WO1996036595A1 - 3,4-disubstituted-phenylsulphonamides and their therapeutic use - Google Patents

3,4-disubstituted-phenylsulphonamides and their therapeutic use Download PDF

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Publication number
WO1996036595A1
WO1996036595A1 PCT/GB1996/001204 GB9601204W WO9636595A1 WO 1996036595 A1 WO1996036595 A1 WO 1996036595A1 GB 9601204 W GB9601204 W GB 9601204W WO 9636595 A1 WO9636595 A1 WO 9636595A1
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Prior art keywords
dimethoxybenzenesulphonamide
benzyl
alkyl
ethyl acetate
optionally substituted
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PCT/GB1996/001204
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French (fr)
Inventor
Hazel Joan Dyke
John Montana
Hannah Jayne Kendall
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Chiroscience Limited
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Publication date
Priority claimed from GBGB9510186.1A external-priority patent/GB9510186D0/en
Priority claimed from GBGB9523678.2A external-priority patent/GB9523678D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU57722/96A priority Critical patent/AU5772296A/en
Publication of WO1996036595A1 publication Critical patent/WO1996036595A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur 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
    • 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
    • C07C311/48—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 having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • 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
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • 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
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel sulphonamide compounds and pharmaceutically acceptable salts thereof, processes for their production and formulation and use as pharmaceuticals.
  • R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cyclothioalkyl, or cyclothioalkenyl ;
  • R is lower alkyl ;
  • R is aryl or heteroaryl;
  • Z and Z are independently oxygen or sulphur.
  • the only sulphonamide exemplified is N-(2- c h l o r o p h e n y l ) - 3 - c y c l o p e n t y l o x y - 4 - methoxybenzenesulphonamide.
  • European Patent Application 306 846 discloses sulphonamides of formula:-
  • R 3 may be sulphonamide, as catechol-O-methyl transferase inhibitors.
  • Phosphodiesterases regulate cyclic AMP concentrations.
  • Phosphodiesterase IV has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. [See Torphy and Creslinski, Molecular Pharmacology 37, 206, (1990); Dent et al British Journal of Pharmacology, 90 163p (1990)].
  • Inhibitors of phosphodiesterase IV have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and the function of eosinophils [See for example Giembycz and Dent, Clinical and Experimental Allergy 22 337 (1992)] and for treating other diseases and conditions characterised by, or having an etiology including, morbid eosinophil accumulation.
  • Inhibitors of phosphodiesterase IV are also implicated in treating inflammatory diseases, proliferative 5 skin disease and conditions associated with cerebral metabolic inhibition.
  • Tumour Necrosis Factor a serum glycoprotein
  • AIDS human acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis
  • pyresis a number of autoimmune diseases, such as
  • HIV Human Immunodeficiency Virus
  • HIV-1 30 strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3.
  • T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte
  • Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
  • Cytokines are implicated in activated T- cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV- infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells, such as Kupffer and glial cells have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV) , influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus herpes virus
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells.
  • Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells.
  • US-A-4948809 discloses thromboxane antagonists including inter alia, arylsulphonamides. They are proposed for the treatment of cardiovascular diseases and asthma. There is no specific disclosure therein of one possible combination of substituents, comprising phenylsulphonamides in which the phenyl group is di(alkoxy)-substituted, and the N substituents are (i) phenyl(C,.
  • alkyl 4 alkyl
  • the phenyl group is 4-substituted by alkyl/alkenyl, for ylalkyl, hydroxyalkyl/ or -D-R 3 where D is -CO- or -CHOH- and R 3 is H, alkyl, hydroxyalkyl or alkylcarboxylic acid, and (ii) H, alkyl, acyl, aralkyl or aralkenyl, any aryl moiety being optionally substituted by halogen, alkyl, alkoxy, OH, CF 3 , CN, N0 2 , NH 2 , alkylamino, dialkylamino, acylamino, acyl or azido.
  • novel compounds of formula (i) have utility to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV.
  • the novel compounds are of formula (i) :
  • R represents C ⁇ alkyl (optionally substituted with one or more substituents chosen from amongst halogen, C ⁇ alkoxy, aryloxy, arylalkyloxy, C, ⁇ alkylamino, arylalkylamino or arylamino) or cycloalkyl (optionally substituted with one or more substituents chosen from amongst halogen, C ⁇ alkoxy, aryloxy, arylalkyloxy, C 6 alkylamino, arylalkylamino or arylamino) ;
  • R 2 represents Cl-3 alkyl optionally substituted with halogen
  • R 3 represents arylalkyl, heteroarylalkyl, heterocycloalkyl, C0R 7 , S(0) m R 7 , C ⁇ alkyl optionally substituted with one or more substituents chosen from amongst hydroxy, C, ⁇ alkoxy, -C0 2 H, C0 2 R 8 , SO 2 NR 9 R 10 , CONR 9 R 10 , -CN, carbonyl oxygen, N sR 6 , COR-, S(0) n R 7 ;
  • R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl
  • R 3 and/or R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl
  • the alkyl portion may be optionally substituted with one or more substituents chosen from amongst C0 2 H, C0 2 R g , sO j NR ⁇ ,,, CONR j R ⁇ , hydroxy, C,_ 6 alkoxy, NR 5 6 , COR 7 , S(0) n R 7 , -CN or carbonyl oxygen and/or the aryl/heteroaryl/heterocyclo portion may be optionally substituted with one or more substituents C0-6 alkyl-R n ;
  • R g and R 6 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C 1 . 6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, C,. 6 alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl heteroarylcarbonyl, heterocyclocarbonyl or C,_ 6 alkylsulphonyl, provided that when R j is C ⁇ .
  • R 6 is not C ⁇ alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C 6 alkylsulphonyl, R 6 is not C ⁇ alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C,_ 6 alkylsulphonyl ;
  • R 7 represents aryl, heteroaryl, heterocyclo or C 1 . 6 alkyl, any of which may be optionally substituted with one or more substituents chosen from amongst halogen, aryl, heteroaryl, heterocyclo, C 6 alkoxy, hydroxy, C0 2 H, C0 2 R 8 , SO 2 NR-,R 10 , CON c ⁇ R,,,, NR g R g or carbonyl oxygen;
  • R 8 represents C 1 . 6 alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • R, and R 10 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C ⁇ alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl;
  • R represents H, aryl, heteroaryl, heterocyclo, hydroxy
  • n 0-2;
  • Preferred compounds of the invention include those in which, independently or in any combination:
  • R 1 is C,. 6 alkyl (optionally substituted with aryloxy) or cycloalkyl;
  • R 2 is methyl optionally substituted with halogen
  • R 3 is arylalkyl, heteroarylalkyl, C0R 7 , S0 2 R 7 or C 1 . 6 alkyl (optionally substituted with one or more substituents chosen from amongst hydroxy, C0 2 H, C0 2 R 8 , CONRpR,,., SO j Nl ⁇ R,, ) , CN, carbonyl oxygen, NR j R 6 , COR 7 or S0 2 R 7 ) ;
  • R 4 is arylalkyl or heteroarylalkyl
  • R 3 and/or R 4 represents arylalkyl or heteroarylalkyl
  • the aryl or heteroaryl portion may be optionally substituted with one or more substituents CO-6 alkyl-R ⁇ ;
  • R g and R 6 which may be the same or different , are H, C, ⁇ alkyl , C,_ 6 alkylcarbonyl , C 6 alkylsulphonyl , aryl , heteroaryl , arylsulphonyl , heteroarylsulphonyl , arylcarbonyl , heteroarylcarbonyl , arylalkyl or heteroarylalkyl ;
  • R 7 is C,. 6 alkyl (optionally substituted with CN , C0 2 H, C0 2 R g , CONR ⁇ o , SO 2 NR 9 R 10 , carbonyl oxygen or NR j R 6 ) , aryl or heteroaryl ;
  • R j5 is C,_ 6 alkyl
  • R o and R 10 which may be the same or different, are H, C 1-6 alkyl, arylalkyl or heteroarylalkyl;
  • R ⁇ is aryl, heteroaryl, hydroxy, C 1 . 6 alkoxy, CN, C0 2 H C0 2 R g , CONRoR 10 , SO 2 NRoR 10 , carbonyl oxygen, NR 5 R 6 , C0R 7 or S0 2 R 7 .
  • Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine. Certain of the compounds of formula (i) which contain an amino group form acid addition salts.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, ⁇ -ketoglutarate, ⁇ -glycerophosphate and glucose-1-phosphate.
  • the pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantio ers, and diastereoiso ers and mixtures including racemic mixtures thereof.
  • alkyl when used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms.
  • Alkyl-R ⁇ means that the R ⁇ substituent may be attached at any position on the alkyl group.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • Aryloxy means an aryl-O- group in which the aryl group is as defined below.
  • Arylalkyloxy means an aryl- alkyl-O- group.
  • Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl-N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below) .
  • Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated.
  • Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms.
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heteroarylalkyl means a heteroaryl-alkyl group.
  • Heterocycloalkyl means a heterocyclo-alkyl group.
  • Alkyl amide includes both monoalkyl and dialkyl amides, in which the alkyl groups (previously descirbed) may be the same or different.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described.
  • Arylsulphonyl means an aryl-S0 2 - group in which the aryl group is as previously described.
  • Heteroarylsulphonyl means a heteroaryl-S0 2 - group and heterocyclosulphonyl means a heterocyclo-S0 2 - group.
  • Heteroarylcarbonyl means a heteroaryl-co- group and heterocyclocarbonyl means a heterocyclo-CO- group.
  • Alkoxycarbonyl means an alkyloxy-CO- group in wich the alkoxy group is as previously desribed.
  • Alkylsulphonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
  • Carbonyl oxygen means a -CO- group. It will be appreciated that carbonyl oxygen can not be a substituent on an aryl or heteroaryl ring.
  • Carbocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system which may be saturated or partially unsaturated.
  • Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms.
  • Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF-jS also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including: asthma, chronic bronchitis
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease) , memory impairment associated with Parkinson's disease, depression and multi- infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i) .
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV) , which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of formula (i) are preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • the invention further provides a process for the preparation of a compound of formula (i) , in which R ⁇ R ⁇ and m-n are as defined above.
  • functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene.
  • the process for preparing compounds of formula (i) in which R 3 contains a -C0 2 H comprises deprotecting (for example by hydrolysis) a compound of formula (i) in which R 3 contains an appropriate -C0 2 R wherein R represents a suitable protecting group (eg methyl) .
  • a process for the preparation of a compound of formula (ia) comprises reaction of an appropriate sulphonyl chloride of formula (ii) with a suitable amine of formula (iii)
  • R 1a represents R 1 as defined in relation to formula (i) or a group convertable to R.
  • R 2a -R 4a similarly represent R 2 -R 4 or groups convertable to R 2 -R 4 respectively; and thereafter, if required, converting any group R 1a to R 1 and/or R 2a to R 2 and/or R 3a to R 3 and/or R 4a to R 4 .
  • the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Sulphonyl chlorides of formula (ii) are either commercially available or are prepared using standard procedures known to those skilled in the art.
  • a sulphonyl chloride of formula (ii) may conveniently be prepared from the appropriate sulphonic acid (iv) by treatment with a suitable agent such as thionyl chloride or oxalyl chloride.
  • An appropriate sulphonic acid may be prepared from a compound of formula (v) by sulphonylation using an approriate sulphonylating agent, for example chlorosulphonic acid.
  • a sulphonyl chloride of formula (ii) may be prepared directly from a compound of formula (v) by using excess chlorosulphonic acid.
  • Compounds of formula (v) are either commercially available or may be prepared by standard procedures known to those skilled in the art.
  • Amines of formula (iii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. Some of the amines of formula (iii) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable amine. This amination may be carried out under any suitable standard conditions known to those skilled in the art.
  • a compound of formula (ia) may also be prepared by reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) to provide a compound of formula (ia) in which R 3 is H, followed by reaction with an appropriate agent of formula (xi) .
  • R 1a -R 4a are as defined earlier and X represents a suitable leaving group such as a halogen.
  • a sulphonyl chloride of formula (ii) with an amine of formula (x) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Amines of formula (x) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • the reaction of a compound of formula (i) in which R 3 is H with an agent of formula (xi) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide.
  • An agent of formula (xi) may be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl bromide or a sulphonylating agent such as ethanesulphonyl chloride.
  • Agents of formula (xi) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • a compound of formula (i) may also be prepared by interconversion of other compounds of formula (i) .
  • a compound in which R 4 contains an alkoxy group may be prepared by appropriate alkylation of a compound in which R 4 contains a hydroxy group.
  • a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stea
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i) may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to lOmg, for example 0.5, 1, 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05,
  • pharmaceutically acceptable encompasses materials suitable for both human and veterinary use.
  • the title compound was obtained as a white solid (lO.llg) .
  • N-Benzyl-3-methanesulphonyloxy-4-methoxybenzenesulphonamide (0.2g) in IM aqueous sodium hydroxide solution (5ml) was stirred at 45°C for 2 hours.
  • the clear solution was acidified with 6M aqueous hydrochloric acid (1ml) and extracted into ethyl acetate (3 x 15ml) .
  • the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. The residue crystallized upon standing to provide the title compound (0.17g) as a white crystalline solid.
  • the aqueous phase was further extracted with ethyl acetate (25ml) ; the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo.
  • the crude product was recrystallized from ethyl acetate/hexane to yield the title compound (253mg) as an off-white solid.
  • Triethylamine (7.9ml) was added to a stirred solution of 3- hydroxybenzyl alcohol (2.0g) in dichloromethane (25ml) at 0°C under a nitrogen atmosphere and the solution stirred for 5 minutes.
  • a solution of methanesulphonyl chloride (3.9ml) in dichloromethane (20ml) was added dropwise over 20 minutes and stirring was continued for a further 10 minutes.
  • the reaction mixture was then washed with 5% aqueous sulfuric acid (50ml) , saturated aqueous sodium hydrogen carbonate solution (50ml) , water (50ml) and brine (50ml) .
  • the organic phase was dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from ethyl acetate/hexane afforded the title compound (3.7g) as an off-white solid.
  • 3-Cyclopentyloxy-4-methoxyaniline (15g) was diazotized in a mixture of concentrated hydrochloric acid (22ml) and water (7.5ml) using a solution of sodium nitrite (5.13g) in water (12.5ml), maintaining the temperature at 0°C.
  • the resulting solution was filtered through celite and the filtrate added to a solution of sulphur dioxide (14.5g) in glacial acetic acid (75ml) which contained copper(II) chloride (2.25g).
  • the mixture was stirred overnight at room temperature, diluted with water and extracted with dichloromethane. The extracts were washed with water, dried (magnesium sulphate) and evaporated in vacuo.
  • N-Furfuryl-3,4-dimethoxybenzenesulphonamide (1.0g) was added to a cooled (0°C) suspension of sodium hydride (60% dispersion in mineral oil, 0.16g) in DMF (6ml) with stirring. After 20 minutes, a solution of 2- phthalimidoethanesulphonyl chloride (0.9g) [J. Med. Chem. , 1977, 20, 1128-34] in dry DMF (6ml) was added dropwise over 10 minutes and the reaction mixture stirred at room temperature overnight. The mixture was poured into water (200ml) and extracted into ethyl acetate (2 x 50ml) .
  • a su s pens i on o f N- f urf ury l -N- ( 2 - phthalimidoethanesulphonyl) -3 , 4-dimethoxybenzene- sulphonamide (210mg) in 50% ethanol-THF (20ml) was heated to reflux to provide a complete solution. Hydrazine monohydrate (0.8ml) was added and after 30 minutes a white precipitate formed. The cooled reaction mixture was concentrated in vacuo. The residue was partitioned between water (60ml) and dichloromethane (50ml) . The aqueous phase was further extracted with dichloromethane (50ml) .
  • Example 2 N-Benzyl-N-(2-phenethyl) -3 ,4- dimethoxybenzenesulphonamide. Purification by column chromatography on silica, eluting with 25% ethyl acetate in hexane provided the title compound (0.77g) as a white solid.
  • Example 18 Methyl 2-[N-(3-cyanopropyl)-3,4- dimethoxybenzenesulphonamido]-3- phenylpropionate. Purification was achieved by column chromatography eluting with 50% ethyl acetate in hexane to afford the title compound (127mg) as an oil.
  • Example 26 N-Benzyl-N-(4-cyanobenzyl) -3,4- dimethoxybenzenesulphonamide. Purification was achieved by column chromatography on silica eluting with 33% ethyl acetate in hexane to afford the title compound (2.33g) as a white solid.
  • the crude product was partitioned between ethyl acetate and 2M HC1.
  • the aqueous phase was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was dried over magnesium sulphate and concentated in vacuo to afford the title compund (40mg) as a clear gum.
  • Example 33 N-Benzyl-N-(3-methoxycarbonyl)benzyl-3,4- dimethoxybenzene-sulphonamide. Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane to afford the title compound (1.76g) as a clear, viscous oil.
  • Lithium aluminium hydride (0.03g) was suspended in anhydrous tetrahydrofuran (10ml) under an atmosphere of nitrogen at room temperature. To this was added, over 15 minutes, a solution of the ethyl ester (0.20g) prepared as above, in anhydrous tetrahydrofuran (10ml) . The mixture was heated at 60°C for 5 hours then stirred at room temperature for a further 24 hours. After quenching with hydrochloric acid (4ml, 2M) the mixture was concentrated in vacuo.
  • the following compounds were prepared according to the above procedure from the appropriate sulphonamide and sulphonyl chloride.
  • IR (thin film) n ⁇ 1509, 1366, 1265, 1159 cm '1 .
  • Triethylamine 500 ⁇ l was added to a suspension of N-(2- Aminoethanesulphonyl) -N- (3 -pyridylmethyl) -3 , 4- dimethoxybenzenesulphonamide (1.22g) in dicloromethane (20ml) at 0°C under an inert atmosphere.
  • Benzenesulphonylchloride 340 ⁇ l was then added and the resultant solution was stirred at room temperature overnight.
  • the mixture was diluted with dichloromethane (20ml) and washed with 50% saturated sodium hydrogen carbonate solution (40ml) .
  • the solution was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography eluting with 5% methanol in ethyl acetate to provide the title compound as a pale yellow solid (630mg) .
  • Aqueous sodium hydroxide solution (IM, 25ml) was added to asolutionofN-benzyl-N-(3-methanesulphonyloxybenzyl)-3,4- dimethoxybenzenesulphonamide (2.0g) in 1,4-dioxane (25ml) and the mixture heated at 85°C for 3 hours.
  • the solvent was removed in vacuo and the residue partitioned between ethyl acetate (75ml) and 2M aqueous hydrochloric acid (75ml) .
  • the aqueous layer was further extracted with ethyl acetate (75ml) and the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from diethyl ether/hexane afforded an off- white solid (1.5g) .
  • Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4 -carboxybenzyl ) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. Ammonium hydroxide solution (8ml) was added to the reaction; the resulting precipitate was filtered off, washed with water and dried in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.13g) as a white solid.
  • Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4-carboxybenzyl) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. The reaction mixture was then added to aqueous methylamine solution (40%, 10ml) . After stirring for a further 60 minutes, the layers were separated. The organic phase was washed with dilute hydrochloric acid (25ml) , water (20ml) , brine (20ml) , dried over magnesium sulphate and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.39g) as a white solid.
  • N- (2-Aminoethanesulphonyl) -N- (3-pyridylmethyl) -3,4- dimethoxybenzenesulphonamide (240mg) , nicotinic acid (71mg) , 1-hydroxybenzotriazole (172mg) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochoride (240mg) in dichloromethane (10ml) and tetrahydrofuran (5ml) were stirred at room temperature overnight under an inert atmosphere. The resulting solution was diluted with dichloromethane (20ml) and extracted with 50% saturated sodium hydrogen carbonate solution (40ml) .
  • Benzaldehyde (62 ⁇ l) was added to a stirred solution of N- (2-aminoethanesulphonyl)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide (250mg) in dicloromethane (10ml) under an inert atmosphere.
  • Sodium triacetoxyborohydride (190mg) was then added and the reaction stirred at room temperature overnight.
  • the resulting solution was diluted with dichloromethane (40ml) and extracted with 50% saturated sodium hydrogen carbonate solution (50ml) .
  • the organic phase was dried over magnesium sulphate and concentrated in vacuo.
  • the residue was purified by column chromatography on silica eluting with 1% triethylamine/ 7.5% methanol in ethyl acetate providing the title compound as a clear oil (81mg) .
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (i) are standard assay procedures as disclosed by Schilling et al Anal. Biochem. 216 154 (1994), Thompson and Strada Adv. Cycl. Nucl. Res. 8 119 (1979) and Gristwood and Owen Br. J. Pharmacol. 87 91P (1986) .

Abstract

3,4-Disubstituted benzenesulphonamides of general formula (i), in which R3 represents arylalkyl, heteroarylalkyl, heterocycloalkyl, COR7, S(O)mR7, optionally substituted C1-6 alkyl, R4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl, and the other substituents are as defined in Claim 1, have therapeutic utility via phosphodiesterase IV inhibition.

Description

3,4-DISUBSTITUTED-PHENYLSULPHONAMIDES AND THEIR THERAPEUTIC USE
Field of the invention
The present invention relates to novel sulphonamide compounds and pharmaceutically acceptable salts thereof, processes for their production and formulation and use as pharmaceuticals.
Description of the prior art.
International Patient Application WO 94/02465 discloses inhibitors of phosphodiesterase IV and TNF including sulphonamides of formula:-
Figure imgf000003_0001
wherein R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cyclothioalkyl, or cyclothioalkenyl ; R is lower alkyl ; R is aryl or heteroaryl; Z and Z are independently oxygen or sulphur. The only sulphonamide exemplified is N-(2- c h l o r o p h e n y l ) - 3 - c y c l o p e n t y l o x y - 4 - methoxybenzenesulphonamide.
European Patent Application 306 846 discloses sulphonamides of formula:-
Figure imgf000004_0001
as thromboxane A2 antagonists. European Patent Application 0589 037 discloses structures similar to the above also as thromboxane A2 antagonists.
United States Patents 5,283,352 and 4,963,590 disclose compounds of formula
Figure imgf000004_0002
in which R3 may be sulphonamide, as catechol-O-methyl transferase inhibitors.
Phosphodiesterases regulate cyclic AMP concentrations. Phosphodiesterase IV has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. [See Torphy and Creslinski, Molecular Pharmacology 37, 206, (1990); Dent et al British Journal of Pharmacology, 90 163p (1990)]. Inhibitors of phosphodiesterase IV have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and the function of eosinophils [See for example Giembycz and Dent, Clinical and Experimental Allergy 22 337 (1992)] and for treating other diseases and conditions characterised by, or having an etiology including, morbid eosinophil accumulation. Inhibitors of phosphodiesterase IV are also implicated in treating inflammatory diseases, proliferative 5 skin disease and conditions associated with cerebral metabolic inhibition.
Excessive or unregulated production of Tumour Necrosis Factor (TNF) , a serum glycoprotein, has been implicated in
10 mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory
15 distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to
20 infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS) , AIDS, ARC, (AIDS related complex) , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as
25 multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV) . At least three types or
30 strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte
35. activation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
Cytokines, specifically TNF, are implicated in activated T- cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV- infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as Kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al, The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al, Proc. Natl. Acad. Sci., 87:782-784, (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV) , influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al. , Infection and Immunity, 58(9) :2750-54, (1990); and Jafari et al., Journal of Infectious Diseases, 164:389-95, (1991). See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35, (10):2046- 48, (1991); and Luke et al. , Journal of Infectious Diseases, 162:211-214, (1990)].
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
US-A-4948809 discloses thromboxane antagonists including inter alia, arylsulphonamides. They are proposed for the treatment of cardiovascular diseases and asthma. There is no specific disclosure therein of one possible combination of substituents, comprising phenylsulphonamides in which the phenyl group is di(alkoxy)-substituted, and the N substituents are (i) phenyl(C,.4 alkyl) and the phenyl group is 4-substituted by alkyl/alkenyl, for ylalkyl, hydroxyalkyl/ or -D-R3 where D is -CO- or -CHOH- and R3 is H, alkyl, hydroxyalkyl or alkylcarboxylic acid, and (ii) H, alkyl, acyl, aralkyl or aralkenyl, any aryl moiety being optionally substituted by halogen, alkyl, alkoxy, OH, CF3, CN, N02, NH2, alkylamino, dialkylamino, acylamino, acyl or azido.
Summary of the invention
It has been found that novel compounds of formula (i) have utility to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV. According to the invention, the novel compounds are of formula (i) :
Figure imgf000008_0001
in which R, represents C^ alkyl (optionally substituted with one or more substituents chosen from amongst halogen, C^ alkoxy, aryloxy, arylalkyloxy, C,^ alkylamino, arylalkylamino or arylamino) or cycloalkyl (optionally substituted with one or more substituents chosen from amongst halogen, C^ alkoxy, aryloxy, arylalkyloxy, C 6 alkylamino, arylalkylamino or arylamino) ;
R2 represents Cl-3 alkyl optionally substituted with halogen;
R3 represents arylalkyl, heteroarylalkyl, heterocycloalkyl, C0R7, S(0)mR7, C^ alkyl optionally substituted with one or more substituents chosen from amongst hydroxy, C,^ alkoxy, -C02H, C02R8, SO2NR9R10, CONR9R10, -CN, carbonyl oxygen, N sR6, COR-, S(0)nR7;
R4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl;
when R3 and/or R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl, the alkyl portion may be optionally substituted with one or more substituents chosen from amongst C02H, C02Rg , sOjNR^,,, CONRjR^, hydroxy, C,_6 alkoxy, NR5 6, COR7, S(0)nR7, -CN or carbonyl oxygen and/or the aryl/heteroaryl/heterocyclo portion may be optionally substituted with one or more substituents C0-6 alkyl-Rn ;
Rg and R6, which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C1.6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, C,.6 alkylcarbonyl, C1.6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl heteroarylcarbonyl, heterocyclocarbonyl or C,_6 alkylsulphonyl, provided that when Rj is C^.& alkylcarbonyl, C,^ alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C 6 alkylsulphonyl, R6 is not C^ alkylcarbonyl, C1.6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C,_ 6 alkylsulphonyl ;
R7 represents aryl, heteroaryl, heterocyclo or C1.6 alkyl, any of which may be optionally substituted with one or more substituents chosen from amongst halogen, aryl, heteroaryl, heterocyclo, C 6 alkoxy, hydroxy, C02H, C02R8 , SO2NR-,R10, CON c^R,,,, NRgRg or carbonyl oxygen;
R8 represents C1.6 alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R, and R10, which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C^ alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl;
R represents H, aryl, heteroaryl, heterocyclo, hydroxy,
C,^ alkoxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, -C02H, C02R8, SO^RyR^, CONR9R10, halogen, -CN, -N ^, COR7, S(0)nR7, -CN or carbonyl oxygen;
m represents 1-2; n represents 0-2;
and pharmaceutically acceptable salts thereof.
Description of the Invention
Preferred compounds of the invention include those in which, independently or in any combination:
R1 is C,.6 alkyl (optionally substituted with aryloxy) or cycloalkyl;
R2 is methyl optionally substituted with halogen;
R3 is arylalkyl, heteroarylalkyl, C0R7, S02R7 or C1.6 alkyl (optionally substituted with one or more substituents chosen from amongst hydroxy, C02H, C02R8, CONRpR,,., SOjNl^R,,), CN, carbonyl oxygen, NRjR6, COR7 or S02R7) ;
R4 is arylalkyl or heteroarylalkyl;
when R3 and/or R4 represents arylalkyl or heteroarylalkyl, the aryl or heteroaryl portion may be optionally substituted with one or more substituents CO-6 alkyl-R^;
Rg and R6, which may be the same or different , are H, C,^ alkyl , C,_6 alkylcarbonyl , C 6 alkylsulphonyl , aryl , heteroaryl , arylsulphonyl , heteroarylsulphonyl , arylcarbonyl , heteroarylcarbonyl , arylalkyl or heteroarylalkyl ;
R7 is C,.6 alkyl (optionally substituted with CN , C02H, C02Rg, CONR^o , SO2NR9R10, carbonyl oxygen or NRjR6) , aryl or heteroaryl ;
Rj5 is C,_6 alkyl; Ro and R10, which may be the same or different, are H, C1-6 alkyl, arylalkyl or heteroarylalkyl;
R^ is aryl, heteroaryl, hydroxy, C1.6 alkoxy, CN, C02H C02Rg, CONRoR10, SO2NRoR10, carbonyl oxygen, NR5R6, C0R7 or S02R7.
Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine. Certain of the compounds of formula (i) which contain an amino group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, α-ketoglutarate,α-glycerophosphate and glucose-1-phosphate. The pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
It will be appreciated by those skilled in the art that some of the compounds of formula (i) may exist in more than one tautomeric form. This invention extends to all tautomeric forms.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantio ers, and diastereoiso ers and mixtures including racemic mixtures thereof.
When used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms. Alkyl-R^ means that the R^ substituent may be attached at any position on the alkyl group. Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.Aryloxy means an aryl-O- group in which the aryl group is as defined below. Arylalkyloxy means an aryl- alkyl-O- group. Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl-N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below) . Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein. Heteroarylalkyl means a heteroaryl-alkyl group. Heterocycloalkyl means a heterocyclo-alkyl group. Alkyl amide includes both monoalkyl and dialkyl amides, in which the alkyl groups (previously descirbed) may be the same or different. Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described. Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described. Arylsulphonyl means an aryl-S02- group in which the aryl group is as previously described. Heteroarylsulphonyl means a heteroaryl-S02- group and heterocyclosulphonyl means a heterocyclo-S02- group. Heteroarylcarbonyl means a heteroaryl-co- group and heterocyclocarbonyl means a heterocyclo-CO- group. Alkoxycarbonyl means an alkyloxy-CO- group in wich the alkoxy group is as previously desribed. Alkylsulphonyl means an alkyl-S02- group in which the alkyl group is as previously described. Carbonyl oxygen means a -CO- group. It will be appreciated that carbonyl oxygen can not be a substituent on an aryl or heteroaryl ring. Carbocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system which may be saturated or partially unsaturated. Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms. Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur. Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur. Halogen means fluorine, chlorine, bromine or iodine.
"TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-jS (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin) , and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise. This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease) , memory impairment associated with Parkinson's disease, depression and multi- infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i) . Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV) , which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
The compounds of this invention may be also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
The compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis.
The compounds of formula (i) are preferably in pharmaceutically acceptable form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
The invention further provides a process for the preparation of a compound of formula (i) , in which R^R^ and m-n are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene. Thus the process for preparing compounds of formula (i) in which R3 contains a -C02H comprises deprotecting (for example by hydrolysis) a compound of formula (i) in which R3 contains an appropriate -C02R wherein R represents a suitable protecting group (eg methyl) .
It will be appreciated that where a particular stereoisomer of formula (i) is required, this may be obtained by conventional resolution techniques such as high performance liquid chromatography or the synthetic processes herein described may be performed using the appropriate homochiral starting material.
A process for the preparation of a compound of formula (ia) comprises reaction of an appropriate sulphonyl chloride of formula (ii) with a suitable amine of formula (iii)
Figure imgf000017_0001
wherein R1a represents R1 as defined in relation to formula (i) or a group convertable to R., and R2a-R4a similarly represent R2-R4 or groups convertable to R2-R4 respectively; and thereafter, if required, converting any group R1a to R1 and/or R2a to R2 and/or R3a to R3 and/or R4a to R4. The reaction of a sulphonyl chloride of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
Sulphonyl chlorides of formula (ii) are either commercially available or are prepared using standard procedures known to those skilled in the art. For example a sulphonyl chloride of formula (ii) may conveniently be prepared from the appropriate sulphonic acid (iv) by treatment with a suitable agent such as thionyl chloride or oxalyl chloride. An appropriate sulphonic acid may be prepared from a compound of formula (v) by sulphonylation using an approriate sulphonylating agent, for example chlorosulphonic acid. Alternatively, a sulphonyl chloride of formula (ii) may be prepared directly from a compound of formula (v) by using excess chlorosulphonic acid. Compounds of formula (v) are either commercially available or may be prepared by standard procedures known to those skilled in the art.
Figure imgf000018_0001
Amines of formula (iii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. Some of the amines of formula (iii) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable amine. This amination may be carried out under any suitable standard conditions known to those skilled in the art.
An alternative method for the preparation of compounds of formula (ia) is shown below. This method involves the protection of an appropriate phenol of formula (vi) with a suitable protecting group (for example methanesulphonyl) under standard conditions known to those skilled in the art to provide a compound of formula (vii) and subsequent conversion to a sulphonyl chloride of formula (viii) by sulphonylation or chlorosulphonylation as descibed earlier. Reaction of sulphonyl chloride (viii) with an amine of formula (iii) as descibed earlier provides a compound of formula (ix) . Deprotection under standard conditions known to those skilled in the art, followed by alkylation under standard conditions known to those skilled in the art provides a compound of formula (ia) .
Figure imgf000019_0001
A compound of formula (ia) may also be prepared by reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) to provide a compound of formula (ia) in which R3 is H, followed by reaction with an appropriate agent of formula (xi) .
Figure imgf000020_0001
wherein R1a-R4a are as defined earlier and X represents a suitable leaving group such as a halogen.The reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
Amines of formula (x) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. The reaction of a compound of formula (i) in which R3 is H with an agent of formula (xi) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide. An agent of formula (xi) may be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl bromide or a sulphonylating agent such as ethanesulphonyl chloride. Agents of formula (xi) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
A compound of formula (i) may also be prepared by interconversion of other compounds of formula (i) . For example, a compound in which R4 contains an alkoxy group may be prepared by appropriate alkylation of a compound in which R4 contains a hydroxy group.
A compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
The active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc, the compounds of the invention are effective in the treatment of humans.
The compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
Compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
Compounds of formula (i) , or if appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
Suitably, the compound of formula (i) , or if appropriate a pharmaceutically acceptable salt thereof, will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
The dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the compound. However, as a general guide suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to lOmg, for example 0.5, 1, 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for a number of weeks or months.
When used herein the term "pharmaceutically acceptable" encompasses materials suitable for both human and veterinary use.
The following illustrates the invention. Intermediate 1 N-(4-Pyridylmethyl) -3,4- dimethoxybenzenesulphona ide
4-(Aminomethyl)pyridine (0.51ml) was added to a solution of 3,4-dimethoxybenzenesulphonyl chloride (1.08g) and triethylamine (0.96ml) in dichloromethane (30ml) at room temperature under a nitrogen atmosphere. The solution was stirred for 16 hours and then concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 10% hexane in ethyl acetate, to provide the title compound (236mg) as an off-white solid.
TLC Rf 0.18 (1% acetic acid/5% methanol in ethyl acetate)
The following compounds were prepared from the appropriate sulphonyl chloride and amine, using the above procedure.
Intermediate 2 N-(3-Pyridylmethyl) -3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 2.0% ethyl acetate in dichloromethane provided the title compound (400mg) as an oil.
TLC Rf 0.15 (20% ethyl acetate in dichloromethane)
Intermediate 3 N-(2-Pyridylmethyl) -3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 10% hexane in ethyl acetate and recrystallization from ethyl acetate yielded the title compound (246mg) as an off- white solid.
TLC Rf 0.20 (10% hexane in ethyl acetate)
Intermediate 4 N-Benzyl-3,4- dimethoxybenzenesulphonamide
Recrystallization from ethyl acetate/hexane afforded the title compound (330mg) as a white solid.
TLC Rf 0.25 (30% ethyl acetate in hexane)
Intermediate 5 N-(2,6-Dichlorobenzyl)-3 ,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 40% ethyl acetate in hexane afforded the title compound (l.Og) as a pale yellow solid.
TLC Rf 0.2 (40% ethyl acetate in hexane)
Intermediate 6 N-Phenethyl-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 50% ethyl acetate in hexane yielded the title compound (2.19g) as an oil which crystallized on standing.
TLC Rf 0.33 (50% ethyl acetate in hexane)
Intermediate 7 N-Furfuryl-3,4- dimethoxybenzenesulphonamide
Recrystallization from ethyl acetate/hexane gave the title compound (5.04g) as white crystals.
TLC Rf 0.45 (60% ethyl acetate in hexane)
Intermediate 8 N-Benzyl-3-methanesulphonyloxy-4- methoxybenzenesulphona ide Recrystallization from ethyl acetate/hexane afforded the title compound (14mg) .
TLC Rf 0.2 (50% ethyl acetate in hexane)
Intermediate 9 N-Furfuryl-3-methanesulphonyloxy-4- methoxybenzene sulphonamide
TLC Rf 0.26 (60% ethyl acetate in hexane)
Intermediate 10 N-(2-(2-Pyridyl)ethyl)-3 ,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with ethyl acetate and trituration with diethyl ether furnished the title compound (300mg) as a white powder
TLC Rf 0.3 (ethyl acetate)
Intermediate 11 N-(2-Methylthiazolylmethyl) -3,4- dimethoxybenzenesulphonamide
Prepared from 2-methyl-4-aminomethylthiazole [J. Gen. Chem. USSR (English Translation), 1961, 31, 1255-9] and 3,4- dimethoxybenzenesulphonyl chloride.
Purification by column chromatography on silica, eluting with 50% ethyl acetate/hexane afforded the title compound (0.84g) as a white solid.
TLC Rf 0.45 (ethyl acetate)
Intermediate 12 N-(4-Methoxybenzyl)-3,4- di ethoxybenzenesulphonamide
Recrystallization from ethyl acetate/hexane yielded the title compound (3.5g) as white crystals. TLC Rf 0.27 (50% ethyl acetate/hexane)
Intermediate 13 N-[4-(1,2,3-Thiadiazol-4-yl)benzyl]-
3,4-dimethoxybenzene-sulphonamide
Recrystallization from ethyl acetate/hexane furnished the title compound (380mg) as a white solid.
TLC Rf 0.45 (15% ethyl acetate in dichloromethane)
The following compounds were prepared from 3,4- dimethoxybenzenesulphonyl chloride and the appropriate amine hydrochloride salts, using the above procedure.
Intermediate 14 N-(Cyanomethyl)-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 15% ethyl acetate in dichloromethane and recrystallization from ethyl acetate/hexane provided the title compound (68mg) as a white solid.
TLC Rf 0.25 (60% ethyl acetate in hexane)
Intermediate 15 N-Pyrazinylmethy1-3,4- dimethoxybenzenesulphonamide
Prepared from aminomethylpyrazine hydrochloride [J. Org. Chem., 1973, 38, 2049-52].
Purification by column chromatography on silica, eluting with ethyl acetate gave the title compound (400mg) .
TLC Rf 0.2 (ethyl acetate)
Intermediate 16 N-(3-Bromobenzyl)-3,4- dimethoxybenzenesulphonamide Purification by column chromatography on silica, eluting with 50% ethyl acetate in hexane furnished the title compound (640mg) as a white crystalline solid.
TLC Rf 0.4 (50% ethyl acetate/hexane)
Intermediate 17 N-(4-Bromobenzyl)-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica, eluting with 50% ethyl acetate in hexane and trituration with diethyl ether afforded the title compound (634mg) as a white solid.
TLC Rf 0.35 (50% ethyl acetate in hexane)
Intermediate 18 N-Propyl-3,4- dimethoxybenzenesulphonamide
The title compound was obtained as a white solid (lO.llg) .
TLC Rf 0.18 (dichloromethane)
Intermediate 19 2-(Methanesulphonyloxy)methoxybenzene
A solution of 2-methoxyphenol (0.65ml) in pyridine (20ml) was cooled to 0°C under a nitrogen atmosphere. After stirring for 5 minutes, methanesulphonyl chloride (0.62ml) was added dropwise, and stirring was continued for 15 minutes at 0°C followed by 1.5 hours at room temperature. The solvent was removed in vacuo and the residue partitioned between water (25ml) and ethyl acetate (25ml) . The organic phase was dried (magnesium sulphate) and evaporated in vacuo. The crude product was purified by column chromatography on silica, eluting with 20% ethyl acetate in hexane to furnish the title compound (1.76g) as an oil. TLC Rf 0.25 (30% ethyl acetate in hexane)
Intermediate 20 3-Methanesulphonyloxy-4- methoxybenzenesulphonyl chloride
A solution of 2-(methanesulphonyloxy)methoxybenzene (0.822g) in dichloromethane (15ml) was stirred and cooled to -10°C under a nitrogen atmosphere. A solution of chlorosulphonic acid (0.27ml) in dichloromethane (5ml) was then added dropwise over a period of 1 hour, maintaining the temperature below 0°C. The mixture was stirred for a further 4 hours, allowing the temperature to rise to 10°C. The mixture was evaporated to dryness in vacuo to yield an oil which was suspended in toluene (20ml) with stirring under a nitrogen atmosphere. Oxalyl chloride (0.36ml) was added dropwise, followed by the addition of DMF (5 drops) . After stirring for 2 hours at room temperature, dichloromethane (15ml) and oxalyl chloride (0.36ml) were added and the reaction stirred overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica, eluting with 60% ethyl acetate in hexane to furnish the title compound (0.99g) as a white crystalline solid.
TLC Rf 0.4 (60% ethyl acetate in hexane)
Intermediate 21 N-Benzyl-3-hydroxy-4- methoxybenzenesulphonamide
N-Benzyl-3-methanesulphonyloxy-4-methoxybenzenesulphonamide (0.2g) in IM aqueous sodium hydroxide solution (5ml) was stirred at 45°C for 2 hours. The clear solution was acidified with 6M aqueous hydrochloric acid (1ml) and extracted into ethyl acetate (3 x 15ml) . The combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. The residue crystallized upon standing to provide the title compound (0.17g) as a white crystalline solid.
TLC Rf 0.47 (60% ethyl acetate in hexane)
The following compound was prepared from the appropriate starting material, using the above procedure.
Intermediate 22 N-Furfury1-3-hydroxy-4- ethoxybenzenesulphonamide
TLC Rf 0.27 (60% ethyl acetate in hexane)
Intermediate 23 Ethyl 3-(furfurylamino)propanoate
Ethyl acrylate (30g) was added dropwise to a stirred solution of furfurylamine (116.5g) in toluene (400ml). The mixture was stirred overnight at room temperature, then heated at reflux for 2 hours. The solution was evaporated in vacuo and the residue was distilled to yield the title compound (45g) .
b.p. 106-109°C (1.5mmHg)
The following compounds were prepared from the appropriate starting materials, using the above procedure.
Intermediate 24 3-(Tetrahydrofurfurylamino)propionitrile
Distillation afforded the title compound (64g) .
b.p. 100-104°C (0.7mmHg)
Intermediate 25 3-(Furfurylamino)propionitrile
Intermediate 26 3-Cyclopentyloxy-4-methoxyaniline 3-Cyclopentyloxy-4-methoxybenzoic acid (lOg) was heated at reflux with toluene (120ml) with azeotropic removal of water. On cooling, thionyl chloride (6.7g) and a few drops of DMF were added. The mixture was heated at reflux for 5 hours, cooled, filtered and evaporated in vacuo. A solution of this residue (26.7g) in dioxane (250ml) was added dropwise to a cooled (0°C) and stirred solution of sodium azide (8.2g) in water (250ml) and dioxan (250ml). The mixture was stirred at room temperature for 1 hour, then diluted with water (300ml) and extracted with toluene (2 x 300ml) . The toluene extracts were washed with water (500ml) then dried (magnesium sulfate) . This solution was added dropwise with stirring to toluene (300ml) at reflux. After addition, the solution was heated at reflux and stirred for 1 hour. Evaporation of the solvent in vacuo afforded the crude isocyanate (60g) which was then heated at reflux and stirred in absolute ethanol (400ml) for 1 hour. After evaporation of the solvent in vacuo, the resulting oil was heated at reflux and stirred with 10% aqueous sodium hydroxide solution (600ml) and ethanol (600ml) for 6 hours. On cooling, the reaction mixture was diluted with water (500ml) and extracted with dichloromethane (3 x 500ml) . The organic extracts were washed with water (2 x 500ml) , dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled under reduced pressure to give the title compound (32g) .
b.p. 128-130°C (0.3mmHg)
Intermediate 27 N-Benzyl-N-(4-methanesulphonyloxybenzyl)-
3,4-dimethoxy-benzenesulphonamide.
Sodium hydride (60% dispersion, 26mg) was added to a st irred so lut ion of N-benzyl- 3 , 4 - dimethoxybenzenesulphonamide (200mg) in DMF (5ml) at 0°C under a nitrogen atmosphere and the mixture stirred for 5 minutes. O-Methanesulphonyl-4-methanesulphonyloxybenzyl alcohol (200mg, prepared according to Tetrahedron, 1982, 38, 787-798) was then added and the mixture stirred for 3 hours. The DMF was removed in vacuo and the residual oil partitioned between ethyl acetate (25ml) and water (25ml) . The aqueous phase was further extracted with ethyl acetate (25ml) ; the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/hexane to yield the title compound (253mg) as an off-white solid.
TLC Rf 0.8 (15% ethyl acetate in hexane)
The following compounds were prepared according to the above procedure.
Intermediate 28 N-Benzyl-N-methanethiomethyl-3,4- dimethoxybenzenesulphonamide
Prepared using chloromethyl methyl sulphide and N-benzyl- 3,4-dimethoxybenzene-sulphonamide.
Crystallization from ethyl acetate/hexane furnished the title compound (259mg) as a cream solid.
TLC Rf 0.53 (50% ethyl acetate in hexane)
Intermediate 29 N-(3-Pyridyl)-N-methanethiomethyl-3,4- dimethoxybenzene-sulphonamide
Prepared using chloromethyl methyl sulphide and N-(3- pyridyl) -3,4-dimethoxybenzene-sulphonamide.
Crystallization from ethyl acetate/hexane gave the title compound (270mg) as a pale yellow solid.
TLC Rf 0.58 (10% methanol in ethyl acetate) Intermediate 30 O-Methanesulphonyl-3- methanesulphonyloxybenzy1 alcohol.
Triethylamine (7.9ml) was added to a stirred solution of 3- hydroxybenzyl alcohol (2.0g) in dichloromethane (25ml) at 0°C under a nitrogen atmosphere and the solution stirred for 5 minutes. A solution of methanesulphonyl chloride (3.9ml) in dichloromethane (20ml) was added dropwise over 20 minutes and stirring was continued for a further 10 minutes. The reaction mixture was then washed with 5% aqueous sulfuric acid (50ml) , saturated aqueous sodium hydrogen carbonate solution (50ml) , water (50ml) and brine (50ml) . The organic phase was dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from ethyl acetate/hexane afforded the title compound (3.7g) as an off-white solid.
TLC Rf 0.55 (15% ethyl acetate/dichloromethane)
Intermediate 31 N-Benzyl-3-[ (3-phenoxypropyl)oxy]-4- methoxybenzenesulphonamide
Cesium carbonate (55mg) was added to a stirred solution of N-(benzyl)-3-hydroxy-4-methoxybenzenesulphonamide (50mg) in DMF (5ml) under a nitrogen atmosphere. 3-Phenoxypropyl bromide (0.027ml) was then added dropwise and the mixture heated for 1 hour at 50°C. The cooled mixture was poured into concentrated potassium carbonate solution (20ml) and extracted with diethyl ether (3 x 20ml) . The combined organic phases were dried (magnesium sulphate) , filtered and evaporated under high vacuum. Trituration with diethyl ether and hexane afforded the title compound (32mg) as a white crystalline solid.
TLC Rf 0.69 (60% ethyl acetate in hexane) The following compound was prepared using the above procedure.
Intermediate 32 N-Furfuryl-3-[ (3-phenoxypropyl)oxy]-4- methoxybenzene-sulphonamide
Purification by column chromatography on silica, eluting with 55% ethyl acetate in hexane provided the title compound (116mg) as a white solid.
TLC Rf 0.54 (60% ethyl acetate in hexane)
Intermediate 33 N-Furfuryl-3-cyclopentyloxy-4- methoxybenzenesulphonamide.
3-Cyclopentyloxy-4-methoxyaniline (15g) was diazotized in a mixture of concentrated hydrochloric acid (22ml) and water (7.5ml) using a solution of sodium nitrite (5.13g) in water (12.5ml), maintaining the temperature at 0°C. The resulting solution was filtered through celite and the filtrate added to a solution of sulphur dioxide (14.5g) in glacial acetic acid (75ml) which contained copper(II) chloride (2.25g). The mixture was stirred overnight at room temperature, diluted with water and extracted with dichloromethane. The extracts were washed with water, dried (magnesium sulphate) and evaporated in vacuo. The residue was dissolved in ether and filtered through celite and then through silica. The solvent was removed in vacuo to yield an oil (9.3g). A portion of this product (4.5g) was dissolved in dichloromethane (50ml) and added to a solution of 3-(furfurylamino)propionitrile (2.3g) and triethylamine (l.72g) in dichloromethane (50ml). The mixture was stirred at room temperature for 3 hours, then washed with water, dried and evaporated in vacuo to yield an oil which crystallized on standing. Recrystallization from ethanol furnished the title compound (l.Og) . TLC Rf 0.45 (50% ethyl acetate in hexane)
Intermediate 34 N-Furfuryl-N-(2- phthalimidoethanesulphonyl) -3,4- dimethoxy-benzenesulphonamide
N-Furfuryl-3,4-dimethoxybenzenesulphonamide (1.0g) was added to a cooled (0°C) suspension of sodium hydride (60% dispersion in mineral oil, 0.16g) in DMF (6ml) with stirring. After 20 minutes, a solution of 2- phthalimidoethanesulphonyl chloride (0.9g) [J. Med. Chem. , 1977, 20, 1128-34] in dry DMF (6ml) was added dropwise over 10 minutes and the reaction mixture stirred at room temperature overnight. The mixture was poured into water (200ml) and extracted into ethyl acetate (2 x 50ml) . The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (50ml) , dilute aqueous hydrochloric acid (50ml) and brine (50ml) , then dried (magnesium sulphate) , filtered and evaporated in vacuo. Purification by column chromatography on silica, eluting with 20%-60% ethyl acetate in hexane furnished the title compound (240mg) .
TLC Rf 0.4 (5% ethyl acetate in dichloromethane)
Intermediate 35 N-(2-A inoethanesulphony1)-N-f rfury1-
3,4-dimethoxybenzene-sulphonamide
A su s pens i on o f N- f urf ury l -N- ( 2 - phthalimidoethanesulphonyl) -3 , 4-dimethoxybenzene- sulphonamide (210mg) in 50% ethanol-THF (20ml) was heated to reflux to provide a complete solution. Hydrazine monohydrate (0.8ml) was added and after 30 minutes a white precipitate formed. The cooled reaction mixture was concentrated in vacuo. The residue was partitioned between water (60ml) and dichloromethane (50ml) . The aqueous phase was further extracted with dichloromethane (50ml) . The combined organic phases were washed with water (50ml) , brine (50ml) and then dried (magnesium sulphate) . filtered and evaporated in vacuo to afford the title compound (140mg) as a colourless oil.
TLC Rf 0.15 (5% methanol in dichloromethane)
Intermediate 36 N-[4-(3-Pyridyl)benzyl]-3,4- dimethoxybenzenesulphonamide
Diethyl ( 3-pyridyl ) borane ( llδmg ) , tetrakis(triphenylphosphine)palladium(0) (50mg) and tetrabutylammonium iodide (149mg) were placed in a flask at room temperature under nitrogen. THF (12ml) was added and stirred, followed by the addition of powdered potassium hydroxide (135mg) . The stirred mixture was heated to reflux for 28h. The reaction mixture was cooled and the solvent evaporated in vacuo. The residue was partitioned between water (50ml) and ethyl acetate (50ml) . The aqueous phase was reextracted with ethyl acetate (2 x 50ml) . The combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with ethyl acetate to afford the title compound (232mg) as a pale cream crystalline solid.
TLC Rf 0.2 (ethyl acetate)
The following compound was prepared according to the above procedure.
Intermediate 37 N-[3-(3-Pyridyl)benzyl]-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica furnished the title compound (219mg) as a white foam. TLC Rf 0.3 (ethyl acetate)
Intermediate 38 N-[2-(3-Pyridyl) benzyl]-3 ,4- dimethoxybenzenesulphonamide
Purification by column chromatography on silica furnished the title compound (112mg) as a clear oil.
TLC Rf 0.33 (ethyl acetate)
Example 1 N,N-Dibenzyl-3,4-dimethoxybenzenesulphonamide.
Dibenzylamine (10.45ml) was added to a suspension of 3,4- dimethoxybenzenesulphonyl chloride (0.50g) in dichloromethane (15ml). Triethylamine (0.44ml) was then added and the resultant solution was stirred at room temperature for 20 hours. The mixture was diluted with dichloromethane (25ml) and then washed successively with saturated aqueous sodium hydrogen carbonate solution (15ml) , 2N aqueous hydrochloric acid (15ml) and brine
(20ml) . The solution was dried (magnnesium sulphate) and concentrated in vacuo. Purification by column chromatography on silica, eluting with 25% ethyl acetate in hexane afforded the title compound (0.73g) as a colourless oil which crystallized on standing.
TLC Rf 0.25 (25% ethyl acetate in hexane) m.p. 79-80°C
The following compounds were prepared from 3,4- dimethoxybenzenesulphonyl chloride and the appropriate amine, using the above procedure.
Example 2 N-Benzyl-N-(2-phenethyl) -3 ,4- dimethoxybenzenesulphonamide. Purification by column chromatography on silica, eluting with 25% ethyl acetate in hexane provided the title compound (0.77g) as a white solid.
TLC Rf 0.25 (25% ethyl acetate in hexane) m.p. 92-93°C
Example 3 N-(2-Cyanoethyl) -N-benzyl-3,4- dimethoxybenzenesulphonamide.
Recrystallization from ethanol furnished the title compound (12.31g) .
m.p. 95-98°C TLC Rf 0.33 (50% ethyl acetate in hexane)
Example 4 N-(2-Cyanoethy1)-N-(tetrahydrofurfury1)-3,4- dimethoxybenzene-sulphonamide.
Recrystallization from ethanol provided the title compound (6.37g).
m.p. 77-80°C
TLC Rf 0.18 (50% ethyl acetate in hexane)
Example 5 N-(2-Cyanoethy1)-N-furfury1-3,4- dimethoxybenzenesulphonamide.
m.p. 110-112°C TLC Rf 0.7 (ethyl acetate)
Example 6 3-[N-Furfuryl-3,4- dimethoxybenzenesulphona ido]propanoic acid
2M aqueous sodium hydroxide solution (150ml) was added to a solution of ethyl 3- [N-f rf uryl-3 , 4- dimethoxybenzenesulphonamido]propanoate (lOg) in ethanol (150ml) . The mixture was stirred overnight at room temperature, then acidified with glacial acetic acid and the ethanol removed in vacuo. The suspension was allowed to cool, the product was filtered off and washed with water. Recrystallization from toluene provided the title compound (6.5g) as a white solid.
m.p. 136-139°C
TLC Rf 0.2 (1% acetic acid/50% ethyl acetate in hexane)
Example 7 N-Benzyl-N-[ (4-npropyloxy)benzyl]-3,4- dimethoxybenzenesulphonamide.
Cesium carbonate (O.llg) was added to a stirred solution of N-ben z y l -N- ( 4 -hydroxy ) ben z y l - 3 , 4 - dimethoxybenzenesulphonamide (O.lg) in DMF (5ml) under a nitrogen atmosphere. 1-Bromopropane (0.03ml) was then added dropwise and the mixture heated at 75°C for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate, washed with 10% potassium carbonate solution then dried over magnesium sulphate and concentrated in vacuo to afford the title compound (0.10g) as a clear oil.
IR (Nujol) v^ 1509, 1330, 1261 cm"1.
TLC Rf 0.32 (30% ethyl acetate in hexane).
The following compounds were prepared from the appropriate starting materials, using the above procedure.
Example 8 N-Benzyl-N-[ (3-npropyloxy)benzyl]-3,4- dimethoxybenzenesulphonamide.
Crystallization from ethyl acetate/hexane afforded the title compound (0.21g) as a white solid.
m.p. 85-86°C TLC Rf 0.32 (30% ethyl acetate in hexane).
Example 9 N-(3-Cyanopropyl) -N-(4-pyridylmethyl) -3,4- dimethoxybenzene-sulphonamide.
Sodium hydride (60% dispersion in oil, 29mg) was added to a solution of N-(4-
pyridylmethyl)-3,4-dimethoxybenzenesulphonamide (202mg) in anhydrous N,N-dimethylformamide (5ml) under an atmosphere of nitrogen at room temperature. After 30 minutes 4- bromobutyronitile (78 l) was added and stirring continued for 24 hours. The mixture was concentrated in vacuo, then purified by column chromatography on silica eluting with 1% methanol in dichloromethane to afford the title compound as a colourless oil (125mg) that solidified on standing.
m.p. 108-110°C
TLC Rf 0.25 (25% ethyl acetate in hexane)
The following compounds were prepared using the above general procedure from the starting sulphonamide and appropriate halide.
Example 10 N-(3-Cyanopropyl)-N-(2-pyridylmethyl) -3,4- dimethoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 1% methanol in dichloromethane to afford the title compound (96mg) as an oil.
IR (Nujol) n_3X 1154, 1340, 2242 cm"1.
TLC Rf 0.25 (1% methanol in dichloromethane).
Example 11 N-(3-Cyanopropyl)-N-(2,6-dichlorobenzyl) -
3 ,4-dimethoxybenzene-sulphonamide. Purification was achieved by column chromatography on silica eluting with 5% ethyl acetate in dichloromethane to afford the title compound (345mg) as an oil that solidified on standing.
m.p. 120-122°C
TLC Rf 0.35 (5% ethyl acetate in dichloromethane).
Example 12 N-(3-Cyanopropy1)-N-(3-pyridylmethy1)-3,4- dimethoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 1% methanol in dichloromethane to afford the title compound (I68mg) as an oil that solidified on standing.
m.p. 86-88°C
TLC Rf 0.20 (1% methanol in dichloromethane).
Example 13 N-(3-Cyanopropy1) -N-phenethyl -3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 55% ethyl acetate in hexane to afford the title compound (I54mg) as an oil.
IR (thin film) n^ 1154, 1332, 2247 cm*1. TLC Rf 0.25 (50% ethyl acetate in hexane) .
Example 14 N-Benzyl-N-(3-Cyanopropy1)-3-(3- phenoxypropoxy)-4-methoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane followed by crystallisation from ethyl acetate-hexane to afford a colourless solid (23mg) . m.p. 78-80°C
TLC Rf 0.50 (60% ethyl acetate in hexane) .
Example 15 N-(3-Cyanopropy1)-N-furfury1-3-(3- phenoxypropoxy)-4-methoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane followed by crystallisation from ethyl acetate-hexane to afford a colourless solid (33mg) .
m.p. 80-82°C
TLC Rf 0.47 (60% ethyl acetate in hexane).
Example 16 N-(Carboethoxymethyl) -N-furfuryl -3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography eluting with 50% ethyl acetate in hexane to afford the title compound as an oil that solidified on standing.
m.p. 56 -57°C
TLC Rf 0.56 (60% ethyl acetate in hexane).
Example 17 N-(Carbomethoxymethyl) -N-furfuryl -3,4- dimethoxybenzenesulphonamide.
Crystallisation from ethyl acetate-hexane afforded pale yellow crystals (257mg) .
m.p. 86.5 - 87.5°C
TLC Rf 0.48 (60% ethyl acetate in hexane) .
Example 18 Methyl 2-[N-(3-cyanopropyl)-3,4- dimethoxybenzenesulphonamido]-3- phenylpropionate. Purification was achieved by column chromatography eluting with 50% ethyl acetate in hexane to afford the title compound (127mg) as an oil.
IR (thin film) n^ 1138, 1334, 1738, 2246 cm"1. TLC Rf 0.33 (50% ethyl acetate in hexane).
Example 19 N-Furfuryl-N-(2-oxopropyl) -3,4- dimethoxybenzenesulphonamide.
Crystallisation from ethyl acetate-hexane afforded pale yellow crystals (229mg) .
m.p. 100 - 102°C TLC Rf 0.43 (60% ethyl acetate in hexane).
Example 20 N-Furfuryl-N-cyanomethyl-3,4- dimethoxybenzenesulphonamide.
Trituration of the crude product with hexane then crystallization from ethanol afforded the title compound (4.98g) .
m.p. 98 -101°C TLC Rf 0.48 (50% ethyl acetate in hexane) .
Example 21 N-(3-Cyanopropy1)-N-furfury1-3,4- dimethoxybenzenesulphonamide.
Crystallization from toluene-hexane afforded the title compound.
m.p. 103 -105°C
TLC Rf 0.34 (50% ethyl acetate in hexane).
Example 22 N- Furf ury l - N - pr opy l - 3 , 4 - dimethoxybenzenesulphonamide . Crystallization from ethanol afforded the title compound.
m.p. 83 -84°C
TLC Rf 0.60 (50% ethyl acetate in hexane).
Example 23 N-Benzyl-N- (4-chlorobenzyl) -3 , 4 - dimethoxybenzenesulfonamide.
Purification was achieved by column chromatography on silica eluting with 66% diethyl ether in hexane to afford the title compound (0.61g) as a white solid.
m.p. 97-98°C
TLC Rf 0.74 (50% ethyl acetate in hexane).
Example 24 N-Benzyl-N-(3-chlorobenzyl)-3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 66% diethyl ether in hexane to afford the title compound (0.46g) as a white solid.
m.p. 89-91°C
TLC Rf 0.2 (66% diethyl ether in hexane) .
Example 25 N-Benzyl-N-(2-chlorobenzyl)-3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane to afford the title compound (0.57g) as a white solid.
m.p. 108-110°C
TLC Rf 0.86 (50% ethyl acetate in hexane).
Example 26 N-Benzyl-N-(4-cyanobenzyl) -3,4- dimethoxybenzenesulphonamide. Purification was achieved by column chromatography on silica eluting with 33% ethyl acetate in hexane to afford the title compound (2.33g) as a white solid.
m.p. 105-107°C
TLC Rf 0.52 (50% ethyl acetate in hexane) .
Example 27 N-Benzyl-N-(3-cyanobenzy1)-3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 75% diethyl ether in hexane to afford the title compound (2.22g) as a white solid.
m.p. 82-83°C
TLC Rf 0.1 (66% diethyl ether in hexane).
Example 28 N-Benzyl-N-(2-cyanobenzyl) -3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 66% diethyl ether in hexane to afford the title compound (0.l9g) as a white solid.
m.p. 82-83 C
TLC Rf 0.52 (66% diethyl ether in hexane).
Example 29 N-(3-Cyanopropy1)-N-(1-phenylethyl)-3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 10% ethyl acetate in dichloromethane to afford the title compound (0.74g) as a clear oil.
IR (KBr disc) IT-. 1509, 1262, 1328 cm"1.
TLC Rf 0.27 (10% ethyl acetate in dichloromethane). Example 30 N-Benzyl-N-(3-aminopropyl)-3,4- dimethoxybenzenesulphonamide.
The crude product was partitioned between ethyl acetate and 2M HC1. The aqueous phase was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and concentated in vacuo to afford the title compund (40mg) as a clear gum.
IR (KBr disc) n__x 1509, 1329, 1262 cm"1
TLC Rf 0.32 (9% methanol/1% triethylamine in dichloromethane) .
Example 31 N-Benzyl-N-(3-methanesulphonyloxy)benzyl-
3,4-dimethoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 60% ethyl acetate in hexane to afford the title compound (2.4g) as a white solid.
m.p. 77-78°C
TLC Rf 0.77 (15% ethyl acetate in dichloromethane).
Example 32 N-Benzyl-N-(4-methoxycarbonyl)benzyl-3,4- dimethoxybenzene-sulphonamide.
Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane to afford the title compound (1.43g) as a white solid.
m.p. 86-88°C
TLC Rf 0.48 (50% ethyl acetate in hexane).
Example 33 N-Benzyl-N-(3-methoxycarbonyl)benzyl-3,4- dimethoxybenzene-sulphonamide. Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane to afford the title compound (1.76g) as a clear, viscous oil.
IR (thin film) n^ 1720, 1508, 1331 cm"1. TLC Rf 0.58 (50% ethyl acetate in hexane).
Example 34 N-Benzyl-N-(2-pyridylmethyl) -3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 10% ethyl acetate in dichloromethane to afford the title compound (lOOmg) as a clear gum.
IR (thin film) n^ 1508, 1329, 1262 cm"1.
TLC Rf 0.31 (10% ethyl acetate in dichloromethane).
Example 35 N-Benzyl-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide.
Purification was achieved by column chromatography on silica eluting with 75% ethyl acetate in hexane to afford the title compound (90mg) as a clear gum.
IR (thin film) !!___ 1508, 1331, 1139 cm"1.
TLC Rf 0.77 ( 75% ethyl acetate in hexane) .
Example 36 N-(3-Cyanopropy1)-N-[2-(2-pyridy1)ethyl]- 3,4-dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with ethyl acetate provided the title compound as a clear oil (llOmg) .
TLC Rf 0.22 (ethyl acetate). IR (thin film) n^ 1589, 1509, 1139 cm"1, Example 37 N,N-Di-(3-pyridylmethyl) -3 ,4- dimethoxybenzenesulphonamide.
Purification by column chromatography eluting with 10% methanol/ 1% triethylamine in ethyl acetate provided the title compound as a beige solid (165mg) .
TLC Rf 0.08 (1% acetic acid/ 5% methanol in ethyl acetate), m.p. 109-110°C.
Example 38 N-(Carboxamidomethyl)-N-benzyl-3 ,4- dimethoxybenzenesulphonamide
Purification by column chromatography eluting with 40% ethyl acetate in hexane afforded the title compound as a white solid (74mg) .
TLC Rf 0.2 (40% ethyl acetate in hexane) . m.p. 135-137°C.
Example 39 N-Propyl-N-[4-(3-pyridy1)benzyl]-3,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with ethyl acetate furnished the above compound (181mg) as a white foam.
TLC Rf 0.4 (ethyl acetate)
IR n__χ 1587, 1508, 1464, 1403, 1330, 1261, 1237, 1152, 1138, 1092, 1020 cm"1.
Example 40 N-Furfuryl-N-methyl-3,4- dimethoxybenzenesulphonamide.
Trituration with diethyl ether afforded the title compound (263mg) as an off-white solid. TLC Rf 0.7 (50% ethyl acetate in hexane) m.p. 133-134°C
The following compounds were prepared according to the above procedure from N-propyl-3 , 4- dimethoxybenzenesulphonamide and the appropriate halide.
Example 41 N-(2-Methoxycarbonylfurfuryl)-N-propyl-3,4- dimethoxybenzene-sulphonamide.
Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane provided the title compound (0.59g) as a clear oil.
TLC Rf 0.8 (15% ethyl acetate in dichloromethane) IR _m 1727, 1588, 1509, 1306, 1262, 1139 cm"1.
Example 42 N-(4-Methoxycarbonylbenzyl)-N-propyl-3,4- dimethoxybenzene-sulphonamide.
Purification by column chromatography on silica eluting with 5% ethyl acetate in dichloromethane yielded the title compound (1.61g) as a white solid.
TLC Rf 0.45 (50% ethyl acetate in hexane) m.p. 112.5 - 113.5°C
Example 43 N-Furfuryl-N-(2-hydroxyethyl)-3,4- dimethoxybenzenesulphonamide.
Lithium aluminium hydride (0.03g) was suspended in anhydrous tetrahydrofuran (10ml) under an atmosphere of nitrogen at room temperature. To this was added, over 15 minutes, a solution of the ethyl ester (0.20g) prepared as above, in anhydrous tetrahydrofuran (10ml) . The mixture was heated at 60°C for 5 hours then stirred at room temperature for a further 24 hours. After quenching with hydrochloric acid (4ml, 2M) the mixture was concentrated in vacuo. The residue was redissolved in ethyl acetate (20ml) then washed with dilute hydrochloric acid (20ml, 2M) , water (20ml) and saturated brine (20ml) . The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo to yield a colourless oil.
Purification by column chromatography on silica eluting with 70% ethyl acetate in hexane followed by crystallization from ethyl acetate-hexane afforded a colourless solid (34mg) .
m.p. 84 -86°C
TLC Rf 0.24 (60% ethyl acetate in hexane).
Example 44 N-Benzyl-N-ethanesulphonyl-3,4- dimethoxybenzenesulphonamide.
Sodium hydride (60% dispersion, 72mg) was added to a st irred so lution of N-benz y l - 3 , 4 - dimethoxybenzenesulphonamide (500mg) in DMF (15ml) at 0°C under nitrogen. The mixture was stirred at 0°C for 15 minutes before a solution of ethanesulphonyl chloride (230mg) in DMF (5ml) was added. The solution was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane (50ml) and washed with water (2 x 20ml) and brine (20ml) . The solution was dried (magnesium sulphate) , filtered and evaporated in vacuo. Purification by column chromatography on silica eluting with dichloromethane afforded the title compound (506mg) as a clear gum.
TLC Rf 0.63 (dichloromethane)
IR (KBr) n_3X 2941, 1587, 1509, 1369, 1267, 1239, 1156, 1094, 1021 cm'1. The following compounds were prepared according to the above procedure from the appropriate sulphonamide and sulphonyl chloride.
Example 45 N-Benzyl-N-benzenesulphonyl-3 ,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with dichloromethane afforded the title compound (600mg) as a white solid.
m.p. 108-109°C
TLC Rf 0.48 (dichloromethane)
Example 46 N-Benzyl-N-methanesulphonyl-3,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane and subsequent recrystallization from ethyl acetate/hexane yielded the title compound (0.92g) as a white solid.
m.p. 113-114.5°C
TLC Rf 0.36 (50% ethyl acetate/hexane)
Example 47 N-Methanesulphonyl-N-(3-pyridylmethyl)-3,4- dimethoxybenzene-sulphonamide.
Purification by column chromatography on silica eluting with ethyl acetate and recrystallization from ethyl acetate/hexane furnished the title compound (553mg) as a white solid.
m.p. 121-122°C TLC Rf 0.42 (ethyl acetate) Example 48 N-Benzyl-N-(2-phthalimidoethanesulphonyl)- 3,4-dimethoxybenzene-sulphonamide.
Purification by column chromatography on silica eluting with 3% ethyl acetate in dichloromethane yielded the title compound (240mg) as a white solid.
m.p. 160-161°C
TLC Rf 0.75 (5% ethyl acetate/dichloromethane)
Example 49 N-Methanesulphony1-N-[2-(2-pyridy1)ethyl]- 3,4-dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with 35% ethyl acetate-hexane provided the title compound as a clear oil (I9mg) .
TLC Rf 0.35 (35% ethyl acetate in hexane). IR (thin film) !!___ 1590, 1510, 1364, 1159 cm"1.
Example 50 N-Methanesulphonyl-N-[1,2,3-thiadiazol-4- yl)benzyl]-3,4-dimethoxy-benzenesulphonamide
Purification by column chromatography eluting with 55% ethyl acetate-hexane and subsequent trituration with diethyl ether provided the title compound as a white solid (94mg) .
TLC Rf 0.35 (55% ethyl acetate in hexane). m.p. 172-173°C.
Example 51 N-Methanesulphonyl-N-(4-methoxybenzyl)-3,4- dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with 33% ethyl acetate-hexane provided the title compound as a white solid (2.6g) . TLC Rf 0.43 (50% ethyl acetate in hexane) . m.p. 149-150°C.
Example 52 N-Methanesulphonyl-N-(2-pyridylmethyl)-3,4- dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with 50% ethyl acetate-hexane afforded the title compound as a colourless solid (lOOmg) .
TLC Rf 0.74 (ethyl acetate), m.p. 123-124°C.
Example 53 N-Methanesulphonyl-N-pyrazinylmethyl-3,4- dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with ethyl acetate provided the title compound as a white solid (lOOmg) .
TLC Rf 0.45 (ethyl acetate), m.p. 141-142°C.
Example 54 N-Methanesulphonyl-N-[4-(3-pyridy1)benzyl]- 3,4-dimethoxybenzene-sulphonamide.
Purification by column chromatography eluting with ethyl acetate and subsequent trituration with diethyl ether/hexane provided the title compound as a white solid (61mg) .
TLC Rf 0.33 (ethyl acetate), m.p. 132-134°C.
Example 55 N-Methanesulphonyl-N-[3-(3-pyridyl)benzyl]-
3 ,4-dimethoxybenzene-sulphonamide Purification by column chromatography eluting with ethyl acetate and subsequent evaporation in vacuo from diethyl ether/hexane provided the title compound as a white foam (56mg) .
TLC Rf 0.3 (ethyl acetate).
IR (thin film) n^ 1509, 1366, 1265, 1159 cm'1.
Example 56 N-Methanesulphonyl-N-[2-(3-pyridyl)benzyl]- 3,4-dimethoxybenzene-sulphonamide
Purification by column chromatography eluting with ethyl acetate and subsequent evaporation in vacuo from diethyl ether provided the title compound as an off-white foam (26mg) .
TLC Rf 0.35 (ethyl acetate)
IR n^ 1587, 1509, 1366, 1266, 1159, 1142 cm"1.
Example 57 N-Furfuryl-N-methanesulphonyl-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography eluting with 50% ethyl acetate-hexane provided the title compound as a clear oil (400mg) which solidified on standing.
TLC Rf 0.5 (50% ethyl acetate in hexane). m.p. 110-112°C.
Example 58 N- (2-Phthalimidoethanesulphonyl) -N- (3- pyridylmethyl)-3,4-dimethoxy-benzenesulphonamide
Purification by crystallisation from ethyl acetate/hexane provided the title compound as a cream solid (236mg) .
TLC Rf 0.56 (10% methanol in ethyl acetate) m.p. 177-178°C. Example 59 N-Methanesulphonyl-N-(2-methylthiazol-4- ylmethyl)-3,4-dimethoxy-benzenesulphonamide
Purification by column chromatography eluting with with 50%ethyl acetate-hexane provided the title compound as a white solid (250mg) .
TLC Rf 0.75 (ethyl acetate).
IR (thin film) n^ 1509, 1367, 1266, 1160 cm'1,
The following compounds were prepared by the above procedure from N-benzyl-3,4-dimethoxybenzenesulphonamide, the appropriate acid chloride and a reaction time of 4 days.
Example 60 N-Benzoyl-N-benzyl-3,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with dichloromethane gave the title compound (0.57g) as a white solid.
m.p. 104°C
TLC Rf 0.38 (dichloromethane)
Example 61 N-Benzyl-N-propionyl-3,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with dichloromethane yielded the title compound (0.44g) as a clear gum.
TLC Rf 0.3 (dichloromethane)
IR n^ 2941, 1702, 1588, 1511, 1457, 1408, 1357, 1266, 1240, 1161, 1141, 1092, 1020 cm"1. Example 62 N-[2-Amino(N- benzenesulphony1)ethanes lphonyl]-N-(3- pyridylmethyl) -3,4-dimethoxybenzenesulphonamide
Triethylamine (500μl) was added to a suspension of N-(2- Aminoethanesulphonyl) -N- (3 -pyridylmethyl) -3 , 4- dimethoxybenzenesulphonamide (1.22g) in dicloromethane (20ml) at 0°C under an inert atmosphere. Benzenesulphonylchloride (340μl) was then added and the resultant solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20ml) and washed with 50% saturated sodium hydrogen carbonate solution (40ml) . The solution was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography eluting with 5% methanol in ethyl acetate to provide the title compound as a pale yellow solid (630mg) .
TLC Rf 0.56 (10% methanol in ethyl acetate) . m.p. 68-70°C.
The following compounds were prepared from the appropriate starting materials using the above procedure.
Example 63 N-[2-Amino(N-benzoyl)ethanesulphonyl]-N-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
Purification by column chromatography eluting with 5% methanol in ethyl acetate provided the title compound as a white solid (20mg) .
TLC Rf 0.61 (10% methanol in ethyl acetate), m.p. 134-135.5°C.
Example 64 N-[2-(N,N-
Dibenzenesulphonyl)aminoethanesulphonyl]-(3- pyridyl ethyl)-3,4-dimethoxybenzenesulphonamide Purification by column chromatography eluting with l%-5% methanol in dichloromethane afforded the title compound as a yellow oil (120mg) .
TLC Rf 0.46 (4% methanol in dichloromethane).
IR (thin film) n^ 1509, 1377, 1267, 1168 cm*1.
Example 65 N-[2-Amino(N- benzenesulphonyl)ethanesulphonyl]-N-furfury1-3,4- dimethoxybenzenesulphonamide
Purification by column chromatography eluting with 20%-50% ethyl acetate in hexane provided the title compound as an off-white semi-solid (120mg) .
TLC Rf 0.35 (50% ethyl acetate in hexane).
IR (thin film) n 1509, 1374, 1266, 1160 cm' ,
Example 66 N-Benzyl-N-(3-hydroxybenzyl)-3,4- dimethoxybenzenesulphonamide.
Aqueous sodium hydroxide solution (IM, 25ml) was added to asolutionofN-benzyl-N-(3-methanesulphonyloxybenzyl)-3,4- dimethoxybenzenesulphonamide (2.0g) in 1,4-dioxane (25ml) and the mixture heated at 85°C for 3 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (75ml) and 2M aqueous hydrochloric acid (75ml) . The aqueous layer was further extracted with ethyl acetate (75ml) and the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from diethyl ether/hexane afforded an off- white solid (1.5g) .
m.p. 107-108°C TLC Rf 0.47 (15% ethyl acetate in dichloromethane) The following compound was prepared by the above procedure using the appropriate starting material.
Example 67 N-Benzyl-N-(4-hydroxybenzyl) -3,4- dimethoxybenzenesulphonamide.
Purification by column chromatography on silica eluting with 15% ethyl acetate in dichloromethane afforded the title compound as a clear oil.
TLC Rf 0.6 (15% ethyl acetate in dichloromethane)
IR (thin film) !!___ 3447, 2936, 1614, 1590, 1509, 1326,
1263, 1238, 1138, 1094, 1020 cm"1.
Example 68 N-Benzyl-N-(4-carboxamidobenzyl) -3 ,4- dimethoxybenzenesulphonamide.
Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4 -carboxybenzyl ) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. Ammonium hydroxide solution (8ml) was added to the reaction; the resulting precipitate was filtered off, washed with water and dried in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.13g) as a white solid.
m.p. 172°C TLC Rf 0.42 (ethyl acetate).
The following compounds were prepared from the appropriate starting materials, using the above procedure.
Example 69 N-Benzyl-N-(3-carboxamidobenzyl)-3,4- dimethoxybenzenesulphonamide. The title compound (0.20g) was obtained as a white solid.
m.p. 146-148°C
TLC Rf 0.38 (ethyl acetate).
Example 70 N-(4-Carboxamidobenzyl)-N-propyl-3,4- dimethoxybenzenesulphonamide.
The title compound (0.21g) was obtained as a white solid.
m.p. 173 - 175°C
TLC Rf 0.45 (ethyl acetate)
Example 71 N-Benzyl-N-[4-(N-methyl)carboxamidobenzyl]- 3,4-dimethoxybenzene-sulphonamide.
Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4-carboxybenzyl) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. The reaction mixture was then added to aqueous methylamine solution (40%, 10ml) . After stirring for a further 60 minutes, the layers were separated. The organic phase was washed with dilute hydrochloric acid (25ml) , water (20ml) , brine (20ml) , dried over magnesium sulphate and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.39g) as a white solid.
m.p. 140-142 C
TLC Rf 0.41 (ethyl acetate).
The following compounds were prepared using the appropriate starting materials, using the above procedure.
Example 72 N-Benzy1-N-[3-(N-methyl)carboxamidobenzy1]- 3,4-dimethoxybenzene-sulphonamide.
The title compound (0.28g) was obtained as a white solid.
m. p. 102-104°C
TLC Rf 0.44 (ethyl acetate) .
Example 73 N- [ 4- (N-Methyl) carboxamidobenzy 1 ] -N-propyl-
3 , 4 -dimethoxybenzene-sulphonamide .
The title compound (0.26g) was obtained as a white solid.
m.p. 151.5 - 153°C
TLC Rf 0.4 (ethyl acetate)
Example 74 N-[4-(N,N-Dimethy1)carboxamidobenzy1]-N- propyl-3,4-dimethoxybenzene-sulphonamide.
The title compound (0.35g) was obtained as a clear oil.
TLC Rf 0.35 (ethyl acetate)
IR n^ 2964, 2934, 1632, 1588, 1509, 1462, 1404, 1330,
1262, 1237, 1153, 1092, 1019 cm"1.
Example 75 N-Benzyl-N-(4-carboxybenzyl) -3,4- dimethoxybenzenesulphonamide.
N-Benzyl-N- (4-methoxycarbonyl) benzyl-3 , 4 - dimethoxybenzenesulphonamide (l.lg) was dissolved in tetrahydrofuran (20ml) , treated with aqueous lithium hydroxide (0.2g in water (20ml)) and then stirred for 24 hours at room temperature. Concentration in vacuo gave a residue which was diluted with water and acidified with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and concentrated in vacuo to afford the title compound (1.07g) as a white solid. m.p. 193-195 C
TLC Rf 0.28 (50% ethyl acetate in hexane) .
The following compounds were prepared from the appropriate starting materials, using the above procedure.
Example 76 N-Benzyl-N-(3-carboxybenzy1)-3,4- dimethoxybenzenesulphonamide.
The title compund (0.97g) was obtained as a white solid.
m.p. 55-57°C
TLC Rf 0.27 (50% ethyl acetate in hexane).
Example 77 N-(2-Carboxyfurfuryl)-N-propyl-3 ,4- dimethoxybenzenesulphonamide.
The title compound (0.44g) was obtained as a white solid.
TLC Rf 0.1 (50% ethyl acetate in hexane) m.p. 152.5-153.5°C
Example 78 N-4-Carboxybenzyl-N-propyl-3 , 4 - dimethoxybenzenesulphonamide.
The title compound (1.41g) was obtained as a white solid.
TLC Rf 0.14 (50% ethyl acetate in hexane) m.p. 151 - 152.5°C
Example 79 N-Benzyl-N-(methanesulphonylmethyl)-3,4- dimethoxybenzene-sulphonamide
A solution of oxone™ (390mg) in water (2ml) was added to a a stirred solution of N-Benzyl-N-(methanethiomethyl)-3,4- dimethoxybenzenesulphonamide (150mg) in methanol (5ml) at
0-5°C. The resultant slurry was stirred at 0-5°C for 1 hour and then at room temperature overnight. The reaction mixture was partitioned betwen diethyl ether (2x30ml) and water (30ml) and the combined organic phases were dried over magnesium sulphate and concentrated in vacuo. Purification by recrystallisation from ethyl acetate/hexane afforded the title compound as a pale yellow solid (99mg) .
TLC Rf 0.31 ( 50% ethyl acetate in hexane) . m.p. 117-118°C.
The following compound was prepared from the appropriate starting materials, using the above procedure.
Example 80 N-(Methanesulphonylmethyl)-N-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
Purification by recrystallisation from ethyl acetate/hexane provided the title compound as a cream solid (275mg) .
TLC Rf 0.45 (10% methanol in ethyl acetate), m.p. 124.5-126°C.
Example 81 N-[2-Amino(N-pyridin-3-oyl)ethanesulphonyl]- N-(3-pyridylmethyl) -3,4-dimethoxybenzenesulphonamide
N- (2-Aminoethanesulphonyl) -N- (3-pyridylmethyl) -3,4- dimethoxybenzenesulphonamide (240mg) , nicotinic acid (71mg) , 1-hydroxybenzotriazole (172mg) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochoride (240mg) in dichloromethane (10ml) and tetrahydrofuran (5ml) were stirred at room temperature overnight under an inert atmosphere. The resulting solution was diluted with dichloromethane (20ml) and extracted with 50% saturated sodium hydrogen carbonate solution (40ml) . The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography eluting with 1% triethylamine/10% methanol in ethyl acetate and subsequently crystallised using dichloromethane/hexane to provide the title compound as a white solid (142mg) .
TLC Rf 0.16 (10% methanol in ethyl acetate) m.p. 149-150.5°C.
Example 82 N-[2-Amino(N-Benzyl)ethanesulphonyl]-N-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
Benzaldehyde (62μl) was added to a stirred solution of N- (2-aminoethanesulphonyl)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide (250mg) in dicloromethane (10ml) under an inert atmosphere. Sodium triacetoxyborohydride (190mg) was then added and the reaction stirred at room temperature overnight. The resulting solution was diluted with dichloromethane (40ml) and extracted with 50% saturated sodium hydrogen carbonate solution (50ml) . The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 1% triethylamine/ 7.5% methanol in ethyl acetate providing the title compound as a clear oil (81mg) .
TLC Rf 0.36 (10% methanol in ethyl acetate). IR (thin film) n^ 1509, 1371, 1265, 1155 cm'1.
The following compound was prepared using the appropriate starting materials using the above procedure.
Example 83 N-[2-Amino(N,N-dibenzyl)ethanesulphonyl]-N- (3-pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
Purification by column chromatography eluting with 1% triethylamine/ 7.5% methanol in ethyl acetate provided the title compound as a pale yellow oil (59mg) .
TLC Rf 0.67 (10% methanol in ethyl acetate). IR (thin film) n 1509, 1372, 1266, 1157 cm'1.
Example 84 N-(2-A inoethanesulphony1)-N-(3- pyridylmethyl)-3,4-dimethoxy-benzenesulphonamide
Hydrazine monohydrate (1.21ml) was added to a solution of
N-(2-Pthalimidoethane-sulphonyl)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide (290mg) in ethanol (10ml) and tetrahydrofuran (10ml) at reflux. After stirring at reflux for 30 minutes the reaction was cooled to room temperature and water (2.5ml) was added. The resulting solution was concentrated in vacuo, with the residue being partitioned between saturated sodium hydrogen carbonate solution (40ml) and dichloromethane (2x40ml) . The organic phase was dried over magnesium sulphate and concentrated in vacuo to yield the title compound as a yellow oil (220mg) .
TLC Rf 0.09 (1% triethylamine/10% methanol in ethyl acetate) . IR (thin film) nMX 1509, 1369, 1266, 1156 cm*1.
The following compound was prepared using the appropriate starting materials using the above procedure.
Example 85 N-Benzyl-N-(2-aminoethanesulphony1)-3,4- dimethoxybenzene-sulphonamide
Purification was achieved by partitioning the crude residue between IM hydrochloric acid (40ml) and dichloromethane (2x40ml) . The aqueous phase was then bascified to pH 14 using sodium hydroxide pellets and subsequently extracted with dichloromethane (2x100ml) . The organic phase was dried over magnesium sulphate and concentrated in vacuo to provide the title compound as a clear oil (61mg) .
TLC Rf 0.42 (10% methanol in ethyl acetate) IR (thin filming 1509, 1369, 1266, 1155 cm"1, Assay methods
The assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (i) are standard assay procedures as disclosed by Schilling et al Anal. Biochem. 216 154 (1994), Thompson and Strada Adv. Cycl. Nucl. Res. 8 119 (1979) and Gristwood and Owen Br. J. Pharmacol. 87 91P (1986) .
Compounds of formula (i) have exhibited activity at levels consistent with those believed to be useful in treating phosphodiesterase IV related disease states in those assays.

Claims

1. Compounds of the general formula (i)
Figure imgf000068_0001
in which R1 represents C,_6 alkyl (optionally substituted with one or more substituents chosen from amongst halogen, C1.6 alkoxy, aryloxy, arylalkyloxy, C1.6 alkylamino, arylalkylamino or arylamino) or cycloalkyl (optionally substituted with one or more substituents chosen from amongst halogen, C1.6 alkoxy, aryloxy, arylalkyloxy, C1.6 alkylamino, arylalkylamino or arylamino) ;
R2 represents Cl-3 alkyl optionally substituted with halogen;
R3 represents arylalkyl, heteroarylalkyl, heterocycloalkyl, C0R7, S(0)mR7, C1.6 alkyl optionally substituted with one or more substituents chosen from amongst hydroxy, C^_6 alkoxy, -C02H, C02Rg, SO2NRoR10, CONRoR10, -CN, carbonyl oxygen, NRjR6, COR7, S(0)nR7,
R4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl;
when R3 and/or R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl, the alkyl portion may be optionally substituted with one or more substituents chosen from amongst C02H, C02R8 , S02NRoR10, CONR9R10, hydroxy, C,_6 alkoxy, NRgR6, COR7, S(0)nR7, -CN or carbonyl oxygen and/or the aryl/heteroaryl/heterocyclo portion may be optionally substituted with one or more substituents C0-6 alkyl-R^ ;
Rj and R6, which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C^ alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, G,.6 alkylcarbonyl, C 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl heteroarylcarbonyl, heterocyclocarbonyl or C.,.6 alkylsulphonyl, provided that when R- is C,_6 alkylcarbonyl, C,_6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, he eroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C,_6 alkylsulphonyl, R6 is not C 6 alkylcarbonyl, C,_6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C._ 6 alkylsulphonyl ;
R7 represents aryl, heteroaryl, heterocyclo or C,^ alkyl, any of which may be optionally substituted with one or more substituents chosen from amongst halogen, aryl, heteroaryl, heterocyclo, C 6 alkoxy, hydroxy, C02H, C02R8 , SO2NRQR10, CONR^O, NRJR6, or carbonyl oxygen;
R8 represents C 6 alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
Hς and R10, which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C1.6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl;
Rυ represents H, aryl, heteroaryl, heterocyclo, hydroxy, C1.6 alkoxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, -C02H, CO^, SO2NRoR10, CONRoR10, halogen, -CN, -NR5R6, COR7, S(0)nR7, -CN or carbonyl oxygen;
m represents 1-2; and
n represents 0-2;
and pharmaceutically acceptable salts thereof, and, where applicable, all stereoisomers including enantiomers and diastereoisomers and mixtures including racemic mixtures thereof.
2. A compound of claim 1, wherein
when R3 is alkyl, any substituents are selected from OH, alkoxy, COOH, (and C^ alkyl esters and C1.6 alkyl amides thereof), CN, carbonyl oxygen, NRgR6, C0R7 and S(O)0.
2R7*
for R4, and when R3 is arylalkyl, heteroarylalkyl or heterocycloalkyl, the alkyl portion is optionally substituted by COOH (and C,_6 alkyl esters and C 6 alkyl amides thereof), OH, alkoxy, NRgR6, COR7, S(O)0.2R7, CN or carbonyl oxygen, and the aryl/heteroaryl/heterocyclo portion is optionally substituted by one or more of aryl, heteroaryl, heterocyclo, OH, alkoxy, COOH (and C1.6 alkyl esters and C^.6 alkyl amides thereof) , halogen, CN, NRjR6,
C0R7, S(O)0.2R7 and alkyl optionally substituted by one or more of aryl, heteroaryl, heterocyclo, COOH (and C^ alkyl esters and C 6 alkyl amides thereof) , OH-, alkoxy, NRjR6, C0R7, S(O)0.2R7, CN and carbonyl oxygen;
Rj and R6 are independently selected from H, alkyl, alkylcarbonyl, alkoxycarbonyl, arylsulphonyl, arylcarbonyl and alkylsulphonyl;
R7 is alkyl optionally substituted by one or more of halogen, aryl, heteroaryl, alkoxy, OH, COOH, (and C 6 alkyl esters and C1.6 alkyl amides thereof), NRjR6, S(O)0.2R8 and carbonyl oxygen; and
R8 is alkyl, aryl or heteroaryl.
3. A compound of claim 2, wherein R1 is alkyl or cycloalkyl, either being optionally substituted by halogen, alkoxy, aryloxy or arylalkoxy; and
R3 is arylaklyl, heteroarylalkyl, heterocycloalkyl or alkyl optionally substituted by OH, alkoxy, COOH (or C,_6 alkyl esters or C1.6 alkyl amides thereof) , COOalk, CN or carbonyl oxygen;
for R4 and when R3 is arylalkyl, heteroarylalkyl or heterocycloalkyl, the alkyl portion is optionally substituted by OH, alkoxy, for COOH (or C^ alkyl esters or C 6 alkyl amides thereof) , NRjR6, CN or carbonyl oxygen, and the aryl/heteroaryl/heterocyclo portion is optionally substituted by OH, alkoxy, COOH (or C,^ alkyl esters or C,_6 alkyl amides thereof) , halogen, CN or NRjR6.
4. A compound of any preceding claim hwerin R, is alkyl optionally substituted by aryloxy, or cycloalkyl.
5. A compound of any preceding claim, wherein R2 is methyl optionally substituted by halogen.
6. A compound of any preceding claim, wherein R3 is arylalkyl, heteroarylalkyl, COR7, S(0) R7 or optionally- substituted alkyl and R4 is arylalkyl or heteroarylalkyl;
the aryl or heteroaryl portion is optionally substituted by C0.6 alkyl-R,,;
Rj and R6 are independently selected from H, alkyl, alkylcarbonyll, alkylsulphonyl, aryl, heteroaryl, arylsulphonyl, heteroarylsulphonyl, arylcarbonyl, heteroarylcarbonyl, arylalkyl and heteroarylalkyl;
R7 is aryl, heteroaryl, or alkyl optoinally substituted by CN, COOH, C00R8, CONR^, SO-^^R,-, carbonyl oxygen or NRjR6;
R8 is alkyl;
R, and R10 are independently selected from H, alkyl, arylalkyl and heteroarylalkyl; and
Rnι is aryl, heteroaryl, OH, alkoxy, CN, COOH, COOR8, CONR9R10, SO2NR9R10, carbonyl oxygen, NRjR6, COR7 or S02R7.
7. A compound of claim 1, selected from
N,N-Dibenzyl-3,4-dimethoxybenzenesulphonamide,
N-Benzyl-N-(2-phenethyl)-3,4-dimethoxybenzenesulphonamide,
N-(2-Cyanoethy1)-N-benzyl-3,4-dimethoxybenzenesulphonamide,
N-(2-Cyanoethy1)-N-(tetrahydrofurfuryl)-3,4- dimethoxybenzenesulphonamide,
3-[N-Furfuryl-3,4 dimethoxybenzenesulphonamido]propanoic acid,
N-(3-Cyanopropyl)-N-(4-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide,
N-(3-Cyanopropy1) -N-(2-pyridylmethyl) -3,4- dimethoxybenzenesulphonamide,
N-(3-Cyanopropy1)-N-(2 ,6-dichlorobenzyl)-3,4- dimethoxybenzenesulphonamide, N-(3-Cyanopropy1)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphona ide ,
N-(3-Cyanopropy1)-N-phenethy1-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-Cyanopropy1)-3-(3-phenoxypropoxy)-4- methoxybenzenesulphonamide,
N-(3-Cyanopropy1)-N-furfuryl-3-(3-phenoxypropoxy)-4- methoxybenzenesulphonamide,
N-(Carboethoxymethyl)-N-furfury1-3,4- dimethoxybenzenesulphonamide,
N-(Carbomethoxymethyl)-N-furfuryl-3,4- dimethoxybenzenesulphonamide,
Methyl 2-[N-(3-cyanopropyl)-3,4- dimethoxybenzenesulphonamido]-3-phenylpropionate,
N-Furfuryl-N-(2-oxopropyl)-3,4- dimethoxybenzenesulphonamide,
N-Furfuryl-N-cyanomethy1-3,4-dimethoxybenzenesulphonamide,
N-(3-Cyanopropy1)-N-furfury1-3,4- dimethoxybenzenesulphonamide,
N-Furf ryl-N-propy1-3,4-dimethoxybenzenesulphonamide,
N-Furfuryl-N-(2-hydroxyethyl)-3,4- dimethoxybenzenesulphonamide.
8. A compound of claim 1, selected from N-(2-Cyanoethy1)-N-furfury1-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-[(4-npropyloxy)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-[ (3-"propyloxy)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(4-chlorobenzyl)-3,4- dimethoxybenzenesulfonamide,
N-Benzyl-N-(3-chlorobenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(2-chlorobenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(4-cyanobenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-cyanobenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(2-cyanobenzyl)-3,4- dimethoxybenzenesulphonamide,
N-(3-Cyanopropy1)-N-(1-phenylethyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-aminopropyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-methanesulphonyloxy)benzyl-3,4- dimethoxybenzenesulphonamide, N-Benzyl-N-(4-methoxycarbonyl)benzyl-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-methoxycarbonyl)benzyl-3,4-dimethoxybenzene- sulphonamid,
N-Benzyl-N-(2-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-ethanesulphonyl-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-benzenesulphonyl-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-methanesulphonyl-3 ,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-(3-pyridylmethyl)-3,4- dimethoxybenzene-sulphonamide,
N-Benzyl-N-(2-phthalimidoethanesulphonyl)-3,4- dimethoxybenzene-sulphonamide,
N-Benzoyl-N-benzyl-3,4-dimethoxybenzenesulphonamide,
N-Benzyl-N-propionyl-3,4-dimethoxybenzenesulphonamide.,
N-Benzyl-N-(3-hydroxybenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(4-hydroxybenzyl)-3,4- dimethoxybenzenesulphonamide, N-Benzyl-N-(4-carboxamidobenzy1)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-carboxamidobenzy1)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-[4-(N-methyl)carboxamidobenzy1]-3,4- dimethoxybenzene-sulphonamide,
N-Benzyl-N-[3-(N-methyl)carboxamidobenzyl]-3,4- dimethoxybenzene-sulphonamide,
N-Benzyl-N-(4-carboxybenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(3-carboxybenzyl)-3,4- dimethoxybenzenesulphonamide.
9. A compound of claim 1, selected from
N-(3-Cyanopropyl)-N-[2-(2-pyridyl)ethyl]-3,4- dimethoxybenzenesulphonamide,
N,N-Di-(3-pyridylmethyl)-3,4-dimethoxybenzenesulphonamide,
N-(Carboxamidomethyl)-N-benzyl-3,4- dimethoxybenzenesulphonamide,
N-Propyl-N-[4-(3-pyridyl)benzyl]-3 , - dimethoxybenzenesulphonamide,
N-Furfuryl-N-methyl-3,4-dimethoxybenzenesulphonamide,
N-(2-Methoxycarbonylfurfuryl)-N-propyl-3,4- dimethoxybenzenesulphonamide, N-(4-Methoxycarbonylbenzyl)-N-propyl-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-[2-(2-pyridyl)ethyl]-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-[1,2,3-thiadiazol-4-yl)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-(4-methoxybenzyl)-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-(2-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-pyrazinylmethyl-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-[4-(3-pyridyl)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-[3-(3-pyridyl)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Methanesulphonyl-N-[2-(3-pyridyl)benzyl]-3,4- dimethoxybenzenesulphonamide,
N-Furfury1-N-methanesulphony1-3,4- dimethoxybenzenesulphonamide,
N-(2-Phthalimidoethanesulphonyl)-N-(3-pyridylmethyl)-3,4- di ethoxybenzenesulphonamide,
N-Methanesulphonyl-N-(2-methylthiazol-4-ylmethyl)-3,4- dimethoxybenzenesulphonamide, N-[2-Amino(N-benzenesulphonyl)ethanesulphonyl]-N-(3- pyridyl ethyl)-3,4-dimethoxybenzenesulphonamide,
N-[2-Amino(N-benzoy1)ethanesulphonyl]-N-(3-pyridylmethyl)- 3,4-dimethoxybenzenesulphonamide,
N-[2-(N,N-Dibenzenesulphonyl)aminoethanesulphonyl]-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
N-[2-Amino(N-benzenesulphonyl)ethanesulphonyl]-N-furfuryl- 3,4-dimethoxybenzenesulphonamide,
N-(4-Carboxamidobenzy1)-N-propy1-3,4- dimethoxybenzenesulphonamide,
N-[4-(N-Methyl)carboxamidobenzy1]-N-propy1-3,4- dimethoxybenzene-sulphonamide,
N-[4-(N,N-Dimethyl)carboxamidobenzyl]-N-propyl-3,4- dimethoxybenzene-sulphonamide,
N-(2-Carboxyfurfury1)-N-propy1-3,4- dimethoxybenzenesulphonamide,
N-4-Carboxybenzyl-N-propyl-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(methanesulphonylmethyl)-3,4-dimethoxybenzene¬ sulphonamide,
N-(Methanesulphonylmethyl)-N-(3-pyridylmethyl)-3,4- dimethoxy-benzenesulphonamide,
N-[2-Amino(N-pyridin-3-oyl)ethanesulphonyl]-N-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide, N-[2-Amino(N-Benzyl)ethanesulphonyl]-N-(3-pyridylmethyl)- 3,4-dimethoxybenzenesulphonamide,
N-[2-Amino-(N,N-dibenzyl)ethanesulphonyl]-N-(3- pyridylmethyl)-3,4-dimethoxybenzenesulphonamide
N-(2-Aminoethanesulphonyl)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide,
N-Benzyl-N-(2-aminoethanesulphony1)-3,4-dimethoxybenzene sulphonamide
10. A compound of calim 1, in the form of an enantiomer or diastereoisomer, or any mixture of either.
11. A pharmaceutical composition containing a compound according to any of claims 1 to 10 as active ingredient, in combination with suitable excipients.
12. A method for treating a disease state capable of being modulated by inhibiting production of phosphodiesterase IV, comprising administering to a patient suffering from said disease an effective amount of a compound according to any of claims 1 to 10.
13. The method of claim 12, wherein the disease state is a pathological condition associated with a function of phosphodiesterase IV, eosinophil accumulation or a function of the eosinophil.
14. The method of claim 13, wherein the pathological condition is selected from asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, rheumatoid arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome, diabetes insipidus, keratosis, atopic dermatitis, atopic eczema, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, stroke and intermittent claudication.
15. The method of claim 14, wherein the pathological condition is asthma.
16. A method for treating a disease state capable of being modulated by inhibiting TNF, comprising administering to a patient suffering from said disease an effective amount of a compound according to any of claims 1 to 10.
17. The method of claim 16, wherein the disease state is an inflammatory disease or autoimmune disease.
18. The method of claim 17, wherein the disease state is selected from joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, asthma, bone resorption diseases, reperfusion injury, graft vs host reaction, allograft rejection, fever and myalgias due to infection, such as influenza, malaria, myalgias, HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease and leukaemia.
19. The method of claim 18, wherein the disease state is joint inflammation.
20. The method of claim 12 or claim 16, wherein the disease state is tardive dyskinesia.
21. The method of claim 16, wherein the disease state is i a yeast or fungal infection.
22. A method for gastroprotection, comprising administering to a patient in need thereof an effective amount of a compound according to any of claims 1 to 10.
PCT/GB1996/001204 1995-05-19 1996-05-20 3,4-disubstituted-phenylsulphonamides and their therapeutic use WO1996036595A1 (en)

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