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WO2001098274A2 - Derives sulfonamides - Google Patents

Derives sulfonamides 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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WO
WIPO (PCT)
Prior art keywords
benzoic acid
benzoylamino
group
formula
compounds
Prior art date
Application number
PCT/GB2001/002705
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English (en)
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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Publication date
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/fr

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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.

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PCT/GB2001/002705 2000-06-20 2001-06-20 Derives sulfonamides WO2001098274A2 (fr)

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Cited By (12)

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WO2003064389A1 (fr) * 2002-01-31 2003-08-07 Ono Pharmaceutical Co., Ltd. Composes bicycliques contenant de l'azote et medicaments contenant ces composes en tant qu'ingredient actif
WO2008119057A2 (fr) 2007-03-27 2008-10-02 Omeros Corporation Utilisation d'inhibiteurs pde7 dans le traitement des troubles du
US7713972B2 (en) 2003-06-13 2010-05-11 Asubio Pharma Co., Ltd. Imidazotriazinone derivatives as PDE 7 (phosphodiesterase 7) inhibitors
US7932250B2 (en) 2004-07-01 2011-04-26 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
US7943624B2 (en) 2003-06-13 2011-05-17 Asubio Pharma Co. Ltd. Pyridinylpyrazolopyrimidinone derivatives as PDE 7 inhibitors
WO2012064667A2 (fr) 2010-11-08 2012-05-18 Omeros Corporation Traitement d'addiction et de troubles de contrôle des impulsions au moyen d'inhibiteurs de la pde7
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
EP2800568A4 (fr) * 2012-01-06 2015-06-10 Univ South Florida Compositions, procédés d'utilisation et procédés de traitement
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
EP3412651A1 (fr) * 2017-06-06 2018-12-12 Institut National De La Sante Et De La Recherche Medicale (Inserm) Inhibiteurs de rac1 contre asthme
US11685745B2 (en) 2017-07-12 2023-06-27 Dart Neuroscience, Llc Substituted benzoxazole and benzofuran compounds as PDE7 inhibitors
WO2024038089A1 (fr) 2022-08-18 2024-02-22 Mitodicure Gmbh Utilisation d'un agent thérapeutique ayant une activité inhibitrice de phosphodiestérase-7 pour le traitement et la prévention de maladies associées à la fatigue, à l'épuisement et/ou à l'intolérance à l'effort chroniques

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* Cited by examiner, † Cited by third party
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US7378428B2 (en) 2002-01-31 2008-05-27 Ono Pharmaceutical Co., Ltd. Nitrogen-containing bicyclic compounds and drugs containing the same as the active ingredient
WO2003064389A1 (fr) * 2002-01-31 2003-08-07 Ono Pharmaceutical Co., Ltd. Composes bicycliques contenant de l'azote et medicaments contenant ces composes en tant qu'ingredient actif
US7943624B2 (en) 2003-06-13 2011-05-17 Asubio Pharma Co. Ltd. Pyridinylpyrazolopyrimidinone derivatives as PDE 7 inhibitors
US7713972B2 (en) 2003-06-13 2010-05-11 Asubio Pharma Co., Ltd. Imidazotriazinone derivatives as PDE 7 (phosphodiesterase 7) inhibitors
EP2433943A1 (fr) 2004-07-01 2012-03-28 Daiichi Sankyo Company, Limited Dérivés de thiénopyrazole ayant une activité inhibitrice de la PDE7
US7932250B2 (en) 2004-07-01 2011-04-26 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
US8901315B2 (en) 2004-07-01 2014-12-02 Daiichi Sankyo Company, Limited Thienopyrazole derivative having PDE7 inhibitory activity
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
WO2008119057A2 (fr) 2007-03-27 2008-10-02 Omeros Corporation Utilisation d'inhibiteurs pde7 dans le traitement des troubles du
US9119822B2 (en) 2007-03-27 2015-09-01 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
US11464785B2 (en) 2010-11-08 2022-10-11 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
WO2012064667A2 (fr) 2010-11-08 2012-05-18 Omeros Corporation Traitement d'addiction et de troubles de contrôle des impulsions au moyen d'inhibiteurs de la pde7
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
EP4275752A2 (fr) 2010-11-08 2023-11-15 Omeros Corporation Traitement d'addiction et de troubles de contrôle des impulsions au moyen d'inhibiteurs de la pde7
EP2800568A4 (fr) * 2012-01-06 2015-06-10 Univ South Florida Compositions, procédés d'utilisation et procédés de traitement
US10604493B2 (en) 2012-01-06 2020-03-31 University Of South Florida Compositions, methods of use, and methods of treatment
US9556131B2 (en) 2012-01-06 2017-01-31 University Of South Florida Compositions, methods of use, and methods of treatment
WO2018224560A1 (fr) * 2017-06-06 2018-12-13 Institut National De La Sante Et De La Recherche Medicale (Inserm) Inhibiteurs de rac1 et leurs utilisations pour induire une bronchodilatation
EP3412651A1 (fr) * 2017-06-06 2018-12-12 Institut National De La Sante Et De La Recherche Medicale (Inserm) Inhibiteurs de rac1 contre asthme
US11607419B2 (en) 2017-06-06 2023-03-21 Inserm (Institut National De La Sante Et De La Recherche Medicale) Inhibitors of RAC1 and uses thereof for inducing bronchodilatation
US11685745B2 (en) 2017-07-12 2023-06-27 Dart Neuroscience, Llc Substituted benzoxazole and benzofuran compounds as PDE7 inhibitors
WO2024038089A1 (fr) 2022-08-18 2024-02-22 Mitodicure Gmbh Utilisation d'un agent thérapeutique ayant une activité inhibitrice de phosphodiestérase-7 pour le traitement et la prévention de maladies associées à la fatigue, à l'épuisement et/ou à l'intolérance à l'effort chroniques

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