-2-ethylphenylsulfamoyl)-benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(117mg) and 4-bromo-2-ethylaniline (66mg) to provide the title compound (165mg) as a red-brown solid.
TLC Rf 0.5 (50% ethyl acetate in hexane)
MS (ESI+) 517, 519 (M+1)
EXAMPLE 13
2-{3-[2-Methyl-4-(morpholine-4-carbonyl)phenylsulfamoyl] benzoylamino}benzoic acid methyl ester
Prepared from 1 -(4-amino-3-methylphenyl)-1 -morpholin-4-yl-methanone
(48mg) and 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester
(77mg) to afford the title compound (98mg) as an off-white solid.
TLC Rf 0.5 (50% ethyl acetate in hexane) 1H NMR (200MHz, CDCI3) δ 12.20 (1H, s), 8.85 (1 H, d), 8.52 (1H, d), 8.23 (1H, d), 8.13 (1H, d), 8.00 (1 H, d), 7.59-7.70 (2H, m), 7.28-7.37 (2H, m), 7.10-7.22 (3H, m), 4.00 (3H, s), 3.10-3.90 (8H, m), 2.10 (3H, s). EXAMPLE 14 2-[3-(2-Methyl-6-trifluoromethylpyridin-3-ylsulfamoyl)benzoylamino]- benzoic acid methyl ester
Prepared from 3-amino-2-methyl-6-trifluoromethylpyridine (75mg) and 2- (3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (150mg) to give the title compound (113mg) as a white foam. TLC Rf 0.6 (50% ethyl acetate in hexane) 1H NMR (200MHz, CDCI3) δ 12.24 (1 H, s), 8.88 (1 H, d), 8.52 (1 H, s), 8.30
(1H, d), 8.13 (1 H, dd), 7.90-8.05 (2H, m), 7.61-7.75 (2H, m), 7.55 (1 H, d),
7.20 (1 H, t), 7.10 (1 H, s), 4.02 (3H, s), 2.48 (3H, s).
EXAMPLE 15
2-[3-(4-Chlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (200mg) and 4-chloroaniIine (140mg) to give the title compound (52mg) as a white solid. TLC Rf 0.6 (50% ethyl acetate in hexane) 1H NMR (400MHz, CDCI3) δ 12.15 (1 H, s), 8.79 (1H, d), 8.61 (1H, s), 8.18 (1 H, d), 8.07 (1H, d), 7.92 (1H, d), 7.86 (1H, s), 7.55-7.62 (2H, m), 7.10- 7.20 (5H, m).
EXAMPLE 16 2-[3-(2-Methyl-4-fluorophenylsulfamoyl)-benzoylamino]benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) and 4-fluoro-2-methylaniline (39mg). The residue was purified by column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound (110mg) as an off-white solid. Rf 0.4 (50% ethyl acetate in hexane) MS 443 (M+H)
1H NMR (200MHz, CDCI3) δ 2.10 (s, 3H), 4.00 (s, 3H), 6.70 (s, 1 H), 6.65-
6.90 (m, 2H), 7.10-7.25 (m, 2H), 7.60 (t, 2H), 7.85 (d, 1H), 8.10 (d, 1 H), 8.20 (d, 1 H), 8.55 (s, 1 H), 8.90 (d, 1 H), 12.30 (s, 1 H).
EXAMPLE 17
2-({1-[3-(4-Trifluoromethylphenylsulfamoyl)phenyl]methanoyl> amino)benzoic acid methyl ester
Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) and 4-aminobenzotrifluoride (91 mg) to yield the title compound
(120mg) as an off-white solid.
Rf 0.62 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 3.85 (s, 3H), 7.20-7.40 (m, 3H), 7.55-7.70 (m, 3H), 7.80 (t, 1 H), 7.95-8.10 (m, 2H), 8.20 (d, 1 H), 8.30-8.50 (m, 2H), 11.10 (s, 1 H), 11.50 (s, 1H). EXAMPLE 18
2-({1-[3-(3-Chloropheny.sulfamoyl)pheny.]methanoyl}amino)benzoic acid methyl ester Prepared from 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) and 3-chloroaniline (36mg) to yield the title compound (41 mg) as an off white solid. MS 445 (M+H) H NMR (200MHz, CDCI3) δ 3.95 (s, 3H), 7.00-7.20 (m, 5H), 7.55-7.65 (m, 2H), 8.00 (d, 1 H), 8.10 (d, 1H), 8.65 (s, 1 H), 8.80-8.85 (m, 2H), 12.20 (s, 1 H).
EXAMPLE 19 2-[3-(4-Ethylcarbamoyl-2-methylphenylsulfamoyl)benzoylamino]- benzoic acid methyl ester
A solution of 2-[3-(4-hydroxycarbonyl-2-methylphenylsulfamoyl)benzoyl- amino]benzoic acid methyl ester (40mg) in dichloromethane (5ml) was stirred at room temperature. 1 -(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (20mg) was added followed by ethylamine (2M solution in tetrahydrofuran, 0.05ml) and the resulting mixture stirred overnight. Washing with water (20ml) and saturated sodium bicarbonate solution (20ml), drying (magnesium sulfate) and removal of the solvent in vacuo gave a yellow solid. Purification by wet flash chromatography on silica eluting with diethyl ether gave the title compound (30mg) as a white solid. TLC Rf 0.20 (diethyl ether) EXAMPLE 20
3-[3-(4-Chlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester A mixture of 3-(4-chlorophenylsulfamoyl)benzoic acid (100mg), methyl 3- aminobenzoate (48mg) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (92mg) in dichloromethane (15ml) was stirred at room temperature under an atmosphere of nitrogen for 3.5h. Wet flash chromatography on silica eluting with 50% ethyl acetate in hexane followed by washing with 2N hydrochloric acid (100ml) and brine (80ml), drying (magnesium sulfate) and removal of the solvent in vacuo gave the title compound (100mg) as a white solid. TLC Rf 0.53 (50% ethyl acetate in hexane)
The following compound was prepared by a similar procedure. EXAMPLE 21
2-Chloro-3-({1-[3-(4-trifluoromethylphenylsulfamoyl) phenyl]methanoy.}amino)benzoic acid methyl ester Prepared from 3-(4-trifluoromethyl-phenylsulfamoyl)benzoic acid (100mg) and 2-chloro-3-aminobenzoic acid methyl ester (55mg) to afford the title compound (10mg) as a solid. TLC Rf 0.5 (50% ethyl acetate in hexane) MS (ES|-) 511 (M-1) EXAMPLE 22
3-(4-Chlorophenylsulfamoyl)-/V-(2-cyanophenyl)benzamide A suspension of 3-(4-chlorophenylsulfamoyl)benzoic acid (0.75g), in dichloromethane (100ml) was stirred at room temperature under an atmosphere of nitrogen. Oxalyl chloride (0.32ml) was added followed by 2 drops of DMF. The mixture was stirred for 2h before removal of the solvent in vacuo. Co-evaporation from hexane removed excess oxalyl chloride. The resulting residue was dissolved in dichloromethane (100ml); anthranilonitrile (0.34g) was added followed by pyridine (0.25ml). After stirring overnight the mixture was washed with 1 N hydrochloric acid (2 x 50ml) and saturated sodium hydrogencarbonate solution (2 x 50ml), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by wet flash chromatography on silica eluting with 10% ethyl acetate in dichloromethane gave the title compound (0.31 g) as a white solid. TLC Rf 0.45 (50% ethyl acetate in hexane) EXAMPLE 23
4-[3-(2-Nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid ferf-butyl ester
A solution of 3-(2-nitrophenylcarbamoyl)benzenesulfonyl chloride (250mg) in dichloromethane (15ml) was stirred at room temperature under an atmosphere of nitrogen. Te/ -butyl-4-aminobenzoate (149mg) was added, followed by pyridine (0.09ml) and the reaction left to stir for 48h. The mixture was diluted with dichoromethane (30ml), washed with 2N hydrochloric acid (80ml) and saturated sodim hydrogencarbonate solution (80ml), dried (magnesium sulfate) and the solvent removed in vacuo to give a yellow solid. Purification by wet flash chromatography on silica eluting with 33% hexane in ethyl acetate gave the title compound (172mg) as a yellow solid.
1H NMR (200MHz, d6-DMSO) δ 11.00-10.95 (2H, m), 8.40 (1 H, s), 8.20 (1H, d), 8.10-8.00 (2H, m), 7.85-7.70 (5H, m), 7.50-7.40 (1H, m), 7.25 (2H, d), 1.50 (9H, s)
TLC Rf 0.37 (33% ethyl acetate in hexane) EXAMPLE 24
4-[3-(2-Nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid A solution of 4-[3-(2-nitrophenyIcarbamoyl)benzenesulfonylamino]- benzoic acid terf-butyl ester (160mg) in a mixture of trifluoroacetic acid (2ml) and dichloromethane (10ml) was stirred at room temperature under an atmosphere of nitrogen for 50 minutes before removal of the solvent in vacuo. Co-evaporation from toluene to remove excess trifluoroacetic acid gave the title compound (139mg) as a yellow solid. 1H NMR (200MHz, d6-DMSO) δ 12.85-12.60 (1 H, b), 11.00 (2H, s), 8.45 (1 H, s), 8.20 (1 H, d), 8.10-8.00 (2H, m), 7.90-7.70 (5H, m), 7.55-7.45 (1H, m), 7.25 (2H, d) TLC Rf 0.62 (ethyl acetate) EXAMPLE 25 4-[3-(2-Nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid ethyl amide
A mixture of 4-[3-(2-nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid (132mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86mg) and ethylamine (2.0M solution in tetrahydrofuran, 0.38ml) in dichloromethane (15ml) was stirred overnight at room temperature under an atmosphere of nitrogen. The mixture was diluted with 5% methanol in dichloromethane (20ml), washed with water (60ml) and 1 N hydrochloric acid (60ml), dried (magnesium sulfate) and the solvent removed in vacuo to leave a yellow residue. Trituration with diethyl ether then purification by wet flash chromatography on silica eluting with ethyl acetate gave the title compound (19mg) as a yellow solid.
1H NMR (200MHz, d6-DMSO) δ 11.00 (1 H, s), 10.80 (1 H, s), 8.40 (1 H, s), 8.35 (1 H, t), 8.20 (1 H, d), 8.05 -7.95 (2H, m), 7.85-7.65 (5H, m), 7.45 (1 H, m), 7.15 (2H, d), 3.30-3.15 (2H, m), 1.05 (3H, t) TLC Rf 0.62 (ethyl acetate) EXAMPLE 26 2-[3-(4-Chloro-3-nitrophenylsulfamoyl)benzoylamino]benzoic acid
A suspension of 2-[3-(4~chloro-3-nitrophenylsulfamoyl)benzoylamino]- benzoic acid methyl ester (0.30g) in 50% aqueous tetrahydrofuran (20ml) was stirred at room temperature. Lithium hydroxide (0.13g) was added and the resulting mixture stirred overnight. The tetrahydrofuran was removed in vacuo, the residual aqueous portion was acidified with 2N hydrochloric acid and extracted with dichloromethane (3 x 20ml). The combined organic extracts were dried (magnesium sulfate) and the solvent removed in vacuo. Trituration with ether gave the title compound (0.15g) as an off-white solid.
1H NMR (200MHz, d6-DMSO) δ 8.65 (1 H, d), 8.45 (1 H, s), 8.20 (1 H, d), 8.10-8.00 (2H, m), 7.90-7.60 (4H, m), 7.40 (1 H, dd), 7.25 (1 H, t), TLC Rf 0.3 (50% ethyl acetate in hexane)
The following compounds were prepared in a similar manner.
EXAMPLE 27 2-[3-(4-Chloro-2-methylphenylsulfamoyl)benzoylamino]benzoic acid
Prepared from 2-[3-(4-chloro-2-methylphenylsulfamoyl)benzoylamino]- benzoic acid methyl ester (93mg) to give the title compound (35mg) as a white solid.
1H NMR (200MHz, d6-DMSO) δ 8.65 (1 H, d), 8.30 (1 H, s), 8.20 (1H, dm), 8.05 (1 H, dt), 7. 90 -7. 75 (2H, m), 7.70 (1 H, dt), 7.30-7.10 (3H, m), 7.00
(1H, d)
TLC Rf 0.6 (ethyl acetate)
EXAMPLE 28
2-[3-(2-Bromo-5-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid
Prepared from 2-[3-(2-bromo-5-trifluoromethylphenylsulfamoyl)benzoyl- aminojbenzoic acid methyl ester (0.14g) to give the title compound (0.12g) as a white solid. 1H NMR (200MHz, d6-DMSO) δ 8.65 (1 H, d), 8.30 (1 H, s), 8.20 (1 H, d), 8.10 (1 H, d), 7.95-7.80 (3H, m), 7.70 (1 H, dt), 7.55 (1 H, dd), 7.45 (1 H, d), 7.35 (1 H, dt)
TLC Rf 0.4 (50% ethyl acetate in hexane) EXAMPLE 29
2-[3-(2-Chloro-4-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid
Prepared from 2-[3-(2-chloro-4-trifluoromethylphenylsulfamoyl)benzoyl- amino]-benzoic acid methyl ester (120mg) to give the title compound (61 mg) as an off white solid.
1HMR (200MHz, d6-DMSO) δ 8.65 (1 H, d), 8.40 (1 H, s), 8.35 (1 H, d), 8.00- 8.15 (2H, m), 7.00-7.90 (2H, m), 7.75-7.65 (2H, m), 7.55 (1H, d), 7.25 (1H, dt)
TLC Rf 0.70 (ethyl acetate) EXAMPLE 30
2-[3-(2,4-Dimethylphenylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(2,4-dimethylphenylsulfamoyl)benzoylamino]benzoic acid methyl ester (72mg) to give the title compound (57mg) as an off white solid. 1H NMR (200MHz, d6-DMSO) δ 12.45 (1 H, b), 9.65 (1 H, s), 8.65 (1 H, d), 8.30 (1 H, s), 8.20 (1 H, dd), 8.05 (1 H, dd), 7.90-7.75 (2H, m), 7.70 (1 H,dt), 7.25 (1 H, t), 6.95 (1H, d), 6.90 (1 H, dd), 6.80 (1 H, d) TLC Rf 0.4 (50% ethyl acetate in hexane) EXAMPLE 31 2-[3-(4-Bromophenylsulfamoyl)benzoylamino]benzoic acid
Prepared from 2-[3-(4-bromophenylsulfamoyl)benzoylamino]benzoic acid methyl ester (50mg) to give the title compound (45mg) as a white solid.
1H NMR (200MHz, CDCI3) δ 12.55 (1 H, s), 9.70 (1 H, s), 9.85 (1 H, d), 8.55 (1H, s), 8.20-8.10 (2H, m), 7.85 (1H, d), 7.60-7.45 (2H, m), 7.35-7.25 (2H, m), 7.15-7.00 (3H. m)
TLC Rf 0.33 (diethyl ether) EXAMPLE 32
2-[3-(4-Bromo-2-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid Prepared from 2-[3-(4-bromo-2-trifluoromethylphenylsulfamoyl)- benzoylaminojbenzoic acid methyl ester_(0.58g) to give the title compound (0.45g) as a white solid.
1H NMR (200MHz, CDCI3) δ 12.55 (1 H, s), 8.85 (1 H, d), 8.55 (1 H, s), 8.25 (1 H, dd), 8.15 (1 H, dd), 7.90 (1 H, dd), 7.65-7.50 (5H, m), 7.10 (1 H, dt) MS (El") 542 (M - H). EXAMPLE 33
2-[3-(2,4-Dichlorophenylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(2,4-dichlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester (0.46g) to give the title compound (0.40g) as a white solid.
1H NMR (200MHz, CDCI3) δ 12.15 (1 H, s), 8.90 (1 H, d), 8.50 (1 H, s), 8.30 (1 H, dd), 8.30 (1 H, dd), 7.90 (1 H, dd), 7.75-7.60 (3H, m), 7.35 (1 H, s), 7.30-7.15 (3H, m) MS (El") 463,465 (M - H) EXAMPLE 34
2-[3-(2-Chloro-4-methylphenylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(2-chloro-4-methylphenylsulfamoyl)benzoylamino]- benzoic acid methyl ester (0.44g) to give the title compound (0.38g) as a white solid.
1H NMR (200MHz, CDCI3) δ 12.55 (1 H, s), 8.80 (1H, d), 8.45 (1 H, d), 8.20 (1 H, dd), 8.10 (1 H, dd), 7.85-7.75 (2H, m), 7.60-7.40 (3H, m), 7.10 (1 H, dt), 7.00 -6.95 (2H, m) MS (El") 443, 445(M - H) EXAMPLE 35
2-[3-(4-Chloronaphthalen-1-ylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(4-chloronaphthalen-1 -ylsulfamoyl)benzoylamino]- benzoic acid methyl ester (0.40g) to give the title compound (0.35g) as a white solid. 1H NMR (200MHz, d6-DMSO) δ 12.25 (1 H, b), 10.60 (1 H, b), 8.85 (1 H, dd), 8.60 (1 H, d), 8.40 (1 H, dd), 8.30 (1 H, d), 8.15 (1 H, dd), 8.05 (1 H, dd), 7.90-7.80 (2H, m), 7.75. -7.60 (3H, m), 7.45 (1 H, dd), 7.30-7.20 (2H, m) TLC Rf 0.4 (diethyl ether) EXAMPLE 36 2-[3-(4-Ethylcarbamoyl-2-methylphenylsulfamoyl)benzoylamino1 benzoic acid
Prepared from 2-[3-(4-ethylcarbamoyl-2-methylphenylsulfamoyl)benzoyl- amino]benzoic acid methyl ester (30mg) to give the title compound (25mg) as a white solid. 1H NMR (400MHz, d6-DMSO) δ 12.40 (1 H, b), 9.65 (1 H, dd), 8.35-8.30 (2H, d), 8.20 (1 H, dd), 8.05 (1 H, dd), 7.90 (1 H, dd), 7.80 (1H, dt), 7.70 (1 H, dt), 7.55 (1 H, dd), 7.20 (1 H, dt), 7.10 (1 H, d) TLC Rf 0.15 (diethyl ether) EXAMPLE 37 3-[3-(4-Chlorophenylsulfamoyl)benzoylamino]benzoic acid
Prepared from 3-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester (92mg) to give the title compound (53mg) as a white solid.
1H NMR (200MHz, d6-DMSO) δ 10.70 (1 H, s), 8.40 (2H, s), 8.25 (1 H, d),
8.05 (1 H, d), 7.95 (1 H, d), 7.80-7.70 (2H, m), 7.5 (1 H, t), 7.30 (2H, d), 7.15 (2H, d)
TLC Rf 0.3 (50% ethyl acetate in hexane)
EXAMPLE 38
2-[3-(4-Bromo-2-ethylphenylsulfamoyl)benzoylamino]benzoic acid
Prepared from 2-[3-(4-bromo-2-ethyl-phenylsulfamoyl)-benzoylamino]- benzoic acid methyl ester (145mg) to provide the title compound (75mg) as an off-white solid.
TLC Rf 0.5 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 8.64 (1 H, d), 8.37 (1 H, s), 8.25 (1 H, d),
8.05 (1 H, d), 7.69-7.85 (2H, m), 7.22-7.40 (3H, m), 7.02 (1 H, t), 6.83 (1 H, d), 2.50 (2H, q), 0.94 (3H, t).
EXAMPLE 39
2-{3-[2-Methyl-4-(morρholine- -carbonyl)phenylsulfamoyl3 benzoylamino}benzoic acid
Prepared from 2-{3-[2-methyl-4-(morpholine-4- carbonyl)phenylsulfamoyl]benzoylamino}-benzoic acid methyl ester
(80mg) to give the title compound (25mg) as a white solid.
MS (ESI+) 524 (M+1)
1H NMR (400MHz, d6-DMSO) δ 12.35 (1H, bs), 9.95 (1H, s), 8.62 (1 H, d), 8.25 (1 H, s), 8.21 (1 H, d), 8.07 (1 H, d), 7.95 (1 H, d), 7.82 (1 H, t), 7.68 (1H, t), 7.14-7.27 (3H, m), 7.05 (1 H, d), 6.58 (1 H, bs), 3.15-3.65 (8H, m), 2.03 (3H, s). EXAMPLE 40
2-[3-(2-Methyl-6-trifluoromethyl-pyridin-3-ylsulfamoyl)benzoylamino] benzoic acid
Prepared from 2-[3-(2-methyl-6-trifluoromethyl-pyridin-3-ylsulfamoyl)- benzoylamino]benzoic acid methyl ester (55mg) to provide the title compound (40mg) as a white solid. TLC Rf 0.25 (50% ethyl acetate in hexane) Η NMR (200MHz, d6-DMSO) δ 12.30 (1 H, s), 8.62 (1 H, d), 8.36 (1 H, s),
8.24 (1 H, d), 7.94-8.10 (2H, m), 7.63-7.89 (4H, m), 7.25 (1 H, t), 2.31 (3H, s).
EXAMPLE 41
2-[3-(4-Chlorophenylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid methyl ester (200mg) to provide the title compound (80mg) as a white solid.
TLC Rf 0.53 (ethyl acetate)
1H NMR (400MHz, d6-DMSO) δ 13.92 (1 H, bs), 12.33 (1 H, bs), 10.65 (1 H, s), 8.64 (1 H, dd), 8.39 (1 H, s), 8.19 (1H, d), 8.08 (1 H, d), 7.97 (1 H, d),
7.80 (1H, t), 7.69 (1 H, t), 7.33 (2H, d), 7.25 (1 H, t), 7.15 (2H, d).
EXAMPLE 42
2-({1-[3-(3-Chlorophenylsulfamoyl)phenyl]methanoyl}amino)benzoic acid Prepared from 2-({1 -[3-(3-chloro-phenylsulfamoyl)-phenyl]-methanoyl}- amino)-benzoic acid methyl ester (41 mg) to yield the title compound
(20mg) as an off white solid.
Rf 0.14 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 7.00-7.20 (m, 5H), 7.55-7.65 (m, 2H), 7.90 (d, 1 H), 8.05-8.25 (m, 1 H), 8.65 (s, 1 H), 8.80-8.85 (m, 2H). EXAMPLE 43
2-({1-[3-(4-Trifluoromethylphenylsulfamoyl)phenyl]methanoyl> amino)benzoic acid Prepared from 2-({1 -[3-(4-trifluoromethyl-phenylsulfamoyl)-phenyl]- methanoyl}-amino)-benzoic acid methyl ester (120mg) to yield the title compound (110mg) as an off-white solid. Rf 0.33 (50% ethyl acetate in hexane) 1H NMR (200MHz, d6-DMSO) δ 3.85 (s, 3H), 7.15-7.40 (m, 3H), 7.60-7.70 (m, 3H), 7.80 (t, 1 H), 7.95-8.10 (m, 2H), 8.20 (d, 1 H), 8.45 (s, 1H), 8.65 (d, 1H), 11.10 (s, 1H), 11.50 (s, 1H). EXAMPLE 44
2-[3-(2-Methyl-4-fluorophenylsulfamoyl)benzoylamino]benzoic acid Prepared from 2-[3-(2-methyl-4-fluorophenylsulfamoyl)benzoylamino] benzoic acid methyl ester (70mg) to yield the title compound (52mg) as an off white solid. Rf 0.1 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 2.00 (s, 3H), 6.90-7.10 (m, 3H), 7.25 (t, 1 H), 7.60-7.90 (m, 3H), 7.65 (t, 2H), 8.05 (d, 1 H), 8.20 (d, 1 H), 8.65 (d, 1 H), 9.85 (s, 1 H), 12.30 (s, 1H). EXAMPLE 45
■V-(2-Nitrophenyl)-3-(pyridin-3-ylsulfamoyl)benzamide A solution of 3-(2-nitrophenylcarbamoyl)benzenesulfonyl chloride (200mg) in dichloromethane (20ml) was stirred at room temperature under nitrogen. 3-Aminopyridine (66mg) and pyridine (0.06ml) were added and the reaction left to stir for 60h. The solvent was removed in vacuo and the residue purified by wet flash chromatography on silica eluting with ethyl acetate then 1% methanol in ethyl acetate to give the title compound (150mg) as a yellow solid.
1H NMR (200MHz, d6-DMSO) δ 11.00 (1H, s), 10.75 (1 H, s), 8.35-8.15
(4H, m), 8.05 -7.95 (2H, m), 7.85-7.65 (3H, m), 7.60-7.40 (2H, m), 7.35-
7.25 (1 H, m)
TLC Rf 0.72 (ethyl acetate) EXAMPLE 46
3-(4-Chlorophenylsulfamoyl)-.V-[2-(1,ty-tetrazol-5-yl)phenyl] benzamide
A solution of 3-(4-chlorophenylsulfamoyl)-/V-(2-cyanophenyl)benzamide
(0.25g) in DMF (10ml) was stirred at 50°C. Sodium azide (79mg) and ammonium chloride (65mg) were added and stirring continued at 50°C overnight. The mixture was cooled, diluted with ice (50ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration and washed with water to give the title compound as a white solid (0.22g). 1H NMR (400MHz, d6-DMSO) δ 11.45 (1 H, s), 10.65 (1 H, s), 8.40 (1 H, s), 8.35 (1 H, d), 8.30 (1 H, d), 8.05-7.95 (2H, m), 8.85 (1 H, t), 7.65 (1 H, t), 7.45 (1 H, t), 7.30 (2H, d), 7.15 (2H, d) MS (El+) 456 (M+H). EXAMPLE 47 5-Methoxy-2-({1-[3-(4-trifluoromethylphenylsulfamoyl)phenyl] methanoyl}amino)benzoic acid
A solution of 1-(3-dimethylaminopropyl)-3-ethyIcarbodiimide hydrochloride (83mg) in dichloromethane (2ml) was added to a suspension of 3-(4- trifluoromethyl-phenylsulfamoyl)benzoic acid (100mg) and 5-methoxy-2- aminobenzoic acid methyl ester (54mg) in dichloromethane (2ml) and the reaction mixture was stirred for 18h under an atmosphere of nitrogen. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (30ml) and 0.7M hydrochloric acid (30ml). The organic phase was concentrated in vacuo; diethyl ether (5ml), dichloromethane (5ml) were added followed by hexane (50ml) to induce crystallization. The mixture was concentrated in vacuo to half of its original volume; the mother liquor was decanted and the solid material dried. This process was repeated to afford 5-methoxy-2-({1-[3-(4- trifluoromethyl-phenylsulfamoyl)-phenyl]-methanoyl}amino)benzoic acid methyl ester. A solution of this ester (47mg) and lithium hydroxide monohydrate (20mg) in tetrahydrofuran (2ml) and water (2ml) was stirred for 24h at room temperature. The reaction mixture was diluted with water (10ml) and extracted with dichloromethane (2 x 5ml). The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate (20ml). The organic phase was dried (magnesium sulfate) and concentrated in vacuo to provide the title compound (59mg). TLC Rf 0.2 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 12.64 (1H, bs), 8.40-8.52 (2H, m), 8.17 (1 H, d), 8.01 (1 H, d), 7.78 (1 H, t), 7.50-7.65 (3H, m), 7.18-7.35 (3H, m), 3.78 (3H, s). The following compound was prepared by a similar procedure.
EXAMPLE 48 3-Nitro-5-({1-[3-(4-trifluoromethylphenylsulfamoyl)phenyl] methanoyl}amino)benzoic acid
Prepared from 3-(4-trifluoromethylphenylsulfamoyl)benzoic acid (100mg) and 3-nitro-5-aminobenzoic acid methyl ester (58mg) to provide the title compound (22mg). TLC Rf 0.2 (50% ethyl acetate in hexane)
1H NMR (200MHz, CD3OD) δ 8.96 (1 H, s), 8.70 (1 H, s), 8.40-8.57 (2H, m), 8.18 (1 H, d), 8.02 (1 H, d), 7.60-7.75 (1 H, m), 7.53 (2H, d), 7.31 (2H, d). EXAMPLE 49 4-[3-(2-Chlorophenylcarbamoyl)benzenesulfonylamino]benzoic acid ethyl ester
A mixture of 3-(chlorosulfonyl)benzoyl chloride (500mg), 2-chloroaniline (0.22ml) and pyridine (0.17ml) in dichloromethane (20ml) was stirred at room temperature under a nitrogen atmosphere for 4.5h. The reaction mixture was diluted with dichloromethane, washed with 1 N hydrochloric acid, dried (magnesium sulfate) and concentrated in vacuo. The residue was dissolved in dichloromethane (20ml), ethyl-4-aminobenzoate (347mg) was added and the reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 20h. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid after purification by preparative HPLC. MS (ES+) 460 (M+1 )
The following compound was prepared by a similar procedure.
EXAMPLE 50
4-[3-(2-Methoxyphenylcarbamoyl)benzenesulfonylamino]benzoic acid methyl ester Prepared from 3-(chlorosulfonyl) benzoyl chloride (500mg), o-anisidine (0.24ml) and ethyl 4-aminobenzoate (347mg) to give the title compound after purification by preparative HPLC. MS (ES+) 455.7 (M+1) EXAMPLE 51
3-[3-(4-Chlorophenylsulfamoyl)benzoylamino]benzamide To a suspension of 3-(4-chlorophenylsuIfamoyl)benzoic acid (100mg) in dichloromethane (10ml) was added oxalyl chloride (0.03ml) and DMF (5 drops). The reaction mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. The solvent was removed in vacuo and the residue evaporated from toluene to afford the acid chloride as a yellow residue. To a solution of the latter in dichloromethane (10ml) was added 3-aminobenzamide (44mg) and pyridine (0.05ml) and the reaction mixture stirred at room temperature for 1.5h. The mixture was diluted with dichloromethane (30ml), washed with 2N hydrochloric acid (70ml) and saturated aqueous sodium hydrogencarbonate solution (70ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with ethyl acetate to afford the title compound (10mg) as a white solid. TLC Rf 0.4 (ethyl acetate)
1H NMR (200MHz, CDCI3) δ 9.96 (1 H, bs), 8.35 (1 H, s), 8.10 (1 H, d), 7.89- 7.98 (2H, m), 7.80 (1 H, d), 7.36-7.61 (3H, m), 7.15 (2H, d), 7.03 (2H, d).
The following compounds were prepared by a similar procedure.
EXAMPLE 52
3-(4-Chlorophenylsulfamoyl)-/V-(2-methanesulfonylphenyl)benzamide
Prepared from 3-(4-chlorophenylsulfamoyl)benzoic acid (330mg) and 2- methylsulfonylaniline (207mg). Purification by flash chromatography on silica, eluting with 50% ethyl acetate in hexane afforded the title compound (311mg) as a white solid. TLC Rf 0.3 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 10.59 (1 H, s), 8.34 (1 H, s), 8.09-8.19 (2H, m), 7.94-8.03 (2H, m), 7.74-7.86 (2H, m), 7.47-7.58 (1 H, m), 7.34 (2H, d), 7.14 (2H, d), 3.30 (3H, s). EXAMPLE 53 .V-(2-Acetylphenyl)-3-(4-chlorophenylsulfamoyl)benzamide
Prepared from 3-(4-chlorophenylsulfamoyl)benzoic acid (311 mg) and 2'- aminoacetophenone (135mg). Purification by flash chromatography on silica eluting with 50% ethyl acetate in hexane gave the title compound (363mg) as a white solid. TLC Rf 0.28 (50% ethyl acetate in hexane)
1H NMR (200MHz, d6-DMSO) δ 12.35 (1 H, s), 10.65 (1 H, s), 8.54 (1 H, d),
8.35 (1 H, s), 8.09-8.12 (2H, m), 7.99 (1H, d), 7.81 (1 H, t), 7.70 (1 H, t), 7.27-7.38 (3H, m), 7.10-7.17 (2H, m), 2.70 (3H, s).
EXAMPLE 54
3-(4-Chlorophenylsulfamoyl)-/V-[2-(1 ιydroxyiminoethyl)phenyl] benzamide
A mixture of Λ/-(2-acetylphenyl)-3-(4-chlorophenylsulfamoyl)benzamide 192mg), hydroxylamine hydrochloride (73mg) and sodium acetate (96mg) in ethanol (10ml) and water (3ml) was heated at 100°C for 75 minutes, then allowed to cool to room temperature. The reaction mixture was diluted with water (20ml) and extracted with ethyl acetate (2 x 25ml). The combined organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 50% ethyl acetate in hexane to give the title compound (139mg) as a white solid. TLC Rf 0.35 (50% ethyl acetate in hexane)
1H NMR (400MHz, d6-DMSO) δ 11.77 (1 H, s), 11.63 (1 H, s), 10.60 (1 H, s), 8.38 (1 H, s), 8.33 (1 H, d), 8.12 (1 H, d), 7.95 (1 H, d), 7.75 (1 H, t), 7.63 (1 H, d), 7.43 (1 H, t), 7.32 (2H, d), 7.25 (1 H, t), 7.13 (2H, d), 2.24 (3H, s). EXAMPLE 55
3-(4-Chlorophenylsulfamoyl)-/V-pyridin-2-yl-benzamide To a suspension of 3-(4-chlorophenylsulfamoyl)benzoic acid (100mg) in dichloromethane (10ml) was added oxalyl chloride (0.03ml) and DMF (5 drops). The reaction mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. The solvent was removed in vacuo and the residue evaporated from toluene to afford the acid chloride as a yellow residue. Sodium hydride (60% dispersion in mineral oil, 18mg) was added to a solution of 2-aminopyridine (36mg) in N,N- dimethylformamide (10ml) and stirred for 0.5h. A solution of the acid chloride in Λ/,/V-dimethylformamide (5ml) was then added to the reaction mixture and stirring was continued for a furtherlδh. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (30ml) and water (60ml). The organic phase was washed with brine, dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica eluting with ethyl acetate to afford the title compound (7mg) as a white solid. TLC Rf 0.8 (ethyl acetate) 1H NMR (200MHz, 10% CD3OD in CDCI3) δ 8.25-8.40 (3H, m), 8.09-8.15 (1 H, m), 7.74-7.85 (2H, m), 7.54 (1 H, t), 7.00-7.18 (5H, m). EXAMPLE 56 3-[3-(4-Chlorophenylsulfamoyi)benzoylamino]-.V-hydroxybenzamide
To a solution of 2-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid (120mg) in dichloromethane (10ml) was added tert- butyldimethylsilylhydroxylamine (62mg) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (81 mg). The reaction mixture was stirred for 1.5h at room temperature under a nitrogen atmosphere. The solvent was removed in vacuo and the residue purified by flash chromatography on silica to furnish Λ/-(4-chlorophenyl)-3-(4-oxo-4H-benzo[D][1 ,3]oxazin-2- yl)benzenesulfonamide (95mg) as a white solid. To a solution of the oxazine (80mg) in tetrahydrofuran (5ml) was added hydroxylamine (50% aqueous solution, 1ml) and the reaction mixture heated at reflux for 10 minutes. The reaction mixture was cooled to room temperature, diluted with water (20ml) and extracted with ethyl acetate (3 x 20ml). The combined organic phases were washed with brine (30ml), dried (magnesium sulfate) and concentrated in vacuo to provide the title compound (35mg) as a white solid. TLC Rf 0.75 (ethyl acetate) 1H NMR (200MHz, d6-DMSO) δ 12.43 (1 H, s), 9.42 (1 H, bs), 8.54 (1 H, d),
8.37 (1 H, s), 8.13 (1 H, d), 7.96 (1 H, d), 7.80 (1 H, t), 7.70 (1H, d), 7.59
(1 H, t), 7.33 (1 H, d), 7.22 (1 H, t), 7.15 (2H, d).
EXAMPLE 57
2-f3-(2-Methyl-5-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid. A solution of 2-(3-chlorosulfonylbenzoylamino)benzoic acid methyl ester (100mg) in dichloromethane (5ml) was treated with 3-amino-4- methylbenzotrifluoride (100mg) and pyridine (0.46ml). The mixture was stirred at room temperature for 12h and then diluted with dichloromethane (40ml). The organic solution was washed with 2M hydrochloric acid, dried (magnesium sulfate) and filtered. The filtrate was evaporated in vacuo to yield a colourless gum. The residue was dissolved in tetrahydrofuran and treated with a solution of lithium hydroxide (59mg) in water (10ml). The mixture was stirred for 12h and then the organic solvent removed in vacuo. The residue was washed with dichloromethane (2 x 20ml), acidified with 2M hydrochloric acid and extracted with dichloromethane (3 x 30ml). The extracts were combined, dried (magnesium sulfate) and filtered. The filtrate was evaporated in vacuo to yield the title compound (120mg) as an off-white solid. Rf 0.66 (ethyl acetate) MS 479 (M+H)
1H NMR (200MHz, d6-DMSO) δ 2.10 (s, 3H), 3.85 (s, 3H), 7.10-7.32 (m, 2H), 7.35-7.55 (m, 2H), 7.6-7.90 (m, 3H), 8.05 (d, 1 H), 8.15-8.30 (m, 2H), 8.65 (d, 1H), 10.10 (s, 1H), 12.30 (s, 1H).
BIOLOGICAL ACTIVITY
The following assay can be used to demonstrate the activity of compounds according to the invention:
Measurement of Cyclic AMP PDE Activity
PDE7 hydrolyses cAMP to 5'AMP, a linear nucleotide. The assay used to determine this activity is based on the observation that linear nucleotides bind preferentially to SPA yttrium silicate beads, compared to cyclic nucleotides, in the presence of zinc sulphate. The 5'AMP, the product, therefore binds directly to the beads and cAMP does not. The binding of the radiolabelled product to the bead brings it into close enough proximity to allow tritium to excite the scintillant in the bead.
The PDE7 assay was carried out using Amersham Pharmacia SPA technology (Amersham Pharmacia Biotech). The assay was buffered with 50mM Tris containing 8.3mM MgCI2 and 1.7mM EGTA pH 7.5. Assay buffer, inhibitor, cAMP 0.029μM, final) and 3H-cAMP (~5nM, final concentration) were pipetted into a 96 well microtitre plate. The reaction was initiated with the addition of 20μl of PDE7 enzyme [see Michaeli, T et al (1993) J. Biol. Chem. 268, 12925-12932] to give a final volume of 100μl. The assay was incubated for 30 minutes at 30°C. The reaction was terminated by the addition of 50μl SPA yttrium silicate beads. The plates were then sealed, mixed and counted on a Packard TopCount scintillation counter (Canberra Packard).
In this assay, compounds according to the invention have IC50 values of around 10μM and less, typically around 1 μM and less.

Claims

1. A compound of formula (1 ):
Figure imgf000044_0001
wherein
W, X, Y and Z which may be the same or different, each represents a nitrogen atom or a C(R5) group [in which R5 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -N02 or -CN group] provided that two or more of W,X,Y and Z are C(R5) groups; R1, R2 and R3, which may be the same or different, each is an atom or group -L1(Alk1)rL2(R6)s in which L1 and L2, which may be the same or different, is each a covalent bond or a linker atom or group, r is zero or the integer 1 , Alk1 is an aliphatic or heteroaliphatic chain, s is an integer 1 , 2 or 3 and R6 is a hydrogen or halogen atom or a group selected from alkyl, -OR7 [where R7 is a hydrogen atom or an optionally substituted alkyl group], -SR7, -NR7R8 [where R8 is as just defined for R7 and may be the same or different], -N02, -CN, -C02R7, -S03H, -S(0)R7, -S02R7, - OC02R7, -CONR7R8, OCONR7R8, -CSNR7R8, -OCR7, -OCOR7, -N(R7)COR8, -N(R7)CSR8, -S(0)NR7R3, -S02NR7R8, -N(R7)S02R8, -N(R7)CON(R8)(R9) [where R9 is a hydrogen atom or an optionally substituted alkyl group], -N(R7)CSN(R8)R9), -N(R )S02N(R8)(R9),
-C(R7)=NO(R8), cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group]; provided that one or more of R\ R2 or R3 is a substituent other than a hydrogen atom; R4 represents an optionally substituted phenyl, 1- or 2- naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group; and the salts, solvates, hydrates and N-oxides thereof; provided that the compound of formula (1) is not 3-(4- bromophenylsulfamoyl)-Λ-(3-nitrophenyl)benzamide.
2. A compound according to Claim 1 of formula (1a):
Figure imgf000045_0001
wherein R\ R2, R3, R4 and R5 are as generally and particularly defined herein for compounds of formula (1 ); and the salts, solvates, hydrates and N-oxides thereof.
3. A compound according to Claim 1 or Claim 2 of formula (1 b):
Figure imgf000045_0002
wherein R2, R4 and R5 are as generally and particularly defined herein for compounds of formula (1 );
R1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1); and the salts, solvates, hydrates and N-oxides thereof.
4. A compound according to Claim 1 or Claim 2 of formula (1c):
R1
Figure imgf000045_0003
wherein R2, R4 and R5 are as generally and particularly defined herein for compounds of formula (1);
R1 is a substituent, other than a hydrogen atom, as defined herein for compounds of formula (1); and the salts, solvates, hydrates and N-oxides thereof.
5. A compound according to any preceding Claim wherein R5 is a hydrogen atom.
6. A compound according to any preceding Claim wherein R4 is a substituted phenyl, 1- or 2- naphthyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group.
7. A compound according to Claim 5 wherein R4 is a substituted phenyl, 1 -naphthyl or pyridyl group.
8. A compound according to Claim 5 or 6 wherein R4 is substituted by one or two R a substituents.
9. A compound according to any preceding Claim wherein R1 is a -C02H, -N02 or tetrazolyl group.
10. A compound which is: 4-[3-(2-nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid te/f-butyl ester; 4-[3-(2-nitrophenylcarbamoyl)benzenesulfonylamino]benzoic acid ethyl amide;
2-[3-(4-chloro-3-nitrophenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-chloro-2-methylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-bromo-5-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-chloro-4-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2,4-dimethylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-bromophenylsulfamoyl)benzoylamino]benzoic acid; 2-[3-(4-bromo-2-trifluoromethylphenylsulfamoyl)benzoylamino] benzoic acid;
2-[3-(2,4-dichlorophenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-chloro-4-methylphenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(4-chloronaphthalen-1-ylsulfamoyl)benzoylamino]benzoic acid; 2-[3-(4-ethylcarbamoyl-2-methylphenylsulfamoyI)benzoylamino] benzoic acid; 3-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid; and the salts, solvates, hydrates and N-oxides thereof.
11.A compound which is: 2-[3-(4-bromo-2-ethyl-phenylsulfamoyl)benzoylamino]benzoic acid;
2-[3-(2-methyl-6-trifluoromethyl-pyridin-3-ylsulfamoyl)benzoylamino] benzoic acid;
2-[3-(4-chlorophenylsulfamoyl)benzoylamino]benzoic acid;
2-({1-[3-(3-chlorophenylsulfamoyl)phenyl]methanoyl}amino)benzoic acid;
2-({1-[3-(4-trifluoromethylphenylsulfamoyl)phenyl]methanoyl}amino) benzoic acid;
2-[3-(2-methyl-4-fluorophenylsulfamoyI)benzoylamino]benzoic acid;
5-methoxy-2-({1-[3-(4-trifluoromethylphenylsulfamoyl)phenyl] methanoyl}amino)benzoic acid;
2-[3-(2-methyl-5-trifluoromethylphenylsulfamoyl)benzoylamino]benzoic acid; and the salts, solvates, hydrates and N-oxides thereof.
12. A pharmaceutical composition comprising a compound according to Claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
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